Role of Various Mediators in Inflammation of Asthmatic Airways

*Poonam Arora and S.H. Ansari*

#### **Abstract**

The degree of airway inflammation is directly related to asthma severity and associated hyper-responsiveness. Airway inflammation is categorized into three types: (a) acute asthmatic inflammation featured by early recruitment of cells into the airways, (b) subacute asthmatic inflammation involving activation of recruited cells in continual inflammation, and (c) chronic inflammation characterized by cellular damage. T-helper lymphocytes, the key factor in the pathogenesis of bronchial asthma, induce B cells to synthesize and secrete IgE through production of IL-4 and induce eosinophil-mediated inflammation. Mediators such as histamine, PG, leukotrienes, and kinins contract airway smooth muscle, increase microvascular leakage, increase airway mucus secretion, and attract other inflammatory cells into airway epithelia that initiate mucociliary clearance signaling pathways through special Toll-like receptor 4 expressed on epithelial cells activated by allergic and infectious triggers. These cells form barrier against mechanical stress, oxidant stress, allergens, pollutants, infectious agents, and leakage of endogenous solutes. Various adhesion molecules and costimulatory factors also promote infiltration of inflammatory cells at the site of inflammation.

**Keywords:** airway inflammation, hyper-responsiveness, bronchial asthma, T-helper lymphocytes, mediators

#### **1. Introduction**

The inflammatory response in asthmatic airways is a complex interplay between respiratory epithelium and immune system. The drive for a chronic inflammatory response initiates with production of bioactive mediators from airway epithelium, which attracts, activates, and recruits the inflammatory cells into lung airways. Infiltrated cells augment inflammatory response through the release of other biochemical mediators. The inflammatory mediators released by these cells are the effectors of chronic inflammation including cytokines classified into lymphokines or immunomodulatory cytokines released by T-helper cells, proinflammatory cytokines that promote and amplify the inflammatory response, chemokines that are chemoattractants for leukocytes, growth factors that promote cell survival, and eicosanoid lipid mediators that have multiple effects in the airway. The products released from leukocytes and epithelial cells induce bronchospasm, damage the epithelium, stimulate airway cells, and recruit additional leukocytes creating a cycle of inflammation that becomes chronic. In acute cases of allergen exposure, mast cells can provide an early source of proinflammatory mediators such as IL-4 and IL-5. Episodes of acute inflammatory reactions are often accompanied by an underlying chronic inflammation even in the absence of continuous allergen exposure.

#### **2. Airway inflammation in asthma**

The degree of airway inflammation and corresponding airway hyper-responsiveness (AHR) is related to clinical symptoms in asthma. Asthmatic inflammation is categorized into three types: (a) acute asthmatic inflammation featured by early recruitment of cells into the airways, (b) subacute asthmatic inflammation involving activation of recruited cells in continual inflammation, and (c) chronic inflammation characterized by cellular damage. Various types of biogenic mediators that play an important part in inflammatory process in asthmatic airways are given in **Figure 1**.

#### **2.1 Cells**

#### *2.1.1 Eosinophils*

Eosinophil infiltration is a characteristic feature of asthmatic airway inflammation that plays a central role in asthma. Allergen inhalation results in a marked increase in eosinophil count in bronchoalveolar (BAL) fluid at the time of the late asthma response with a decrease in peripheral eosinophil counts with the appearance of eosinophil precursors in the circulation. Recruitment of eosinophils to airways is mediated by interleukin (IL)-13, histamine, prostaglandin type 2, and chemokines, such as RANTES (regulated on activation T-cell expressed and secreted), eotaxins, and macrophage chemotactic protein (MCP)-4, expressed in epithelial cells [1, 2].

#### *2.1.2 Neutrophils*

Neutrophils are predominantly observed in the airways and sputum of patients with severe asthma [3], especially during acute exacerbations of asthma and in some patients with long-lasting or corticosteroids dependent or unresponsive to inhaled steroids. They are recruited through Th17 pathways and lead to increased concentrations of IL-8 in sputum, which in turn may be due to the increased levels

**97**

*Role of Various Mediators in Inflammation of Asthmatic Airways*

preventing the development of allergic inflammation [9].

bound granules filled with biologically active mediators.

of oxidative stress in severe asthma [4]. Neutrophils contribute to BHR and airway inflammation through the release of mediators like PAF, thromboxanes, and leukotrienes and tissue damage through secretion of proteases and oxygen radicals [5].

Macrophages, derived from blood monocytes, extend inflammatory process in asthma through production of a variety of cytokines, after being activated by allergen via low-affinity IgE receptors (FceRII) [6]. Macrophages may both increase and decrease inflammation, depending on the stimulus. Alveolar macrophages normally have a suppressive effect on lymphocyte function, but this may get impaired in asthma after allergen exposure [7]. Macrophages secrete an anti-inflammatory protein IL-10 which is reduced in alveolar macrophages from patients with asthma [8]. Macrophages may, therefore, play an important anti-inflammatory role, by

Mast cells are central to the development of type I hypersensitivity reaction. Mast cells are bone marrow-derived cells widely distributed in the body predominantly near blood vessels, subepithelial cells and nerves, mucosal lining of the gut, and upper and lower respiratory tract. Increased numbers of degranulated mast cells have been found in asthma exacerbation [10]. Mast cells contain membrane-

After re-exposure, mast cells get activated by cross-linking of high-affinity IgE Fc receptors present on mast cell surface or by stimuli such as C5a and C3a (anaphylatoxins) and release a wide variety of mediators that result in acute

bronchospasm or perpetuate underlying inflammation through cytokines [11]. Mast cells are an important source of histamine, cysteinyl leukotrienes, prostaglandins, cytokines, and platelet-activating factor, after getting activated by binding of stem cell factor to the surface receptor c-kit, IgE cross-linking, or binding of tyrosine kinase [12], and the process is called degranulation of mast cells (**Figure 2**).

Several types of T-lymphocytes (especially, Th1, Th2, Th9, and Th17) play an important role in coordinating the inflammatory response in asthma through release of a number of cytokines. Traditionally, Th2 cells have been thought to predominate, with characteristic raised levels of IL-4, IL-5, and IL-13. High proportion of TH1 cells that can develop under the influence of IL-18 and interferon γ (IFN-γ) associated with further production of IFN-γ is found in some asthmatics. Th17 cells, expressing IL-17, also play an unusual role in asthmatic patients [13]. Th17 are CD4-positive T cells and result in neutrophils influx. Th9 levels are raised in people with atopy cells, secrete IL-9, and promote allergic responses, probably through activation of mast cells. T-regulatory cells, characterized by secretion of transforming growth factor β (TGF-β) and IL-10, are thought to be important because of their

B cells are important in asthma associated with atopy because they produce IgE. Their

survival is supported by IL-5 and a B-cell-activating factor. B cells need to bind to T cells under the influence of IL-4 or IL-13. Secreted IgE are primarily bound through the

*DOI: http://dx.doi.org/10.5772/intechopen.84357*

*2.1.3 Macrophages*

*2.1.4 Mast cells*

*2.1.5 T-lymphocytes*

*2.1.6 B-lymphocytes*

role in blunting atopic responses [14].

**Figure 1.** *Inflammatory mediators in asthma.*

of oxidative stress in severe asthma [4]. Neutrophils contribute to BHR and airway inflammation through the release of mediators like PAF, thromboxanes, and leukotrienes and tissue damage through secretion of proteases and oxygen radicals [5].

#### *2.1.3 Macrophages*

*Asthma - Biological Evidences*

**2.1 Cells**

*2.1.1 Eosinophils*

*2.1.2 Neutrophils*

**2. Airway inflammation in asthma**

inflammation that becomes chronic. In acute cases of allergen exposure, mast cells can provide an early source of proinflammatory mediators such as IL-4 and IL-5. Episodes of acute inflammatory reactions are often accompanied by an underlying

The degree of airway inflammation and corresponding airway hyper-responsiveness (AHR) is related to clinical symptoms in asthma. Asthmatic inflammation is categorized into three types: (a) acute asthmatic inflammation featured by early recruitment of cells into the airways, (b) subacute asthmatic inflammation involving activation of recruited cells in continual inflammation, and (c) chronic inflammation characterized by cellular damage. Various types of biogenic mediators that play an important part in inflammatory process in asthmatic airways are given in **Figure 1**.

Eosinophil infiltration is a characteristic feature of asthmatic airway inflammation that plays a central role in asthma. Allergen inhalation results in a marked increase in eosinophil count in bronchoalveolar (BAL) fluid at the time of the late asthma response with a decrease in peripheral eosinophil counts with the appearance of eosinophil precursors in the circulation. Recruitment of eosinophils to airways is mediated by interleukin (IL)-13, histamine, prostaglandin type 2, and chemokines, such as RANTES (regulated on activation T-cell expressed and secreted), eotaxins, and macrophage chemotactic protein (MCP)-4, expressed in epithelial cells [1, 2].

Neutrophils are predominantly observed in the airways and sputum of patients with severe asthma [3], especially during acute exacerbations of asthma and in some patients with long-lasting or corticosteroids dependent or unresponsive to inhaled steroids. They are recruited through Th17 pathways and lead to increased concentrations of IL-8 in sputum, which in turn may be due to the increased levels

chronic inflammation even in the absence of continuous allergen exposure.

**96**

**Figure 1.**

*Inflammatory mediators in asthma.*

Macrophages, derived from blood monocytes, extend inflammatory process in asthma through production of a variety of cytokines, after being activated by allergen via low-affinity IgE receptors (FceRII) [6]. Macrophages may both increase and decrease inflammation, depending on the stimulus. Alveolar macrophages normally have a suppressive effect on lymphocyte function, but this may get impaired in asthma after allergen exposure [7]. Macrophages secrete an anti-inflammatory protein IL-10 which is reduced in alveolar macrophages from patients with asthma [8]. Macrophages may, therefore, play an important anti-inflammatory role, by preventing the development of allergic inflammation [9].

#### *2.1.4 Mast cells*

Mast cells are central to the development of type I hypersensitivity reaction. Mast cells are bone marrow-derived cells widely distributed in the body predominantly near blood vessels, subepithelial cells and nerves, mucosal lining of the gut, and upper and lower respiratory tract. Increased numbers of degranulated mast cells have been found in asthma exacerbation [10]. Mast cells contain membranebound granules filled with biologically active mediators.

After re-exposure, mast cells get activated by cross-linking of high-affinity IgE Fc receptors present on mast cell surface or by stimuli such as C5a and C3a (anaphylatoxins) and release a wide variety of mediators that result in acute bronchospasm or perpetuate underlying inflammation through cytokines [11]. Mast cells are an important source of histamine, cysteinyl leukotrienes, prostaglandins, cytokines, and platelet-activating factor, after getting activated by binding of stem cell factor to the surface receptor c-kit, IgE cross-linking, or binding of tyrosine kinase [12], and the process is called degranulation of mast cells (**Figure 2**).

#### *2.1.5 T-lymphocytes*

Several types of T-lymphocytes (especially, Th1, Th2, Th9, and Th17) play an important role in coordinating the inflammatory response in asthma through release of a number of cytokines. Traditionally, Th2 cells have been thought to predominate, with characteristic raised levels of IL-4, IL-5, and IL-13. High proportion of TH1 cells that can develop under the influence of IL-18 and interferon γ (IFN-γ) associated with further production of IFN-γ is found in some asthmatics. Th17 cells, expressing IL-17, also play an unusual role in asthmatic patients [13]. Th17 are CD4-positive T cells and result in neutrophils influx. Th9 levels are raised in people with atopy cells, secrete IL-9, and promote allergic responses, probably through activation of mast cells. T-regulatory cells, characterized by secretion of transforming growth factor β (TGF-β) and IL-10, are thought to be important because of their role in blunting atopic responses [14].

#### *2.1.6 B-lymphocytes*

B cells are important in asthma associated with atopy because they produce IgE. Their survival is supported by IL-5 and a B-cell-activating factor. B cells need to bind to T cells under the influence of IL-4 or IL-13. Secreted IgE are primarily bound through the

#### **Figure 2.**

*Activation of mast cells and release of mediators in allergic asthma.*

high-affinity Fc receptors on mast cells and basophils, and when cross-linked by aeroallergen, it causes these cells to degranulate and release their mediators [15].

#### *2.1.7 Innate lymphoid cells*

ILCs are a family of immune cells that are defined by several features including the absence of recombination-activating gene (RAG)-dependent rearranged antigen receptors, their lymphoid morphology, as well as lack of myeloid phenotypic markers and are therefore called cell lineage marker-negative (Lin−) cells. These ILCs are present in the skin, adipose tissues, mesenteric lymph nodes, tonsils, and spleen and mediate inflammatory pathways in various diseases of the lungs and skin. ILCs are classified into three groups according to their transcription factors and cytokine production profile that resembles T-helper (TH) cell subsets [16]. Among these cells, group 2 innate lymphoid cells (ILC2s) are known to play a role in pathogenesis of type 2 inflammatory diseases of the lungs and skin such as asthma and atopic dermatitis [17]. They have the capacity to produce type 2 (TH2) cytokines and interact with both immune and nonimmune cell populations in the local tissue environment. ILC1s produce TH1 inflammatory cytokines, particularly IFN-γ and tumor necrosis factor (TNF-α). They play their role in the pathogenesis of chronic obstructive pulmonary disease (COPD) and human inflammatory bowel (IBD). ILCs generally differentiate into macrophages and granulocytes while stimulating eosinophils and producing Th2 cytokines [18].

**99**

*2.4.1 Histamine*

*Role of Various Mediators in Inflammation of Asthmatic Airways*

Airway epithelial cells play an important role in mucociliary clearance signaling through special receptors Toll-like receptor 4 expressed on epithelial cells activated by allergic and infectious triggers. These cells form barrier against mechanical stress, oxidant stress, allergens, pollutants, infectious agents, and leakage of endogenous solutes. In asthma, epithelial cell-derived cytokines and chemokines (including IL-25, IL-33, thymic stromal lymphopoietin [TSLP], and granulocyte-macrophage colony-stimulating factor [GM-CSF]) signal effector cells (including basophils, eosinophils, mast cells, and lymphocytes) and dendritic cells are of importance in developing characteristic

Like airway epithelial cells, pulmonary dendritic cells are also directly exposed to the external environment. These dendritic cells act as antigen-presenting cells and are directly stimulated by allergens or infectious agents directly after binding with recognition receptors or indirectly stimulated by airway epithelial cells (by mediators such as IL-25, IL-33, GM-CSF); dendritic cells can recruit eosinophils in allergen-presenting regions [20]. Dendritic cells are also found to effect T-cell differentiation and generate Th2 response commonly seen in atopic asthma [21].

These molecules promote infiltration of inflammatory cells at the site of inflammation, recruitment of leukocytes from vascular lumen to tissues, and cell activation [22]. Adhesion molecules are upregulated in allergic inflammation and play a critical role in pathogenesis inflammation. More than 35 adhesion molecules have been identified, for example, integrins, immunoglobulin supergene family, selec-

A number of costimulatory factors are known to play an important role in the development of immunity such as inducible costimulator (ICOS) and ligand for ICOS. ICOS is known to regulate production of Th2 cytokines and to have a signifi-

A number of mediators that account for pathophysiological features of allergic diseases have been implicated in asthma. Mediators such as histamine, PG, leukotrienes, and kinins contract airway smooth muscle, increase microvascular leakage,

Histamine was the first mediator known to be implicated in pathophysiology of asthma. Histamine is synthesized and released by mast cells and basophils in the airways. Histamine causes mucus secretion and bronchoconstriction which is partially mediated by vagal cholinergic reflex. Histamine also acts as a chemoattractant

increase airway mucus secretion, and attract other inflammatory cells.

tins, and carbohydrate ligands including ICAM-1 and VCAM-1.

cant role in lung mucosal inflammatory responses [23, 24].

for eosinophils and activates eosinophils [25].

asthmatic immune response patterns to various types of allergic stimuli [19].

*DOI: http://dx.doi.org/10.5772/intechopen.84357*

*2.1.8 Airway epithelial cells*

*2.1.9 Dendritic cells*

**2.2 Adhesion molecules**

**2.3 Costimulatory factors**

**2.4 Inflammatory mediators**

#### *2.1.8 Airway epithelial cells*

*Asthma - Biological Evidences*

*2.1.7 Innate lymphoid cells*

**Figure 2.**

high-affinity Fc receptors on mast cells and basophils, and when cross-linked by aeroal-

ILCs are a family of immune cells that are defined by several features including the absence of recombination-activating gene (RAG)-dependent rearranged antigen receptors, their lymphoid morphology, as well as lack of myeloid phenotypic markers and are therefore called cell lineage marker-negative (Lin−) cells. These ILCs are present in the skin, adipose tissues, mesenteric lymph nodes, tonsils, and spleen and mediate inflammatory pathways in various diseases of the lungs and skin. ILCs are classified into three groups according to their transcription factors and cytokine production profile that resembles T-helper (TH) cell subsets [16]. Among these cells, group 2 innate lymphoid cells (ILC2s) are known to play a role in pathogenesis of type 2 inflammatory diseases of the lungs and skin such as asthma and atopic dermatitis [17]. They have the capacity to produce type 2 (TH2) cytokines and interact with both immune and nonimmune cell populations in the local tissue environment. ILC1s produce TH1 inflammatory cytokines, particularly IFN-γ and tumor necrosis factor (TNF-α). They play their role in the pathogenesis of chronic obstructive pulmonary disease (COPD) and human inflammatory bowel (IBD). ILCs generally differentiate into macrophages and granulocytes while stimulating eosinophils and producing Th2 cytokines [18].

lergen, it causes these cells to degranulate and release their mediators [15].

*Activation of mast cells and release of mediators in allergic asthma.*

**98**

Airway epithelial cells play an important role in mucociliary clearance signaling through special receptors Toll-like receptor 4 expressed on epithelial cells activated by allergic and infectious triggers. These cells form barrier against mechanical stress, oxidant stress, allergens, pollutants, infectious agents, and leakage of endogenous solutes. In asthma, epithelial cell-derived cytokines and chemokines (including IL-25, IL-33, thymic stromal lymphopoietin [TSLP], and granulocyte-macrophage colony-stimulating factor [GM-CSF]) signal effector cells (including basophils, eosinophils, mast cells, and lymphocytes) and dendritic cells are of importance in developing characteristic asthmatic immune response patterns to various types of allergic stimuli [19].

#### *2.1.9 Dendritic cells*

Like airway epithelial cells, pulmonary dendritic cells are also directly exposed to the external environment. These dendritic cells act as antigen-presenting cells and are directly stimulated by allergens or infectious agents directly after binding with recognition receptors or indirectly stimulated by airway epithelial cells (by mediators such as IL-25, IL-33, GM-CSF); dendritic cells can recruit eosinophils in allergen-presenting regions [20]. Dendritic cells are also found to effect T-cell differentiation and generate Th2 response commonly seen in atopic asthma [21].

#### **2.2 Adhesion molecules**

These molecules promote infiltration of inflammatory cells at the site of inflammation, recruitment of leukocytes from vascular lumen to tissues, and cell activation [22]. Adhesion molecules are upregulated in allergic inflammation and play a critical role in pathogenesis inflammation. More than 35 adhesion molecules have been identified, for example, integrins, immunoglobulin supergene family, selectins, and carbohydrate ligands including ICAM-1 and VCAM-1.

#### **2.3 Costimulatory factors**

A number of costimulatory factors are known to play an important role in the development of immunity such as inducible costimulator (ICOS) and ligand for ICOS. ICOS is known to regulate production of Th2 cytokines and to have a significant role in lung mucosal inflammatory responses [23, 24].

#### **2.4 Inflammatory mediators**

A number of mediators that account for pathophysiological features of allergic diseases have been implicated in asthma. Mediators such as histamine, PG, leukotrienes, and kinins contract airway smooth muscle, increase microvascular leakage, increase airway mucus secretion, and attract other inflammatory cells.

#### *2.4.1 Histamine*

Histamine was the first mediator known to be implicated in pathophysiology of asthma. Histamine is synthesized and released by mast cells and basophils in the airways. Histamine causes mucus secretion and bronchoconstriction which is partially mediated by vagal cholinergic reflex. Histamine also acts as a chemoattractant for eosinophils and activates eosinophils [25].

#### *2.4.2 Leukotrienes*

The cysteinyl leukotrienes, LTC4, LTD4, and LTE4, are eicosanoids derived from arachidonic acid by 5-LOX (lipoxygenase) pathway. They are potent constrictors of human airway and have been reported to increase AHR and play an important role in asthma [3]. They constitute the slow-reacting substance of anaphylaxis. [26]. Potent LTD4 antagonists protect (by 50%) against exercise- and allergen-induced bronchoconstriction, suggesting that leukotrienes contribute to bronchoconstrictor responses**.**

#### *2.4.3 Platelet-activating factor*

Platelet-activating factor (PAF) is a potent inflammatory mediator that mimics many features of asthma, including eosinophil recruitment and activation and induction of AHR, plasma exudation, and mucus hypersecretion. The high level of lyso-PAF (metabolite of PAF) is analyzed in BALF of patients with allergic asthma [27].

#### *2.4.4 Prostaglandin*

Prostaglandins are generated from arachidonic acid by cyclooxygenase (COX) pathway. Increased concentration of PGF2, PGD2, and thromboxane B2 in bronchoalveolar (BAL) fluid of asthmatics is found. When inhaled, they cause bronchoconstriction [28] and increase airway responsiveness to spasmogen.

#### *2.4.5 Proteases*

Tryptase is a mast cell serine protease and plays a role in hemostasis, mucus secretion, and vascular permeability. Elevated levels of tryptase have been found in BAL fluid and sputum of asthmatic patients after allergen challenge [29]. Elevated levels of MMP-9 (metalloproteinase-9), a protease released by eosinophils and alveolar macrophages, are found in bronchoalveolar fluid from asthmatic patients [30].

#### *2.4.6 Kinins*

Kinins are vasoactive peptides secreted from kininogens by the action of kininogenase during the inflammatory response. Bradykinin is an important kinin that has many effects on airway functions mediated by direct activation of B2 receptors of airway smooth muscles. Bradykinin activates alveolar macrophages to release LTB4 and PAF and activates nociceptive nerve fibers in the airways of asthmatic patients only which may mediate cough and chest tightness characteristic features of asthma [31] .

#### *2.4.7 Cytokines*

Cytokines are extracellular signaling proteins secreted by almost every cell under certain conditions and play a critical role in orchestrating all types of inflammatory response in asthma [32]. They act on target cells to cause a wide range of cellular functions like activation, proliferation, chemotaxis, immunomodulation, release of inflammatory mediators, growth and cell differentiation, and apoptosis. In contrast to acute and subacute inflammatory responses, cytokines play a dominant role in maintaining chronic inflammation in allergic diseases. The important cytokines in asthma are lymphokines secreted by T-lymphocytes: IL-1β, IL-3, IL-4, IL-5, IL-6, IL-9, IL-13, TNF-α, etc. where IL-3 is reported to be crucial for

**101**

**Figure 3.**

*Role of Various Mediators in Inflammation of Asthmatic Airways*

the survival of mast cells in tissues, but IL-4 plays an important role in switching B-lymphocytes to produce IgE and expression of VCAM-1 on endothelial cells. IL-5 plays a critical role in differentiation, survival, and priming of eosinophils, thus promoting eosinophilic inflammation, and present in BAL fluid during allergeninduced late-phase asthma [33]. Airway macrophages are important source of IL-1β, TNF- α, and IL-6 which act on epithelial cells to release GM-CSF, IL-8, and RANTES and amplify the inflammatory response leading to influx of secondary

IL-9 and IL-13 are considered as proinflammatory cytokines. IL-9 is known to stimulate proliferation of activated T cells, enhancing IgE production from B cells, promoting proliferation and differentiation of mast cells, upregulating the α-chain of the FcεRI receptor, and inducing CC chemokine expression in lung epithelial cells contributing in allergen-induced airway changes. IL-13 is present in increased amounts in asthmatic airways and possesses biological activities similar to IL-4 [35]. Unlike IL-4 which is central to development of Th2 cells during primary sensitization, IL-13 release is more important during secondary

Another group of proinflammatory cytokines are TNF-α that help in leukocyte recruitment through upregulation of adhesion molecules on vascular endothelial cells and induction of cytokine and chemokine synthesis airway hyper-responsive-

IL-10, IL-12, IL-18, and interferon gamma (IFN-γ) are known as immunomodulatory cytokines. IL-10 is a pleiotropic cytokine that has the potential to downregulate both Th1- and Th2-driven inflammatory processes [38] and beneficial effect on airway remodeling [39]. IL-12 is released by antigen-presenting cells and is known to play an important role in Th1/Th2 differentiation during primary antigen presentation [40]. IL-18 is secreted by macrophages [41], and IFN-γ is reported to

*DOI: http://dx.doi.org/10.5772/intechopen.84357*

cells like eosinophils [34].

antigen exposure [36].

ness and pathogenesis of airway remodeling [37].

*Cytokines involved in the pathogenesis of bronchial asthma.*

*2.4.7.2 Immunomodulatory cytokines*

*2.4.7.1 Proinflammatory cytokines*

#### *Role of Various Mediators in Inflammation of Asthmatic Airways DOI: http://dx.doi.org/10.5772/intechopen.84357*

the survival of mast cells in tissues, but IL-4 plays an important role in switching B-lymphocytes to produce IgE and expression of VCAM-1 on endothelial cells. IL-5 plays a critical role in differentiation, survival, and priming of eosinophils, thus promoting eosinophilic inflammation, and present in BAL fluid during allergeninduced late-phase asthma [33]. Airway macrophages are important source of IL-1β, TNF- α, and IL-6 which act on epithelial cells to release GM-CSF, IL-8, and RANTES and amplify the inflammatory response leading to influx of secondary cells like eosinophils [34].

#### *2.4.7.1 Proinflammatory cytokines*

*Asthma - Biological Evidences*

*2.4.3 Platelet-activating factor*

*2.4.4 Prostaglandin*

*2.4.5 Proteases*

*2.4.6 Kinins*

of asthma [31] .

*2.4.7 Cytokines*

The cysteinyl leukotrienes, LTC4, LTD4, and LTE4, are eicosanoids derived from arachidonic acid by 5-LOX (lipoxygenase) pathway. They are potent constrictors of human airway and have been reported to increase AHR and play an important role in asthma [3]. They constitute the slow-reacting substance of anaphylaxis. [26]. Potent LTD4 antagonists protect (by 50%) against exercise- and allergen-induced bronchoconstriction, suggesting that leukotrienes contribute to bronchoconstrictor

Platelet-activating factor (PAF) is a potent inflammatory mediator that mimics many features of asthma, including eosinophil recruitment and activation and induction of AHR, plasma exudation, and mucus hypersecretion. The high level of lyso-PAF (metabolite of PAF) is analyzed in BALF of patients with allergic asthma [27].

Prostaglandins are generated from arachidonic acid by cyclooxygenase (COX) pathway. Increased concentration of PGF2, PGD2, and thromboxane B2 in bronchoalveolar (BAL) fluid of asthmatics is found. When inhaled, they cause broncho-

Tryptase is a mast cell serine protease and plays a role in hemostasis, mucus secretion, and vascular permeability. Elevated levels of tryptase have been found in BAL fluid and sputum of asthmatic patients after allergen challenge [29]. Elevated levels of MMP-9 (metalloproteinase-9), a protease released by eosinophils and alveolar macrophages, are found in bronchoalveolar fluid from asthmatic patients [30].

Kinins are vasoactive peptides secreted from kininogens by the action of kininogenase during the inflammatory response. Bradykinin is an important kinin that has many effects on airway functions mediated by direct activation of B2 receptors of airway smooth muscles. Bradykinin activates alveolar macrophages to release LTB4 and PAF and activates nociceptive nerve fibers in the airways of asthmatic patients only which may mediate cough and chest tightness characteristic features

Cytokines are extracellular signaling proteins secreted by almost every cell under certain conditions and play a critical role in orchestrating all types of inflammatory response in asthma [32]. They act on target cells to cause a wide range of cellular functions like activation, proliferation, chemotaxis, immunomodulation, release of inflammatory mediators, growth and cell differentiation, and apoptosis. In contrast to acute and subacute inflammatory responses, cytokines play a dominant role in maintaining chronic inflammation in allergic diseases. The important cytokines in asthma are lymphokines secreted by T-lymphocytes: IL-1β, IL-3, IL-4, IL-5, IL-6, IL-9, IL-13, TNF-α, etc. where IL-3 is reported to be crucial for

constriction [28] and increase airway responsiveness to spasmogen.

*2.4.2 Leukotrienes*

responses**.**

**100**

IL-9 and IL-13 are considered as proinflammatory cytokines. IL-9 is known to stimulate proliferation of activated T cells, enhancing IgE production from B cells, promoting proliferation and differentiation of mast cells, upregulating the α-chain of the FcεRI receptor, and inducing CC chemokine expression in lung epithelial cells contributing in allergen-induced airway changes. IL-13 is present in increased amounts in asthmatic airways and possesses biological activities similar to IL-4 [35]. Unlike IL-4 which is central to development of Th2 cells during primary sensitization, IL-13 release is more important during secondary antigen exposure [36].

Another group of proinflammatory cytokines are TNF-α that help in leukocyte recruitment through upregulation of adhesion molecules on vascular endothelial cells and induction of cytokine and chemokine synthesis airway hyper-responsiveness and pathogenesis of airway remodeling [37].

#### *2.4.7.2 Immunomodulatory cytokines*

IL-10, IL-12, IL-18, and interferon gamma (IFN-γ) are known as immunomodulatory cytokines. IL-10 is a pleiotropic cytokine that has the potential to downregulate both Th1- and Th2-driven inflammatory processes [38] and beneficial effect on airway remodeling [39]. IL-12 is released by antigen-presenting cells and is known to play an important role in Th1/Th2 differentiation during primary antigen presentation [40]. IL-18 is secreted by macrophages [41], and IFN-γ is reported to

**Figure 3.** *Cytokines involved in the pathogenesis of bronchial asthma.*

#### **Figure 4.**

*Release of mediators after allergen exposure to airway epithelia.*

prevent the development of antigen-induced airway eosinophilia and hyper-responsiveness [42]. IL-12 and IL-18 act synergistically for inducing IFN-γ and inhibiting IL-4-dependent IgE synthesis as well as inhibiting allergen-induced airway hyperresponsiveness [43]. Balance between Th1 and Th2 cells is thought to be determined by locally released cytokines, such as IL-12, which favor emergence of Th1 cells; contrary to this, IL-4 and IL-13 favor the growth of Th2 cells (**Figures 3** and **4**).

#### *2.4.8 Chemokines*

Chemokines are chemotactic cytokines responsible for recruitment of inflammatory cells in the airways. Chemokines have been categorized into two main groups, (a) CXC (α-type) and CC (β-type) chemokines, and exert their effects through G-protein-coupled chemokine receptors (CCR) [44]. Exacerbation of asthma leads to the synthesis and release of a number of chemokines. Increased expression of eotaxin, eotaxin-2, MCP-3, MCP-4, and CCR3 in the airways of asthmatic patients is found, and this can be correlated to increased AHR [45].

#### *2.4.9 Tachykinins*

Tachykinins are neuropeptides derived from preprotachykinins (PPTs). They are released by sensory nerves of airways and stimulate mucus secretion, plasma exudation, neural activation, bronchoconstriction, and structural changes. These peptides activate macrophages and monocytes to release inflammatory cytokines, IL-6 [46]. Higher concentration of a tachykinin, substance-P (SP), has been found in BALF of asthmatic lungs [47].

#### *2.4.10 Endothelins*

Endothelins are peptide mediators secreted via endothelin-converting enzyme (ECE) through mRNA present in airway epithelial cells and regulated by a number of proinflammatory cytokines in asthma. The biological effects of endothelins are mediated by two receptors: ETA and ETB. Endothelins are potent

**103**

*Role of Various Mediators in Inflammation of Asthmatic Airways*

of endothelin-1 are found in the sputum of asthmatic patients [49].

bronchoconstrictors and induce airway smooth muscle cell proliferation and fibrosis and play an important role in chronic inflammation of asthmatic airways [48]. After the allergen challenge, endothelins (ETs) are secreted de novo. Higher levels

Several nonadrenergic-noncholinergic (NANC) nerves and neuropeptides have been identified in the respiratory tract. Airway nerves may also release neurotransmitters that have inflammatory effects such as substance P (SP), neurokinin A, and calcitonin gene-related peptide, may be released from sensitized inflammatory nerves in the airways, and perpetuate the ongoing inflammatory response. Thus, chronic asthma may be associated with increased neurogenic inflammation, which may provide a mechanism for prolonging the inflammatory response even in the

Antibodies are protein molecules released by immune system in response to foreign bodies, allergens. Five classes of antibodies, namely, IgM, IgG, IgA, IgD, and IgE [48], are known. Of these IgE is the predominant antibody in asthma in humans. IgE is the antibody responsible for all types of allergic reaction and pathogenesis of allergic asthma and development of inflammation in the human body. Elevated levels of IgE are found in bronchial asthma. Monoclonal antibodies against IgE have shown the reduction of IgE and associated asthma symptoms in

The increased level of oxidative stress found in airways of people with allergic asthma activates circulatory inflammatory cells, such as macrophages and eosinophils. Activated inflammatory cells produce more number of reactive oxygen species causing Increased concentrations of 8-isoprostane (a product of oxidized arachidonic acid) [51] and ethane (a product of oxidative lipid peroxidation) in exhaled breath of asthmatic patients [52]. Increased oxidative stress can be related to disease severity and may amplify the inflammatory response and reduce responsiveness to corticosteroids, particularly in severe disease and during exacerbations. Mechanism underlying the role of oxidative stress in asthma severity may be due to reaction of superoxide anions with nitric oxide (NO) forming reactive radical

Measurement of the level of NO in exhaled air of asthmatic patients is increasingly being used as a noninvasive way of monitoring the inflammatory process [53]. NO is produced by NO synthase, but in epithelial cells of asthmatic patients, the enzyme inducible of NO synthase (iNOS) is present. Recent studies report the higher level of NO in the exhaled air of patients with asthma than the level of NO in the exhaled air of normal subjects. The combination of increased oxidative stress and NO may lead to the formation of the potent radical peroxynitrite that may result in nitrosylation of proteins in the airways [54]. Since NO is a potent vasodilator, this may increase plasma exudation in airways, and it may also amplify the

*DOI: http://dx.doi.org/10.5772/intechopen.84357*

absence of initiating inflammatory stimuli.

peroxynitrites that may modify several target proteins.

*2.4.11 Neural mediators*

**2.5 Antibodies**

asthmatics [50].

**2.6 Oxidative stress**

**2.7 Nitric oxide (NO)**

Th2-mediated response.

bronchoconstrictors and induce airway smooth muscle cell proliferation and fibrosis and play an important role in chronic inflammation of asthmatic airways [48]. After the allergen challenge, endothelins (ETs) are secreted de novo. Higher levels of endothelin-1 are found in the sputum of asthmatic patients [49].

#### *2.4.11 Neural mediators*

*Asthma - Biological Evidences*

*2.4.8 Chemokines*

**Figure 4.**

*2.4.9 Tachykinins*

*2.4.10 Endothelins*

in BALF of asthmatic lungs [47].

prevent the development of antigen-induced airway eosinophilia and hyper-responsiveness [42]. IL-12 and IL-18 act synergistically for inducing IFN-γ and inhibiting IL-4-dependent IgE synthesis as well as inhibiting allergen-induced airway hyperresponsiveness [43]. Balance between Th1 and Th2 cells is thought to be determined by locally released cytokines, such as IL-12, which favor emergence of Th1 cells; contrary to this, IL-4 and IL-13 favor the growth of Th2 cells (**Figures 3** and **4**).

*Release of mediators after allergen exposure to airway epithelia.*

Chemokines are chemotactic cytokines responsible for recruitment of inflammatory cells in the airways. Chemokines have been categorized into two main groups, (a) CXC (α-type) and CC (β-type) chemokines, and exert their effects through G-protein-coupled chemokine receptors (CCR) [44]. Exacerbation of asthma leads to the synthesis and release of a number of chemokines. Increased expression of eotaxin, eotaxin-2, MCP-3, MCP-4, and CCR3 in the airways of asthmatic patients is found, and this can be correlated to increased AHR [45].

Tachykinins are neuropeptides derived from preprotachykinins (PPTs). They are released by sensory nerves of airways and stimulate mucus secretion, plasma exudation, neural activation, bronchoconstriction, and structural changes. These peptides activate macrophages and monocytes to release inflammatory cytokines, IL-6 [46]. Higher concentration of a tachykinin, substance-P (SP), has been found

Endothelins are peptide mediators secreted via endothelin-converting enzyme (ECE) through mRNA present in airway epithelial cells and regulated by a number of proinflammatory cytokines in asthma. The biological effects of endothelins are mediated by two receptors: ETA and ETB. Endothelins are potent

**102**

Several nonadrenergic-noncholinergic (NANC) nerves and neuropeptides have been identified in the respiratory tract. Airway nerves may also release neurotransmitters that have inflammatory effects such as substance P (SP), neurokinin A, and calcitonin gene-related peptide, may be released from sensitized inflammatory nerves in the airways, and perpetuate the ongoing inflammatory response. Thus, chronic asthma may be associated with increased neurogenic inflammation, which may provide a mechanism for prolonging the inflammatory response even in the absence of initiating inflammatory stimuli.

#### **2.5 Antibodies**

Antibodies are protein molecules released by immune system in response to foreign bodies, allergens. Five classes of antibodies, namely, IgM, IgG, IgA, IgD, and IgE [48], are known. Of these IgE is the predominant antibody in asthma in humans. IgE is the antibody responsible for all types of allergic reaction and pathogenesis of allergic asthma and development of inflammation in the human body. Elevated levels of IgE are found in bronchial asthma. Monoclonal antibodies against IgE have shown the reduction of IgE and associated asthma symptoms in asthmatics [50].

#### **2.6 Oxidative stress**

The increased level of oxidative stress found in airways of people with allergic asthma activates circulatory inflammatory cells, such as macrophages and eosinophils. Activated inflammatory cells produce more number of reactive oxygen species causing Increased concentrations of 8-isoprostane (a product of oxidized arachidonic acid) [51] and ethane (a product of oxidative lipid peroxidation) in exhaled breath of asthmatic patients [52]. Increased oxidative stress can be related to disease severity and may amplify the inflammatory response and reduce responsiveness to corticosteroids, particularly in severe disease and during exacerbations. Mechanism underlying the role of oxidative stress in asthma severity may be due to reaction of superoxide anions with nitric oxide (NO) forming reactive radical peroxynitrites that may modify several target proteins.

#### **2.7 Nitric oxide (NO)**

Measurement of the level of NO in exhaled air of asthmatic patients is increasingly being used as a noninvasive way of monitoring the inflammatory process [53]. NO is produced by NO synthase, but in epithelial cells of asthmatic patients, the enzyme inducible of NO synthase (iNOS) is present. Recent studies report the higher level of NO in the exhaled air of patients with asthma than the level of NO in the exhaled air of normal subjects. The combination of increased oxidative stress and NO may lead to the formation of the potent radical peroxynitrite that may result in nitrosylation of proteins in the airways [54]. Since NO is a potent vasodilator, this may increase plasma exudation in airways, and it may also amplify the Th2-mediated response.

#### **3. Airway remodeling**

The acute and chronic allergic inflammatory responses in asthmatic lungs result in epithelial shedding, goblet cell hyperplasia, basal membrane thickening, subepithelial fibrosis in peribronchial interstitial tissue, hyperplasia of airway smooth muscle cells, angiogenesis, and dysfunctioning of bronchial blood vessels [55]. These changes contribute to alteration in lung anatomy termed as airway remodeling and are represented by increased thickness of the basement membrane and increased volume of airway smooth muscle associated with increases in growth factors, including TGF-β1 and platelet-derived growth factor, in Th2-driven models of asthma [56–58]. Overexpression of Th2 interleukins, especially IL-4, IL-5, and IL-13, is known to produce demonstrative changes in asthmatic airways. Increased expression of IL-13 causes subepithelial fibrosis, mucus metaplasia, and infiltration of eosinophils and macrophages, whereas increased expression of IL-4 and IL-5 induced airway eosinophilia, mucus metaplasia, and subepithelial fibrosis.

#### **4. Conclusion**

Complex interactions among various bioactive mediators in asthmatic lungs make it a complex disease and therefore need a more detailed research studies to discern its complete physiology.

#### **Acknowledgements**

The author is thankful to Jamia Hamdard for providing guidance in this research work.

#### **Conflict of interest**

The author declares no conflict of interest.

#### **Author details**

Poonam Arora\* and S.H. Ansari Jamia Hamdard, New Delhi, India

\*Address all correspondence to: poonamarora96@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**105**

1994;**7**:1431-1438

*Role of Various Mediators in Inflammation of Asthmatic Airways*

[9] Holt PG, McMenamin C. Defence against allergic sensitization in the healthy lung: The role of inhalation tolerance. Clinical and Experimental

[10] Carroll M, Mutavdzic S, James AL. Distribution and degranulation of airway mast cell in normal and asthmatics subjects. European Respiratory Journal. 2002;**19**:1-7

[11] Abul K, Abbas MD. Disease of immunity. In: Robbins and Cotran Pathologic Basis of Disease. 7th ed. Philadelphia, Pennsylvania: Elsevier

[12] Barnes PJ. Pathophysiology of allergic inflammation. Immunological

[13] Cosmi L, Liotta F, Maggi E,

[14] Lloyd CM, Saglani S. T cells in asthma: Influences of genetics, environment, and T-cell plasticity. Journal of Allergy and Clinical Immunology. 2013;**131**:1267-1274

[15] Bacharier LB, Jabara H, Geha RS.

Maghazachi AA. Innate lymphoid cells (ILCs) as mediators of inflammation, release of cytokines and lytic molecules.

[17] Vivier E, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G, et al. Innate lymphoid cells: 10 years on.

[18] Saenz SA, Siracusa MC, Perrigoue JG, Spencer SP, Urban JF Jr, Tocker

Cell. 2018;**174**(5):1054-1066

Romagnani S, Annunziato F. Th17 cells: New players in asthma pathogenesis.

Saunders; 2005. pp. 194-268

Reviews. 2011;**242**:31-50

Allergy. 2011;**66**:989-998

Molecular mechanisms of immunoglobulin E regulation. International Archives of Allergy and Immunology. 1998;**115**:257-269

[16] Elemam NM, Hannawi S,

Toxins. 2017;**9**:398

Allergy. 1989;**19**:255-262

*DOI: http://dx.doi.org/10.5772/intechopen.84357*

[1] Blease K, Lukacs NW, Hogaboam CM, Kunkel SL. Chemokines and their role in airway hyper-reactivity. Respiratory Research. 2000;**1**:54-61

[2] Meagher LC, Cousin JM, Seckl JR, Haslett C. Opposing effects of

glucocorticoids on the rate of apoptosis in neutrophilic and eosinophilic granulocytes. Journal of Immunology.

[3] Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F. Dupilumab in persistent asthma with elevated eosinophil levels. The New England Journal of Medicine.

[4] Jatakanon A, Uasaf C, Maziak W,

Neutrophilic inflammation in severe persistent asthma. American Journal of Respiratory and Critical Care Medicine.

Lim S, Chung KF, Barnes PJ.

[5] Sur S, Crotly TB, Kephart GM. Sudden-onset fatal asthma: A distinct entity with few eosinophils and relatively more neutrophils in the airway submucosal. The American Review of Respiratory Disease. 1993;**148**:713-719

[6] Lee TH, Lane SJ. The role of macrophages in the mechanisms of airway inflammation in asthma. The American Review of Respiratory Disease. 1992;**145**:S27-S30

and allergic lung disease.

[7] Poulter LW, Burke CM. Macrophages

Immunobiology. 1996;**195**:574-587

[8] Spiteri MA, Knight RA, Jeremy JY, Barnes PJ, Chung KF. Alveolar macrophage-induced suppression of peripheral blood mononuclear cell responsiveness is reversed by in vitro allergen exposure in bronchial asthma. The European Respiratory Journal.

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2013;**368**:2455-2466

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*Role of Various Mediators in Inflammation of Asthmatic Airways DOI: http://dx.doi.org/10.5772/intechopen.84357*

#### **References**

*Asthma - Biological Evidences*

**3. Airway remodeling**

**104**

**Author details**

**4. Conclusion**

discern its complete physiology.

**Acknowledgements**

**Conflict of interest**

work.

Poonam Arora\* and S.H. Ansari Jamia Hamdard, New Delhi, India

provided the original work is properly cited.

\*Address all correspondence to: poonamarora96@gmail.com

The author declares no conflict of interest.

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

The acute and chronic allergic inflammatory responses in asthmatic lungs result in epithelial shedding, goblet cell hyperplasia, basal membrane thickening, subepithelial fibrosis in peribronchial interstitial tissue, hyperplasia of airway smooth muscle cells, angiogenesis, and dysfunctioning of bronchial blood vessels [55]. These changes contribute to alteration in lung anatomy termed as airway remodeling and are represented by increased thickness of the basement membrane and increased volume of airway smooth muscle associated with increases in growth factors, including TGF-β1 and platelet-derived growth factor, in Th2-driven models of asthma [56–58]. Overexpression of Th2 interleukins, especially IL-4, IL-5, and IL-13, is known to produce demonstrative changes in asthmatic airways. Increased expression of IL-13 causes subepithelial fibrosis, mucus metaplasia, and infiltration of eosinophils and macrophages, whereas increased expression of IL-4 and IL-5 induced airway eosinophilia, mucus metaplasia, and subepithelial fibrosis.

Complex interactions among various bioactive mediators in asthmatic lungs make it a complex disease and therefore need a more detailed research studies to

The author is thankful to Jamia Hamdard for providing guidance in this research

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2000;**30**:747-750

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Respiratory Cell and Molecular Biology. 2004;**31**(1):3-7

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2010;**464**:1362-1366

2013;**68**:695-701

2000;**15**:107-113

2001;**2**:597-604

1994;**149**:1506-1511

[25] Raible DG, Lenahan T,

Fayvilevich Y, Kosinski R, Schulman ES. zPharmacological characterization of a novel histamine receptor on human eosinophil. American Journal of Respiratory and Critical Care Medicine.

[26] Drazen JM, Israel E, O'Byrne PM. Treatment of asthma with drugs modifying the leukotriene pathway.

Medicine. 2012;**18**:684-692

JE, et al. IL25 elicits a multipotent progenitor cell population that promotes T(H)2 cytokine responses. Nature.

The New England Journal of Medicine.

Nakamata M, Kayahara H, Nakagawa T. Increased plasma level of plateletactivating factor (PAF) and decreased serum PAF acetylhydrolase (PAFAH) activity in adults with bronchial asthma. Journal of Investigational Allergology and Clinical Immunology. 1996;**6**:22-29

[27] Tsukioka K, Matsuzaki M,

[28] Saroea HG, Inman MD, O'Byene PM. U46619 induced bronchoconstriction in asthmatic subjects is mediated by acetylcholine

release. American Journal of

Marrelli F, Tennor H, et al. Cell infiltration, ICAM-1 expression and eosinophil chemotactic activity in asthmatic sputum. American Journal of Respiratory and Critical Care Medicine.

1995;**151**:321-324

1997;**155**:466-472

Respiratory and Critical Care Medicine.

[29] Louis R, Shule J, Biagi S, Stanciu L,

[30] Mautino G, Oliver N, Chanez P, Bousquet J, Capony F. Increased release of matrix metalloproteinease-9 in bronchoalveolar lavage fluid and by alveolar macrophages of asthmatics. American Journal of Respiratory Cell and Molecular Biology. 1997;**17**:583-591

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[32] Chung KF, Barnes PJ. Cytokines in asthma. Thorax. 1999;**54**:825-857

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[34] Peters-Golden M. The alveolar macrophages: The forgotten cell in asthma. American Journal of

1999;**340**:197-206

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[20] Salazar F, Ghaemmaghami AM. Allergen recognition by innate

immune cells: Critical role of dendritic and epithelial cells. Frontiers in Immunology. 2013;**4**:356

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[22] Walzog B, Gaehtgens P. Adhesion

understanding of acute inflammation. News in Physiological Sciences.

[23] McAdam AJ, Chang TT, Lumelsky AE, Greenfield EA, Boussiotis VA, Duke-Cohan JS, et al. Mouse inducible costimulatory molecule (ICOS) expression is enhanced by CD28 costimulation and regulates differentiation of CD-4- T cells. Journal of Immunology. 2000;**165**:5035-5040

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molecules: The path to a new

**106**

[35] Naseer T, Minshall EM, Leung DY. Expression of IL-12 and IL-13 mRNA in asthma and their modulation in response to steroid therapy. American Journal of Respiratory and Critical Care Medicine. 1997;**155**:845-851

[36] De-Vries JE. The role of IL-13 and its receptor in allergy and inflammatory responses. The Journal of Allergy and Clinical Immunology. 1998;**102**:165-169

[37] Hirata N, Kohrogi H, Iwagoe H, et al. Allergen exposure induces the expression of endothelial adhesion molecules in passively sensitized human bronchus: Time course and the role of cytokines. American Journal of Respiratory Cell and Molecular Biology. 1998;**18**:12-20

[38] Koulis A, Robinson DS. The anti-inflammatory effects of interleukin-10 in allergic disease. Clinical and Experimental Allergy. 2000;**30**:747-750

[39] Selzman CH, McIntyre RC, Shames BD, Whitehill TA, Banerjee A, Harken AH. Interleukin-10 inhibits human vascular smooth muscle proliferation. Journal of Molecular and Cellular Cardiology. 1998;**30**:889-896

[40] Rissoan MC, Soumelis V, Kadowaki NJ. Reciprocal control of T helper cell and dendritic cell differentiation. Science. 1999;**283**:1183-1186

[41] Okamura H, Tsutsi H, Komatsu T. Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature. 1995;**378**:88-91

[42] Lack G, Bradley KL, Hamelmann E. Nebulized IFN-gamma inhibits the development of secondary allergic responses in mice. Journal of Immunology. 1996;**157**:1432-1439

[43] Hofstra CL, Van Ark I, Hofman G, Kool M, Nijkamp FP, Van Oosterhout AJ. Prevention of Th2-like cell responses by co-administration of IL-12 and IL-18 is associated with inhibition of antigeninduced airway hyper-responsiveness, eosinophilia, and serum IgE levels. Journal of Immunology. 1998;**161**:5054-5060

[44] Barnes PJ. Intrinsic asthma: Not so different from allergic asthma but driven by superantigens? Clinical and Experimental Allergy. 2009;**39**:1145-1151

[45] Ying S, Meng Q, Zeibecoglou K, et al. Eosinophil chemotactic chemokines (eotaxin, eotaxin-2, RANTES, monocyte chemoattractant protein-3 (MCP-3), and MCP-4), and C-C chemokine receptor 3 expression in bronchial biopsies from atopic and nonatopic (intrinsic) asthmatics. Journal of Immunology. 1999;**163**:6321-6329

[46] Brunelleschi S, Vanni L, Ledda F, Giotti A, Maggi CA, Fantozzi R. Tachykinins activate guinea pig alveolar macrophages: Involvement of NK-2 and NK1 receptors. British Journal of Pharmacology. 1990;**100**:417-420

[47] Nieber K, Baumgarten CR, Rathsack R, Furkert J, Oehame P, Kunkel G. Substance P and b endorphin-like immunoreactivity in lavage fluids of subjects with and without asthma. The Journal of Allergy and Clinical Immunology. 1992;**90**:646-652

[48] Goldie RG, Henry PJ. Endothelins and asthma. Life Sciences. 1999;**65**:1-15

[49] Redington AE, Springall DR, Ghatei MA. Airway endothelin levels in asthma: Influence of endobronchial allergen challenge and maintenance corticosteroid therapy. The European Respiratory Journal. 1997;**10**:1026-1032

[50] Busse WW, Holgate ST, Simons FER, Yunginger JW, editors. Middleton's Allergy Principles and Practce. 6th ed. Philadelphia: Molsby; 2003. pp. 887-913

[51] Montuschi P, Ciabattoni G, Corradi M, et al. Increased 8-Isoprostane, a marker of oxidative stress, in exhaled condensates of asthmatic patients. American Journal of Respiratory and Critical Care Medicine. 1999;**160**:216-220

[52] Paredi P, Kharitonov SA, Barnes PJ. Elevation of exhaled ethane concentration in asthma. American Journal of Respiratory and Critical Care Medicine. 2000;**162**:1450-1454

[53] Kharitonov SA, Barnes PJ. Clinical aspects of exhaled nitric oxide. The European Respiratory Journal. 2000;**16**:781-792

[54] Saleh D, Ernst P, Lim S, Barnes PJ, Giaid A. Increased formation of the potent oxidant peroxynitrite in the airways of asthmatic patients is associated with induction of nitric oxide synthase: Effect of inhaled glucocorticoid. The FASEB Journal. 1998;**12**:929-937

[55] Fehrenbach H, Wagner C, Wegmann M. Airway remodeling in asthma: What really matters. Cell and Tissue Research. 2017;**367**(3):551-569

[56] Mason RJ, Murray JF, Broaddus VC, Nadel JA, editors. Murray and Nadel's Textbook of Respiratory Medicine. 4th ed. Philadelphia: Saunders/Elseviers Publication; 2005. pp. 51-86

[57] Holgate ST. Epithelium dysfunction in asthma. The Journal of Allergy and Clinical Immunology. 2007;**120**(6):1233-1244

[58] Jeffery PK. Remodeling in asthma and chronic obstructive lung disease. American Journal of Respiratory and Critical Care Medicine. 2001;**164**:S28-S38

**109**

**Chapter 8**

**Abstract**

**1. Introduction**

Pathogenic Roles of MicroRNA in

Asthma is a common and chronic inflammatory disease. Pathogenic mechanism underlying asthma is complicated. The inflammatory reactions in asthma have been recognized to involve mast cells, eosinophils, lymphocytes (T cells, B cells), macrophages, and dendritic cells. MicroRNA (miRNA, miR) is a group of small noncoding RNAs with 21–25 nucleotides (nt) in length, which impact biologic responses through the regulation of mRNA transcription and/or translation. MicroRNAs are related to developmental processes of many immunologic diseases. Most studies showed that regulation of miRNAs to their targeting genes appears to play an important role in the development of asthma. This chapter has discussed altered expression of miRNAs in cells and tissues from patients with asthma, in order to better understand the mechanics of pathogenesis of asthma. In addition, the regulation of miRNAs as a novel therapeutic approach will require a deeper understanding

Pediatric asthma is a global problem. In the last decade, its incidence has highly increased, particular growing by 10% in China [1]. Etiologically, asthma attack, due to gene-environmental interactions, can also be induced by allergy factors, including air pollution, pollen, fungi and dust mites, food, and so on [2]. As a chronic inflammatory disease and a polygenic hereditary disease, the mechanism of asthma is not clearly understood until now. The adaptive and innate immune system with the involvement of mast cells, eosinophils, lymphocytes (T cells, B cells), macrophages, and dendritic cells, even epithelial cells and structure cells, contributed to the inflammation reaction of asthma [3–5]. Moreover, change in the secretion of IgE and cytokines, including gamma-interferon (γ-IFN) and tumor necrosis factor (TNF-α), is important in asthma attacks [6–8]. As an immune regulator, microRNA (miRNA or miR) regulates on target gene mRNA and plays an important role in the

MicroRNAs are a group of small nonprotein-coding RNAs that are 21–25 nucleotides in length. They act as transcriptional regulators involved in many complex human disorders and in biological processes including cell proliferation and apoptosis [9, 10]. Childhood asthma susceptibility is associated with mutations in specific gene mRNA and/or their specific miRNA. For example, HLA-G has been identified as an asthma susceptibility gene [11], which was found to be the target gene of miR-148a,

the Development of Asthma

*Xiaoyan Dong and Nanbert Zhong*

of their function and mechanism of action.

development and pathogenesis of asthma.

**Keywords:** microRNA asthma, inflammation reaction

#### **Chapter 8**

*Asthma - Biological Evidences*

1999;**160**:216-220

2000;**16**:781-792

1998;**12**:929-937

2017;**367**(3):551-569

Publication; 2005. pp. 51-86

[57] Holgate ST. Epithelium

[58] Jeffery PK. Remodeling in asthma and chronic obstructive lung disease. American Journal of Respiratory and Critical Care Medicine.

2007;**120**(6):1233-1244

2001;**164**:S28-S38

dysfunction in asthma. The Journal of Allergy and Clinical Immunology.

Allergy Principles and Practce. 6th ed. Philadelphia: Molsby; 2003. pp. 887-913

[51] Montuschi P, Ciabattoni G, Corradi M, et al. Increased 8-Isoprostane, a marker of oxidative stress, in exhaled condensates of asthmatic patients. American Journal of Respiratory and Critical Care Medicine.

[52] Paredi P, Kharitonov SA, Barnes PJ.

concentration in asthma. American Journal of Respiratory and Critical Care

[53] Kharitonov SA, Barnes PJ. Clinical aspects of exhaled nitric oxide. The European Respiratory Journal.

[54] Saleh D, Ernst P, Lim S, Barnes PJ, Giaid A. Increased formation of the potent oxidant peroxynitrite in the airways of asthmatic patients is associated with induction of nitric oxide synthase: Effect of inhaled glucocorticoid. The FASEB Journal.

[55] Fehrenbach H, Wagner C, Wegmann M. Airway remodeling in asthma: What really matters. Cell and Tissue Research.

[56] Mason RJ, Murray JF, Broaddus VC, Nadel JA, editors. Murray and Nadel's Textbook of Respiratory Medicine. 4th ed. Philadelphia: Saunders/Elseviers

Elevation of exhaled ethane

Medicine. 2000;**162**:1450-1454

**108**

## Pathogenic Roles of MicroRNA in the Development of Asthma

*Xiaoyan Dong and Nanbert Zhong*

#### **Abstract**

Asthma is a common and chronic inflammatory disease. Pathogenic mechanism underlying asthma is complicated. The inflammatory reactions in asthma have been recognized to involve mast cells, eosinophils, lymphocytes (T cells, B cells), macrophages, and dendritic cells. MicroRNA (miRNA, miR) is a group of small noncoding RNAs with 21–25 nucleotides (nt) in length, which impact biologic responses through the regulation of mRNA transcription and/or translation. MicroRNAs are related to developmental processes of many immunologic diseases. Most studies showed that regulation of miRNAs to their targeting genes appears to play an important role in the development of asthma. This chapter has discussed altered expression of miRNAs in cells and tissues from patients with asthma, in order to better understand the mechanics of pathogenesis of asthma. In addition, the regulation of miRNAs as a novel therapeutic approach will require a deeper understanding of their function and mechanism of action.

**Keywords:** microRNA asthma, inflammation reaction

#### **1. Introduction**

Pediatric asthma is a global problem. In the last decade, its incidence has highly increased, particular growing by 10% in China [1]. Etiologically, asthma attack, due to gene-environmental interactions, can also be induced by allergy factors, including air pollution, pollen, fungi and dust mites, food, and so on [2]. As a chronic inflammatory disease and a polygenic hereditary disease, the mechanism of asthma is not clearly understood until now. The adaptive and innate immune system with the involvement of mast cells, eosinophils, lymphocytes (T cells, B cells), macrophages, and dendritic cells, even epithelial cells and structure cells, contributed to the inflammation reaction of asthma [3–5]. Moreover, change in the secretion of IgE and cytokines, including gamma-interferon (γ-IFN) and tumor necrosis factor (TNF-α), is important in asthma attacks [6–8]. As an immune regulator, microRNA (miRNA or miR) regulates on target gene mRNA and plays an important role in the development and pathogenesis of asthma.

MicroRNAs are a group of small nonprotein-coding RNAs that are 21–25 nucleotides in length. They act as transcriptional regulators involved in many complex human disorders and in biological processes including cell proliferation and apoptosis [9, 10]. Childhood asthma susceptibility is associated with mutations in specific gene mRNA and/or their specific miRNA. For example, HLA-G has been identified as an asthma susceptibility gene [11], which was found to be the target gene of miR-148a,

miR-148b, and miR-152. Further support for the theory that miRNA changes may be the cause of childhood asthma. The specific genotype of children with asthma was related to the significant difference in allele polymorphism (SNP) of rs2910164G/C and rs2292832C/T of pre-miRNA [12]. It showed that miR-223 was involved in the maturation and function of neutrophil differentiation [13]. miR-27b-3p, miR-513a-5p, and miR-22-3p were also indicated to have influenced dust mite-induced asthma by regulating its target gene [14, 15]. In a murine model of acute and chronic asthma study, abnormal expression of miRNAs including miR-146b, miR-223, miR-29b, miR-29c, miR-483, miR-5745p, miR-672, and miR-690 in asthma was


**111**

*Pathogenic Roles of MicroRNA in the Development of Asthma*

in asthma, in order to review the pathogenic mechanism of asthma.

**2.1 T cell, follicular helper T cells (TFH cells), and Th17**

Th17-mediated interleukin-17a (IL17a) have declined [49].

In addition, miR-18a directly targeted Smad4, Hif1a, and Rora in the Th17 cell gene expression program. All of these reveal that activating signals influence the outcome of Th cell differentiation via differential regulation of mature microRNAs within a common cluster [50]. miR-18a was the most dynamically upregulated microRNA of the miR-17-92 cluster during Th17 cell differentiation. Based on which, the involvement of miR-18a in the regulation of T-cell differentiation was demonstrated. miR-155, as an important regulator in asthma, was involved in many pathways in allergy disease in **Table 1**. It was shown that the function in macrophage

detected [16]. It was found that miRNA plays an important role in regulating immune pathway(s). A lot of studies have focused on the relationship between miRNA and asthma during decades, which involved not only in inflammation cells and cytokines but also in the treatment of glucocorticoids (**Table 1**). In this chapter, we discuss the relationship of miRNAs to their targeted mRNA(s) involved in the inflammation cell

T cell and B cell play an important role in immune mechanism, especially innate and adaptive immunity, of asthma. As an immune regulator, miRNA influences on these two cells and regulates their proliferation and function. Many studies have been focused on the regulation of miRNA to T cell and B cell in order to clear the

T follicular helper (Tfh) cells are essential for the formation of germinal centers (GCs). As a subset of CD4+, it mediates GC formation and maintenance and provides help to antigen-specific B cells during infection and vaccination. Th17 cells have also been implicated in the pathogenesis of several autoimmune and inflammatory diseases [42–44]. Th17 cells also mediate immune responses that are involved in maintaining epithelial barrier integrity, and it has been widely suggested that some cases of asthma may be caused by dysregulated Th17 responses [44, 45]. MiRNA also regulates the differentiation and function of these cells. It was found that the miR-17-92 cluster's increasing role in regulating the immune system is involved in innate and adaptive immunity, including B cells and subsets of T cells such as Th1, Th2, T follicular helper cells, regulatory T cells, monocytes/macrophages, NK cells, and dendritic cells [46]. Moreover, the study found that the miR-17 approximately 92 cluster is a critical regulator of T cell-dependent antibody responses and follicular helper T cells' (TFH cells) differentiation [47]. We knew that the relationship of miRNA and its target gene mRNA is not a oneto-one correspondence. Target gene mRNA could be regulated by many miRNAs, or one miRNA could regulate a number of mRNAs. A study showed that some miRNAs with strong probability may induce miR-27b, miR-27a, miR-30c, miR-1, and miR-141 or inhibit miR-20b, miR-93, miR-20a, miR-152, miR-21, and miR-106a in Th17 differentiation by targeting negative or positive regulators of Th17 differentiation, respectively [48]. In a regulatory network model of murine T helper cell differentiation, the miR-212~132 and miR-182~183 clusters were significantly upregulated, and the overall miR-106~363 cluster was downregulated, which predicted to affect Th17 cell differentiation. In vitro, when miR-18b, miR-106a, and miR-363-3p were transfected into primary murine Cd4(+) lymphocytes, the expression of retinoidrelated orphan receptor c (Rorc), Rora, IL17a, and IL17f and abolished secretion of

*DOI: http://dx.doi.org/10.5772/intechopen.85922*

**2. miRNA in T cell and B cell**

mechanism of asthma.

#### **Table 1.**

*The relationship of miRNA and inflammation response.*

detected [16]. It was found that miRNA plays an important role in regulating immune pathway(s). A lot of studies have focused on the relationship between miRNA and asthma during decades, which involved not only in inflammation cells and cytokines but also in the treatment of glucocorticoids (**Table 1**). In this chapter, we discuss the relationship of miRNAs to their targeted mRNA(s) involved in the inflammation cell in asthma, in order to review the pathogenic mechanism of asthma.

#### **2. miRNA in T cell and B cell**

*Asthma - Biological Evidences*

**miRNA Inflammatory** 

miRNA-223 Immune

miRNA-147 Immune

miRNA-155 Immune

miRNA-21 Immune

miRNA-148a, miR-148b, and miR-152

miRNA-672, miRNA-143

miRNA-133, miR-133a

miRNA-146, miRNA-146a **response**

inflammatory response

Asthma, innate immune responses

inflammatory response

inflammatory response, asthma

inflammatory response, asthma

*The relationship of miRNA and inflammation response.*

miR-148b, and miR-152. Further support for the theory that miRNA changes may be the cause of childhood asthma. The specific genotype of children with asthma was related to the significant difference in allele polymorphism (SNP) of rs2910164G/C and rs2292832C/T of pre-miRNA [12]. It showed that miR-223 was involved in the maturation and function of neutrophil differentiation [13]. miR-27b-3p, miR-513a-5p, and miR-22-3p were also indicated to have influenced dust mite-induced asthma by regulating its target gene [14, 15]. In a murine model of acute and chronic asthma study, abnormal expression of miRNAs including miR-146b, miR-223, miR-29b, miR-29c, miR-483, miR-5745p, miR-672, and miR-690 in asthma was

miRNA-145 Asthma Comparable to glucocorticoid treatment [20]

polarization

miRNA-124 Allergy inflammation M2 phenotype of monocytic cells [28]

miRNA-126 Asthma Th2 response, airway hyperresponse [30] let-7 Asthma Il-13, regulation of allergic inflammation [31–33]

cytokines

muscle cells

Asthma Upregulation of Rhoa in bronchial smooth muscle cells

inhalation challenge

hyperresponsiveness

Asthma Expression of metalloproteinase [37]

cells by targeting TGFbetaR2 gene

phosphorylation, and proliferation in smooth

asthmatic individuals undergoing an allergen

miRNA-221 Asthma Mast cell activity regulates the production of

miR-19a Asthma Enhances proliferation of bronchial epithelial

miR-192 Asthma Decreased expression in peripheral blood of

miRNA-9 Asthma Regulates steroid-resistant airway

miRNA-203 Asthma Negatively regulates c-Abl, ERK1/2

**Reaction and cell differentiate Reference**

Neutrophils mature and differentiate [13]

Airway epithelium, NF-kappaB pathway [17, 18]

TLR signaling pathway [19]

[21–24]

[25–27]

[34, 35]

[36]

[38]

[39]

[40]

[41]

TLR signaling pathway, regulation of allergic inflammation, macrophage inflammatory response, Th2 priming of dendritic cells

TLR signaling pathway, NF-kB, IL-12p35

Asthma HLA-G [11, 29]

**110**

**Table 1.**

T cell and B cell play an important role in immune mechanism, especially innate and adaptive immunity, of asthma. As an immune regulator, miRNA influences on these two cells and regulates their proliferation and function. Many studies have been focused on the regulation of miRNA to T cell and B cell in order to clear the mechanism of asthma.

#### **2.1 T cell, follicular helper T cells (TFH cells), and Th17**

T follicular helper (Tfh) cells are essential for the formation of germinal centers (GCs). As a subset of CD4+, it mediates GC formation and maintenance and provides help to antigen-specific B cells during infection and vaccination. Th17 cells have also been implicated in the pathogenesis of several autoimmune and inflammatory diseases [42–44]. Th17 cells also mediate immune responses that are involved in maintaining epithelial barrier integrity, and it has been widely suggested that some cases of asthma may be caused by dysregulated Th17 responses [44, 45]. MiRNA also regulates the differentiation and function of these cells.

It was found that the miR-17-92 cluster's increasing role in regulating the immune system is involved in innate and adaptive immunity, including B cells and subsets of T cells such as Th1, Th2, T follicular helper cells, regulatory T cells, monocytes/macrophages, NK cells, and dendritic cells [46]. Moreover, the study found that the miR-17 approximately 92 cluster is a critical regulator of T cell-dependent antibody responses and follicular helper T cells' (TFH cells) differentiation [47].

We knew that the relationship of miRNA and its target gene mRNA is not a oneto-one correspondence. Target gene mRNA could be regulated by many miRNAs, or one miRNA could regulate a number of mRNAs. A study showed that some miRNAs with strong probability may induce miR-27b, miR-27a, miR-30c, miR-1, and miR-141 or inhibit miR-20b, miR-93, miR-20a, miR-152, miR-21, and miR-106a in Th17 differentiation by targeting negative or positive regulators of Th17 differentiation, respectively [48]. In a regulatory network model of murine T helper cell differentiation, the miR-212~132 and miR-182~183 clusters were significantly upregulated, and the overall miR-106~363 cluster was downregulated, which predicted to affect Th17 cell differentiation. In vitro, when miR-18b, miR-106a, and miR-363-3p were transfected into primary murine Cd4(+) lymphocytes, the expression of retinoidrelated orphan receptor c (Rorc), Rora, IL17a, and IL17f and abolished secretion of Th17-mediated interleukin-17a (IL17a) have declined [49].

In addition, miR-18a directly targeted Smad4, Hif1a, and Rora in the Th17 cell gene expression program. All of these reveal that activating signals influence the outcome of Th cell differentiation via differential regulation of mature microRNAs within a common cluster [50]. miR-18a was the most dynamically upregulated microRNA of the miR-17-92 cluster during Th17 cell differentiation. Based on which, the involvement of miR-18a in the regulation of T-cell differentiation was demonstrated.

miR-155, as an important regulator in asthma, was involved in many pathways in allergy disease in **Table 1**. It was shown that the function in macrophage inflammatory response [23] is differentially expressed in allergic T cells exposed to DM extract compared to in nonallergic cells. The level of miR-155 expression was positively associated with the expression of the TH2 cytokines IL-5 and IL-13. When miR-155 was inhibited by glucocorticoids in Jurkat T cells, then the production of these cytokines were inhibited [51].

Several differentially expressed miRNAs in asthma, such as miRNA-34/449, let-7, miRNA-19, miRNA-21, and miRNA-455, were identified in various cell types and tissues including epithelial cells, T cells, type 2 innate lymphoid cells, lung tissues, and smooth muscles. These miRNAs are involved in epithelial differentiation, mucus production, airway remodeling, and inflammation as well [52]. miR-146a has been shown to modulate T-cell immunity as well as enhance class switch and secretion of IgE in B cells by upregulating 14-3-3 sigma expression [53].

#### **2.2 miRNA regulates B cell**

B cells play a critical role in immune responses, but the regulation of microRNAs to B-cell proliferation and function was partially understood. Not only miR-17-92 cluster was involved in B cell [46], but miR-146a also enhances class switch and secretion of IgE in B cells [53]. As an important immune regulatory cell, thrombospondin 1 (TSP1)-producing B cells were regulated by miRNAs as well. miR-98 can suppress the expression of TSP1 in the peripheral B cells of patients with allergic asthma [54]. Further study revealed that overexpression of miR-29b in human B cells precipitated a reduction in overall AID protein whose activity affected the function of class-switch recombination (CSR) and then results in corresponding diminution in CSR to IgE [55].

#### **3. miRNA and mast cell**

It is essential that mast cells have major effector and immune regulatory functions in IgE-associated allergic diseases or in innate and adaptive immune responses. But their mechanism was not clear yet. miRNAs provide an additional layer in the regulation of gene expression acting as repressors with several targets at the posttranscriptional level. Several studies showed that miRNA expression patterns during differentiation and activation of mast cells. The expression of many miRNAs changes following IgE-FcepsilonRI cross-linking in activated mast cells. Upregulated expression of miR-221 promotes IgE-mediated activation of mast cell degranulation by PI3K/Akt/PLCgamma/Ca2+ signaling pathway, in a non-NFkappaB-dependent manner [56]. Downregulation of miR-223 promotes degranulation *via* the PI3K/Akt pathway by targeting IGF-1R in mast cells [57]. In cockroach allergen model of asthma, when miRNA-33b was overexpressed, mast cell degranulation was inhibited through suppression of the calcium release and IgE-FcepsilonRI pathway [58]. In line with this, neutralization of miR-132 by anti-miR inhibitor leads to sustained production of HB-EGF protein in activated mast cells [59].

Cytokine is also related to miRNA and mast cells in inflammation response of asthma. The treatment of IL-10 has been shown to suppress TNF production in mast cells. IL-10 effects are dependent on Stat3 activation, eliciting miR-155 expression, with a resulting loss of suppressor of cytokine signaling-1 [60]. miR-221, which was overexpressed in a murine asthma model, stimulated IL-4 secretion in mast cells through a pathway involving PTEN, p38, and NF-kappaB [61]. miR-223 reduces IL-6 secretion in mast cells by inhibiting the IGF1R/PI3K signaling pathway [62]. Mex-3B, an antisense oligonucleotide targeting, directly upregulates IL-33 expression by inhibiting miR-487b-3p-mediated repression of IL-33 [63].

**113**

*Pathogenic Roles of MicroRNA in the Development of Asthma*

Dendritic cells (DCs) are the professional antigen-presenting cells (APCs) in the lung. They are found to be crucial in the induction and maintenance of allergic asthma by cross-linking innate and adaptive immune responses. After transfection with miR-23b reagents, DCs were evaluated for endocytic ability, surface marker expression, cytokine secretion, and CD4+ T-cell differentiation. The study proved that miR-23b is capable of inducing tolerogenic DC activity and Treg responses in vitro through the inhibition of the Notch1 and NF-kappaB signaling pathways; thus, miR-23b might

represent a therapeutic target for the management of allergic diseases [64]. miR-155 has been shown to be a crucial regulator of the immune system mentioned above. Not only miR-155 can influence on T cell function but also regulate the activity of DCs. Deficiency of miR-155 on DCs was also associated with impaired purinergic receptor signaling and alleviates AAI by diminishing Th2

priming capacity and ATP-/P2R-induced activation of DCs in mice [24].

**5. miRNA and inflammatory phenotype (neutrophilic asthma and** 

Asthma may be classified according to severity and inflammatory phenotype and is likely to be distinguished by specific microRNA (miRNA) expression profiles. The study of miRNA expression in sputum supernatants with the inflammatory cells in severe asthma was taken out. Expression of miR-629-3p, miR-223-3p, and miR-142-3p was significantly upregulated in the sputum of patients with severe asthma compared with that in healthy control subjects and was highest in patients with neutrophilic asthma. It suggested that these miRNAs are related to asthma

Single-nucleotide polymorphisms (SNPs) in miRNAs could affect their efficiency in binding to messenger RNAs (mRNAs), which was taken little into account before. In a study in Korean population, it showed that the CT/CC genotype of miR-196a2 at locus rs11614913 was associated with eosinophilic asthma and a higher sputum eosinophil count than the TT genotype. The CG/GG genotype at rs2910164 of miR-146a had a hyperresponsiveness in airway compared with the CC genotype. The AG/GG genotype at rs3746444 of miR-499 manifested higher predicted values

A study about evaluating clinical potential of plasma miR-21 and miR-146a involved in T helper cell differentiation in childhood asthma found that the levels of miR-21 and miR-146a were not only positively correlated with eosinophil percentage but also associated with FEV1. miR-21 and miR-146a are upregulated in asthmatic children. miR-21 and miR-146a play a role in eosinophilic endotypic classification of asthma [67]. Moreover, its data show that miR-185-5p profile in eosinophils can be used as asthma diagnosis biomarker in serum and that this

Monocytes and macrophages are important roles of the immune system, which possess pleiotropic effector and immunoregulatory functions. Classical activation (M1) and alternative activation (M2) of macrophages are necessary in the function. M1 polarization of macrophages results in the production of proinflammatory cytokines and antimicrobial and tumoricidal activity, whereas M2 polarization

of forced expiratory volume in 1 s (%FEV1) than the AA genotype [66].

*DOI: http://dx.doi.org/10.5772/intechopen.85922*

**4. miRNA and dendritic cells**

**eosinophilic asthma)**

inflammatory phenotype [65].

profile is able to rank asthma severity [68].

**6. miRNA and macrophage**

#### **4. miRNA and dendritic cells**

*Asthma - Biological Evidences*

**2.2 miRNA regulates B cell**

diminution in CSR to IgE [55].

**3. miRNA and mast cell**

tion of these cytokines were inhibited [51].

inflammatory response [23] is differentially expressed in allergic T cells exposed to DM extract compared to in nonallergic cells. The level of miR-155 expression was positively associated with the expression of the TH2 cytokines IL-5 and IL-13. When miR-155 was inhibited by glucocorticoids in Jurkat T cells, then the produc-

Several differentially expressed miRNAs in asthma, such as miRNA-34/449, let-7, miRNA-19, miRNA-21, and miRNA-455, were identified in various cell types and tissues including epithelial cells, T cells, type 2 innate lymphoid cells, lung tissues, and smooth muscles. These miRNAs are involved in epithelial differentiation, mucus production, airway remodeling, and inflammation as well [52]. miR-146a has been shown to modulate T-cell immunity as well as enhance class switch and

B cells play a critical role in immune responses, but the regulation of microRNAs to B-cell proliferation and function was partially understood. Not only miR-17-92 cluster was involved in B cell [46], but miR-146a also enhances class switch and secretion of IgE in B cells [53]. As an important immune regulatory cell, thrombospondin 1 (TSP1)-producing B cells were regulated by miRNAs as well. miR-98 can suppress the expression of TSP1 in the peripheral B cells of patients with allergic asthma [54]. Further study revealed that overexpression of miR-29b in human B cells precipitated a reduction in overall AID protein whose activity affected the function of class-switch recombination (CSR) and then results in corresponding

It is essential that mast cells have major effector and immune regulatory functions in IgE-associated allergic diseases or in innate and adaptive immune responses. But their mechanism was not clear yet. miRNAs provide an additional layer in the regulation of gene expression acting as repressors with several targets at the posttranscriptional level. Several studies showed that miRNA expression patterns during differentiation and activation of mast cells. The expression of many miRNAs changes following IgE-FcepsilonRI cross-linking in activated mast cells. Upregulated expression of miR-221 promotes IgE-mediated activation of mast cell degranulation by PI3K/Akt/PLCgamma/Ca2+ signaling pathway, in a non-NFkappaB-dependent manner [56]. Downregulation of miR-223 promotes degranulation *via* the PI3K/Akt pathway by targeting IGF-1R in mast cells [57]. In cockroach allergen model of asthma, when miRNA-33b was overexpressed, mast cell degranulation was inhibited through suppression of the calcium release and IgE-FcepsilonRI pathway [58]. In line with this, neutralization of miR-132 by anti-miR inhibitor leads to sustained production of HB-EGF protein in activated mast cells [59].

Cytokine is also related to miRNA and mast cells in inflammation response of asthma. The treatment of IL-10 has been shown to suppress TNF production in mast cells. IL-10 effects are dependent on Stat3 activation, eliciting miR-155 expression, with a resulting loss of suppressor of cytokine signaling-1 [60]. miR-221, which was overexpressed in a murine asthma model, stimulated IL-4 secretion in mast cells through a pathway involving PTEN, p38, and NF-kappaB [61]. miR-223 reduces IL-6 secretion in mast cells by inhibiting the IGF1R/PI3K signaling pathway [62]. Mex-3B, an antisense oligonucleotide targeting, directly upregulates IL-33 expression by inhibiting miR-487b-3p-mediated repression of IL-33 [63].

secretion of IgE in B cells by upregulating 14-3-3 sigma expression [53].

**112**

Dendritic cells (DCs) are the professional antigen-presenting cells (APCs) in the lung. They are found to be crucial in the induction and maintenance of allergic asthma by cross-linking innate and adaptive immune responses. After transfection with miR-23b reagents, DCs were evaluated for endocytic ability, surface marker expression, cytokine secretion, and CD4+ T-cell differentiation. The study proved that miR-23b is capable of inducing tolerogenic DC activity and Treg responses in vitro through the inhibition of the Notch1 and NF-kappaB signaling pathways; thus, miR-23b might represent a therapeutic target for the management of allergic diseases [64].

miR-155 has been shown to be a crucial regulator of the immune system mentioned above. Not only miR-155 can influence on T cell function but also regulate the activity of DCs. Deficiency of miR-155 on DCs was also associated with impaired purinergic receptor signaling and alleviates AAI by diminishing Th2 priming capacity and ATP-/P2R-induced activation of DCs in mice [24].

#### **5. miRNA and inflammatory phenotype (neutrophilic asthma and eosinophilic asthma)**

Asthma may be classified according to severity and inflammatory phenotype and is likely to be distinguished by specific microRNA (miRNA) expression profiles. The study of miRNA expression in sputum supernatants with the inflammatory cells in severe asthma was taken out. Expression of miR-629-3p, miR-223-3p, and miR-142-3p was significantly upregulated in the sputum of patients with severe asthma compared with that in healthy control subjects and was highest in patients with neutrophilic asthma. It suggested that these miRNAs are related to asthma inflammatory phenotype [65].

Single-nucleotide polymorphisms (SNPs) in miRNAs could affect their efficiency in binding to messenger RNAs (mRNAs), which was taken little into account before. In a study in Korean population, it showed that the CT/CC genotype of miR-196a2 at locus rs11614913 was associated with eosinophilic asthma and a higher sputum eosinophil count than the TT genotype. The CG/GG genotype at rs2910164 of miR-146a had a hyperresponsiveness in airway compared with the CC genotype. The AG/GG genotype at rs3746444 of miR-499 manifested higher predicted values of forced expiratory volume in 1 s (%FEV1) than the AA genotype [66].

A study about evaluating clinical potential of plasma miR-21 and miR-146a involved in T helper cell differentiation in childhood asthma found that the levels of miR-21 and miR-146a were not only positively correlated with eosinophil percentage but also associated with FEV1. miR-21 and miR-146a are upregulated in asthmatic children. miR-21 and miR-146a play a role in eosinophilic endotypic classification of asthma [67]. Moreover, its data show that miR-185-5p profile in eosinophils can be used as asthma diagnosis biomarker in serum and that this profile is able to rank asthma severity [68].

#### **6. miRNA and macrophage**

Monocytes and macrophages are important roles of the immune system, which possess pleiotropic effector and immunoregulatory functions. Classical activation (M1) and alternative activation (M2) of macrophages are necessary in the function. M1 polarization of macrophages results in the production of proinflammatory cytokines and antimicrobial and tumoricidal activity, whereas M2 polarization

of macrophages is related to immunosuppression, tumorigenesis, wound repair, and elimination of parasites [69]. It also reveals that miRNAs were involved in M macrophages' activity. miR-511 is increased in macrophages following IL-4 and IL-13 stimulation and decreased in M1 macrophages both in vitro and in vivo [70]. Particularly, miR-9, miR-127, miR-155, and miR-125b have been shown to promote M1 polarization, while miR-124, miR-223, miR-34a, let-7c, miR-132, miR-146a, and miR-125a-5p may induce M2 polarization in macrophages by targeting various transcription factors and adaptor proteins. Differentiation of monocytes to macrophages is inhibited by miR-24, miR-30b, miR-142-3p, and miR-199a-5p. MiR-155 and miR-142-3p inhibit macrophage proliferation, compared to let-7a. Interestingly, miR-155 has both pro- and antiapoptotic roles, whereas miR-21 and let-7e negatively regulate macrophage apoptosis [69, 71, 72]. These data revealed that the function of miRNAs in modulating macrophage polarization may have potential way in the treatment of inflammation-related diseases.

On the other hand, studying the development of allergy disease in maternal pregnancy revealed that the embryonic development is highly sensitive to xenobiotic toxicity. If exposed to environmental toxins in utero, it affects physiological responses of the progeny. In the animal model, there was a lower expression of miR-130a and increased expression of miR-16 and miR-221 in the lungs of mice which were exposed to sidestream cigarette smoke (SS) or secondhand smoke exhibit. These miRNAs regulate HIF-1 alpha-regulated apoptotic, angiogenic, and immune pathways. This process will lead to increase incidence of allergic asthma (AA) and bronchopulmonary dysplasia (BPD) in the progenies [73].

Besides, the expression of miRNAs was different in fungal bioaerosols which are ubiquitous in the environment, and human exposure can result in a variety of health effects ranging from systemic, subcutaneous, and cutaneous infections to respiratory morbidity including allergy, asthma, and hypersensitivity pneumonitis. It was found that miRNAs were involved in the inflammatory stimuli exposure to fungal. In studies of exposures to fungi (such as *Aspergillus fumigatus*, *Candida albicans*, and *Cryptococcus neoformans*), it was revealed that several miRNAs that were shared between responses to these species including miR-125 a/miR-125 b, miR-132 [43], miR-146a, and miR-29a/miR-29b were also involved in macrophage polarization/activation, TLR-mediated signaling, natural killer cell function, C-leptin signaling, and inhibition of Th1 immune response, respectively [74]. On the other hand, miR-487b can suppress the levels of mRNA and protein for IL-33, which plays an important role in macrophage activation for innate host defense and proinflammatory responses during the differentiation of bone marrow-derived macrophages (BMDMs) [75].

In summary, miRNAs exert their effect by binding to complementary nucleotide sequences of the targeted messenger RNA, thus forming an RNA-induced silencing complex. miRNAs play important roles in many aspects of macrophage biology and thereby affect many biological and pathological conditions, like monocyte differentiation and development, macrophage polarization, infection, tumor growth, inflammatory activation, and so on [71, 72]. Numerous studies have demonstrated the important role of miRNA in the pathogenesis of childhood asthma, suggesting that miRNA plays a regulatory role between genes and the environment as well as allergic airway inflammation. The mechanism of miRNA activity involves a large number of miRNAs, which take mRNA with multiple functions as target genes and synergistically regulate multiple aspects of complex pathophysiological processes in childhood asthma. The role of miRNAs in inflammation cells is important in both innate and acquired immunity in which T cell, B cell, mast cells, macrophages, and dendritic cells are involved. The role of miRNAs in these cell types, miR-17-92 cluster, miR-221, miR-223, miR-146a, and miR-155, may be crucial

**115**

**Acknowledgements**

**Figure 1.**

**Conflict of interest**

*Pathogenic Roles of MicroRNA in the Development of Asthma*

(**Figure 1**). Depending on these roles of miRNAs in dendritic cells, mast cells, and macrophages, we speculate about possible future directions in the field [76]. It is likely variant miRNAs form a network in which these miRNAs may interact with each other and alter the expression of target genes in the inflammation process of pediatric asthma. On the other hand, it is envisaged that targeted manipulation of specific miRNAs could be developed as a new treatment for asthma. At present, our group has already had some result about the relationship of miRNA to target gene in dust mite-induced asthma. Depending on this review, further investigation should be pursued on the immune regulatory function of miRNA in children's asthma.

*miR-17-92 cluster, miR-221, miR-223, miR-146a, and miR-155 are associated with inflammation cells. (A) Downregulation of miR-223 promotes degranulation via the PI3K/Akt pathway by targeting IGF-1R and reduces IL-6 secretion in mast cells. It also induced M2 polarization. (B) miR-221 promoted IgE-mediated activation of mast cells degranulation by PI3K/Akt/PLCgamma/Ca2+ signaling pathway and stimulated IL-4 secretion in mast cells through a pathway involving PTEN, p38, and NF-kappaB. (C) miR-17~92 cluster as a critical regulator of T-cell-dependent antibody responses and follicular helper T cell (TFH cell) and Th17 differentiation. It enhances class switch and secretion of IgE in B cells. (D) miR-146 modulated T-cell immunity and enhanced class switch and secretion of IgE in B cells. miR-146a played a role in eosinophilic endotypic classification of asthma. It induced M2 polarization as well. (E) miR-155 was associated with Th2 cell and cytokine secretion. Deficiency of miR-155 on DCs was also related to impaired purinergic receptor signaling and alleviates AAI by diminishing Th2 priming capacity and ATP-/P2R-induced activation of DCs. It promoted M1 polarization.*

This study was supported by Shanghai Science and Science Commission International Cooperation Project (No. 18410721300) and Project on the cross

There was no conflict of interest (economic, personal, scientific, healthcare,

project of Shanghai Jiaotong University (YG2017MS34).

educational, religious, and social) interfering with the chapter.

*DOI: http://dx.doi.org/10.5772/intechopen.85922*

*Pathogenic Roles of MicroRNA in the Development of Asthma DOI: http://dx.doi.org/10.5772/intechopen.85922*

#### **Figure 1.**

*Asthma - Biological Evidences*

of macrophages is related to immunosuppression, tumorigenesis, wound repair, and elimination of parasites [69]. It also reveals that miRNAs were involved in M macrophages' activity. miR-511 is increased in macrophages following IL-4 and IL-13 stimulation and decreased in M1 macrophages both in vitro and in vivo [70]. Particularly, miR-9, miR-127, miR-155, and miR-125b have been shown to promote M1 polarization, while miR-124, miR-223, miR-34a, let-7c, miR-132, miR-146a, and miR-125a-5p may induce M2 polarization in macrophages by targeting various transcription factors and adaptor proteins. Differentiation of monocytes to macrophages is inhibited by miR-24, miR-30b, miR-142-3p, and miR-199a-5p. MiR-155 and miR-142-3p inhibit macrophage proliferation, compared to let-7a. Interestingly, miR-155 has both pro- and antiapoptotic roles, whereas miR-21 and let-7e negatively regulate macrophage apoptosis [69, 71, 72]. These data revealed that the function of miRNAs in modulating macrophage polarization may have potential

On the other hand, studying the development of allergy disease in maternal pregnancy revealed that the embryonic development is highly sensitive to xenobiotic toxicity. If exposed to environmental toxins in utero, it affects physiological responses of the progeny. In the animal model, there was a lower expression of miR-130a and increased expression of miR-16 and miR-221 in the lungs of mice which were exposed to sidestream cigarette smoke (SS) or secondhand smoke exhibit. These miRNAs regulate HIF-1 alpha-regulated apoptotic, angiogenic, and immune pathways. This process will lead to increase incidence of allergic asthma (AA) and

Besides, the expression of miRNAs was different in fungal bioaerosols which are ubiquitous in the environment, and human exposure can result in a variety of health effects ranging from systemic, subcutaneous, and cutaneous infections to respiratory morbidity including allergy, asthma, and hypersensitivity pneumonitis. It was found that miRNAs were involved in the inflammatory stimuli exposure to fungal. In studies of exposures to fungi (such as *Aspergillus fumigatus*, *Candida albicans*, and *Cryptococcus neoformans*), it was revealed that several miRNAs that were shared between responses to these species including miR-125 a/miR-125 b, miR-132 [43], miR-146a, and miR-29a/miR-29b were also involved in macrophage polarization/activation, TLR-mediated signaling, natural killer cell function, C-leptin signaling, and inhibition of Th1 immune response, respectively [74]. On the other hand, miR-487b can suppress the levels of mRNA and protein for IL-33, which plays an important role in macrophage activation for innate host defense and proinflammatory responses during the differentiation of bone marrow-derived

In summary, miRNAs exert their effect by binding to complementary nucleotide sequences of the targeted messenger RNA, thus forming an RNA-induced silencing complex. miRNAs play important roles in many aspects of macrophage biology and thereby affect many biological and pathological conditions, like monocyte differentiation and development, macrophage polarization, infection, tumor growth, inflammatory activation, and so on [71, 72]. Numerous studies have demonstrated the important role of miRNA in the pathogenesis of childhood asthma, suggesting that miRNA plays a regulatory role between genes and the environment as well as allergic airway inflammation. The mechanism of miRNA activity involves a large number of miRNAs, which take mRNA with multiple functions as target genes and synergistically regulate multiple aspects of complex pathophysiological processes in childhood asthma. The role of miRNAs in inflammation cells is important in both innate and acquired immunity in which T cell, B cell, mast cells, macrophages, and dendritic cells are involved. The role of miRNAs in these cell types, miR-17-92 cluster, miR-221, miR-223, miR-146a, and miR-155, may be crucial

way in the treatment of inflammation-related diseases.

bronchopulmonary dysplasia (BPD) in the progenies [73].

macrophages (BMDMs) [75].

**114**

*miR-17-92 cluster, miR-221, miR-223, miR-146a, and miR-155 are associated with inflammation cells. (A) Downregulation of miR-223 promotes degranulation via the PI3K/Akt pathway by targeting IGF-1R and reduces IL-6 secretion in mast cells. It also induced M2 polarization. (B) miR-221 promoted IgE-mediated activation of mast cells degranulation by PI3K/Akt/PLCgamma/Ca2+ signaling pathway and stimulated IL-4 secretion in mast cells through a pathway involving PTEN, p38, and NF-kappaB. (C) miR-17~92 cluster as a critical regulator of T-cell-dependent antibody responses and follicular helper T cell (TFH cell) and Th17 differentiation. It enhances class switch and secretion of IgE in B cells. (D) miR-146 modulated T-cell immunity and enhanced class switch and secretion of IgE in B cells. miR-146a played a role in eosinophilic endotypic classification of asthma. It induced M2 polarization as well. (E) miR-155 was associated with Th2 cell and cytokine secretion. Deficiency of miR-155 on DCs was also related to impaired purinergic receptor signaling and alleviates AAI by diminishing Th2 priming capacity and ATP-/P2R-induced activation of DCs. It promoted M1 polarization.*

(**Figure 1**). Depending on these roles of miRNAs in dendritic cells, mast cells, and macrophages, we speculate about possible future directions in the field [76]. It is likely variant miRNAs form a network in which these miRNAs may interact with each other and alter the expression of target genes in the inflammation process of pediatric asthma. On the other hand, it is envisaged that targeted manipulation of specific miRNAs could be developed as a new treatment for asthma. At present, our group has already had some result about the relationship of miRNA to target gene in dust mite-induced asthma. Depending on this review, further investigation should be pursued on the immune regulatory function of miRNA in children's asthma.

#### **Acknowledgements**

This study was supported by Shanghai Science and Science Commission International Cooperation Project (No. 18410721300) and Project on the cross project of Shanghai Jiaotong University (YG2017MS34).

#### **Conflict of interest**

There was no conflict of interest (economic, personal, scientific, healthcare, educational, religious, and social) interfering with the chapter.

*Asthma - Biological Evidences*

#### **Author details**

Xiaoyan Dong1 and Nanbert Zhong2 \*

1 Department of Pulmonary, Shanghai Children's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

2 New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA

\*Address all correspondence to: nanbert.zhong@opwdd.ny.gov

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**117**

*Pathogenic Roles of MicroRNA in the Development of Asthma*

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[11] Tan Z, Randall G, Fan J, Camoretti-Mercado B, Brockman-Schneider R, Pan L, et al. Allele-specific targeting of microRNAs to HLA-G and risk of asthma. American Journal of Human

[12] Su XW, Yang Y, Lv ML, Li LJ, Dong W, Miao L, et al. Association between single-nucleotide polymorphisms in pre-miRNAs and the risk of asthma in a Chinese population. DNA and Cell

[13] Johnnidis JB, Harris MH, Wheeler RT, Stehling-Sun S, Lam MH, Kirak O, et al. Regulation of progenitor cell proliferation and granulocyte function by microRNA-223. Nature.

[14] Dong X, Xu M, Ren Z, Gu J, Lu M, Lu Q, et al. Regulation of CBL and ESR1 expression by microRNA-223p, 513a-5p and 625-5p may impact the pathogenesis of dust mite-induced pediatric asthma. International Journal of Molecular

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Medicine. 2008;**12**:3-21

[10] Pauley KM, Cha S, Chan EK. MicroRNA in autoimmunity and autoimmune diseases. Journal of Autoimmunity. 2009;**32**:189-194

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**116**

**Author details**

Xiaoyan Dong1

Staten Island, NY, USA

provided the original work is properly cited.

and Nanbert Zhong2

University School of Medicine, Shanghai, China

\*

1 Department of Pulmonary, Shanghai Children's Hospital, Shanghai Jiaotong

2 New York State Institute for Basic Research in Developmental Disabilities,

\*Address all correspondence to: nanbert.zhong@opwdd.ny.gov

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

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*Asthma - Biological Evidences*

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[50] Montoya MM, Maul J, Singh PB, Pua HH, Dahlstrom F, Wu N, et al. A distinct inhibitory function for miR-18a in Th17 cell differentiation. Journal of Immunology. 2017;**199**:559-569

[51] Daniel E, Roff A, Hsu MH, Panganiban R, Lambert K, Ishmael F. Effects of allergic stimulation and glucocorticoids on miR-155 in CD4(+) T-cells. American Journal of Clinical and Experimental Immunology. 2018;**7**:57-66

[52] van den Berge M, Tasena H. Role of microRNAs and exosomes in asthma. Current Opinion in Pulmonary Medicine. 2019;**25**:87-93

[53] Li F, Huang Y, Huang YY, Kuang YS, Wei YJ, Xiang L, et al. MicroRNA-146a promotes IgE class switch in B cells via upregulating 14-3-3sigma expression. Molecular Immunology. 2017;**92**:180-189

[54] Chen L, Xu J, Chu X, Ju C. MicroRNA-98 interferes with thrombospondin 1 expression in peripheral B cells of patients with asthma. Bioscience Reports. 2017;**37**

[55] Recaldin T, Hobson PS, Mann EH, Ramadani F, Cousins DJ, Lavender P, et al. miR-29b directly targets activation-induced cytidine deaminase in human B cells and can limit its inappropriate expression in naive B cells. Molecular Immunology. 2018;**101**:419-428

[56] Xu H, Gu LN, Yang QY, Zhao DY, Liu F. MiR-221 promotes IgE-mediated activation of mast cells degranulation by PI3K/Akt/PLCgamma/Ca2+ pathway. Journal of Bioenergetics and Biomembranes. 2016;**48**:293-299

[57] Wang Q, Zhao DY, Xu H, Zhou H, Yang QY, Liu F, et al. Downregulation of microRNA-223 promotes degranulation via the PI3K/Akt pathway by targeting IGF-1R in mast cells. PLoS One. 2015;**10**:e0123575

[58] Niu R, Xiao X, Liu B, Li Y, Zhong Y, Ma L. Inhibition of airway inflammation in a cockroach allergen model of asthma by agonists of miRNA-33b. Scientific Reports. 2017;**7**:7409

[59] Molnar V, Ersek B, Wiener Z, Tombol Z, Szabo PM, Igaz P, et al. MicroRNA-132 targets HB-EGF upon IgE-mediated activation in murine and human mast cells. Cellular and Molecular Life Sciences. 2012;**69**:793-808

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*Pathogenic Roles of MicroRNA in the Development of Asthma*

[67] Hammad Mahmoud Hammad R, Hamed D, Eldosoky M, Ahmad A, Osman HM, Abd Elgalil HM, et al. Plasma microRNA-21, microRNA-146a and IL-13 expression in

asthmatic children. Innate Immunity.

[68] Rodrigo-Munoz JM, Canas JA, Sastre B, Rego N, Greif G, Rial M, et al. Asthma diagnosis using integrated analysis of eosinophil microRNAs. Allergy. Mar 2018;**74**(3):507-517

[69] Shapouri-Moghaddam A,

2018;**233**:6425-6440

Asthma. 2015;**52**:545-553

2015;**27**:237-248

Mohammadian S, Vazini H, Taghadosi M, Esmaeili SA, Mardani F, et al. Macrophage plasticity, polarization, and function in health and disease. Journal of Cellular Physiology.

[70] Karo-Atar D, Itan M, Pasmanik-Chor M, Munitz A. MicroRNA profiling reveals opposing expression patterns for miR-511 in alternatively and classically activated macrophages. The Journal of

[71] Porta C, Riboldi E, Ippolito A, Sica A. Molecular and epigenetic basis of macrophage polarized activation. Seminars in Immunology.

[72] Weiss G, Schaible UE. Macrophage

intracellular bacteria. Immunological

[73] Singh SP, Chand HS, Langley RJ, Mishra N, Barrett T, Rudolph K, et al. Gestational exposure to sidestream (secondhand) cigarette smoke

promotes transgenerational epigenetic transmission of exacerbated allergic asthma and bronchopulmonary dysplasia. Journal of Immunology.

[74] Croston TL, Lemons AR, Beezhold DH, Green BJ. MicroRNA regulation of

defense mechanisms against

Reviews. 2015;**264**:182-203

2017;**198**:3815-3822

2018;**24**:171-179

*DOI: http://dx.doi.org/10.5772/intechopen.85922*

[60] Qayum AA, Paranjape A, Abebayehu D, Kolawole EM, Haque TT, McLeod JJ, et al. IL-10-induced miR-155 targets SOCS1 to enhance IgEmediated mast cell function. Journal of Immunology. 2016;**196**:4457-4467

[61] Zhou Y, Yang Q, Xu H, Zhang J, Deng H, Gao H, et al. miRNA-221-3p enhances the secretion of interleukin-4 in mast cells through the phosphatase and tensin homolog/p38/ nuclear factor-kappaB pathway. PLoS

[62] Yang Q, Xu H, Yang J, Zhou Y, Zhao D, Liu F. MicroRNA-223 affects IL-6 secretion in mast cells via the IGF1R/ PI3K signaling pathway. International Journal of Molecular Medicine.

[63] Yamazumi Y, Sasaki O, Imamura M, Oda T, Ohno Y, Shiozaki-Sato Y, et al. The RNA binding protein Mex-3B is required for IL-33 induction

in the development of allergic airway inflammation. Cell Reports.

[64] Zheng J, Jiang HY, Li J, Tang HC, Zhang XM, Wang XR, et al. MicroRNA-23b promotes tolerogenic properties of dendritic cells in vitro through inhibiting Notch1/NF-kappaB

signalling pathways. Allergy.

show differential microRNA expression in sputum. The Journal of Allergy and Clinical Immunology.

[65] Maes T, Cobos FA, Schleich F, Sorbello V, Henket M, De Preter K, et al. Asthma inflammatory phenotypes

[66] Trinh HKT, Pham DL, Kim SC, Kim RY, Park HS, Kim SH. Association of the miR-196a2, miR-146a, and miR-499 polymorphisms with asthma phenotypes in a Korean population. Molecular Diagnosis & Therapy.

One. 2016;**11**:e0148821

2016;**38**:507-512

2016;**16**:2456-2471

2012;**67**:362-370

2016;**137**:1433-1446

2017;**21**:547-554

*Pathogenic Roles of MicroRNA in the Development of Asthma DOI: http://dx.doi.org/10.5772/intechopen.85922*

[60] Qayum AA, Paranjape A, Abebayehu D, Kolawole EM, Haque TT, McLeod JJ, et al. IL-10-induced miR-155 targets SOCS1 to enhance IgEmediated mast cell function. Journal of Immunology. 2016;**196**:4457-4467

*Asthma - Biological Evidences*

Pathology. 2013;**8**:477-512

2019;**118**:2-6

2013;**14**:840-848

2015;**572**:153-162

[45] Pappu R, Rutz S, Ouyang

inflammatory diseases of the intestines, lungs, and skin. Annual Review of

[52] van den Berge M, Tasena H. Role of microRNAs and exosomes in

Medicine. 2019;**25**:87-93

[54] Chen L, Xu J, Chu X, Ju C. MicroRNA-98 interferes with thrombospondin 1 expression in peripheral B cells of patients with asthma. Bioscience Reports. 2017;**37**

[55] Recaldin T, Hobson PS, Mann EH, Ramadani F, Cousins DJ, Lavender P, et al. miR-29b directly targets activation-induced cytidine deaminase in human B cells and can limit its inappropriate expression in naive B cells. Molecular Immunology.

[56] Xu H, Gu LN, Yang QY, Zhao DY, Liu F. MiR-221 promotes IgE-mediated activation of mast cells degranulation by PI3K/Akt/PLCgamma/Ca2+

pathway. Journal of Bioenergetics and Biomembranes. 2016;**48**:293-299

[57] Wang Q, Zhao DY, Xu H, Zhou H, Yang QY, Liu F, et al. Down-

One. 2015;**10**:e0123575

2012;**69**:793-808

[58] Niu R, Xiao X, Liu B, Li Y, Zhong Y, Ma L. Inhibition of airway inflammation in a cockroach allergen model of asthma by agonists of miRNA-33b. Scientific Reports. 2017;**7**:7409

[59] Molnar V, Ersek B, Wiener Z, Tombol Z, Szabo PM, Igaz P, et al. MicroRNA-132 targets HB-EGF upon IgE-mediated activation in murine and human mast cells. Cellular and Molecular Life Sciences.

regulation of microRNA-223 promotes degranulation via the PI3K/Akt pathway by targeting IGF-1R in mast cells. PLoS

2018;**101**:419-428

asthma. Current Opinion in Pulmonary

[53] Li F, Huang Y, Huang YY, Kuang YS, Wei YJ, Xiang L, et al. MicroRNA-146a promotes IgE class switch in B cells via upregulating 14-3-3sigma expression. Molecular Immunology. 2017;**92**:180-189

W. Regulation of epithelial immunity by IL-17 family cytokines. Trends in Immunology. 2012;**33**:343-349

[46] Kuo G, Wu CY, Yang HY. MiR-17- 92 cluster and immunity. Journal of the Formosan Medical Association.

[47] Baumjohann D, Kageyama R, Clingan JM, Morar MM, Patel S, de Kouchkovsky D, et al. The microRNA cluster miR-17 approximately 92 promotes TFH cell differentiation and represses subset-inappropriate gene expression. Nature Immunology.

[48] Honardoost MA, Naghavian R, Ahmadinejad F, Hosseini A, Ghaedi K. Integrative computational mRNAmiRNA interaction analyses of the autoimmune-deregulated miRNAs and well-known Th17 differentiation regulators: An attempt to discover new potential miRNAs involved in Th17 differentiation. Gene.

[49] Kastle M, Bartel S, Geillinger-Kastle K, Irmler M, Beckers J, Ryffel B, et al. microRNA cluster 106a~363 is involved in T helper 17 cell differentiation. Immunology. 2017;**152**:402-413

[50] Montoya MM, Maul J, Singh PB, Pua HH, Dahlstrom F, Wu N, et al. A distinct inhibitory function for miR-18a in Th17 cell differentiation. Journal of Immunology. 2017;**199**:559-569

[51] Daniel E, Roff A, Hsu MH, Panganiban R, Lambert K, Ishmael F. Effects of allergic stimulation and glucocorticoids on miR-155 in CD4(+) T-cells. American Journal of Clinical and Experimental Immunology.

**120**

2018;**7**:57-66

[61] Zhou Y, Yang Q, Xu H, Zhang J, Deng H, Gao H, et al. miRNA-221-3p enhances the secretion of interleukin-4 in mast cells through the phosphatase and tensin homolog/p38/ nuclear factor-kappaB pathway. PLoS One. 2016;**11**:e0148821

[62] Yang Q, Xu H, Yang J, Zhou Y, Zhao D, Liu F. MicroRNA-223 affects IL-6 secretion in mast cells via the IGF1R/ PI3K signaling pathway. International Journal of Molecular Medicine. 2016;**38**:507-512

[63] Yamazumi Y, Sasaki O, Imamura M, Oda T, Ohno Y, Shiozaki-Sato Y, et al. The RNA binding protein Mex-3B is required for IL-33 induction in the development of allergic airway inflammation. Cell Reports. 2016;**16**:2456-2471

[64] Zheng J, Jiang HY, Li J, Tang HC, Zhang XM, Wang XR, et al. MicroRNA-23b promotes tolerogenic properties of dendritic cells in vitro through inhibiting Notch1/NF-kappaB signalling pathways. Allergy. 2012;**67**:362-370

[65] Maes T, Cobos FA, Schleich F, Sorbello V, Henket M, De Preter K, et al. Asthma inflammatory phenotypes show differential microRNA expression in sputum. The Journal of Allergy and Clinical Immunology. 2016;**137**:1433-1446

[66] Trinh HKT, Pham DL, Kim SC, Kim RY, Park HS, Kim SH. Association of the miR-196a2, miR-146a, and miR-499 polymorphisms with asthma phenotypes in a Korean population. Molecular Diagnosis & Therapy. 2017;**21**:547-554

[67] Hammad Mahmoud Hammad R, Hamed D, Eldosoky M, Ahmad A, Osman HM, Abd Elgalil HM, et al. Plasma microRNA-21, microRNA-146a and IL-13 expression in asthmatic children. Innate Immunity. 2018;**24**:171-179

[68] Rodrigo-Munoz JM, Canas JA, Sastre B, Rego N, Greif G, Rial M, et al. Asthma diagnosis using integrated analysis of eosinophil microRNAs. Allergy. Mar 2018;**74**(3):507-517

[69] Shapouri-Moghaddam A, Mohammadian S, Vazini H, Taghadosi M, Esmaeili SA, Mardani F, et al. Macrophage plasticity, polarization, and function in health and disease. Journal of Cellular Physiology. 2018;**233**:6425-6440

[70] Karo-Atar D, Itan M, Pasmanik-Chor M, Munitz A. MicroRNA profiling reveals opposing expression patterns for miR-511 in alternatively and classically activated macrophages. The Journal of Asthma. 2015;**52**:545-553

[71] Porta C, Riboldi E, Ippolito A, Sica A. Molecular and epigenetic basis of macrophage polarized activation. Seminars in Immunology. 2015;**27**:237-248

[72] Weiss G, Schaible UE. Macrophage defense mechanisms against intracellular bacteria. Immunological Reviews. 2015;**264**:182-203

[73] Singh SP, Chand HS, Langley RJ, Mishra N, Barrett T, Rudolph K, et al. Gestational exposure to sidestream (secondhand) cigarette smoke promotes transgenerational epigenetic transmission of exacerbated allergic asthma and bronchopulmonary dysplasia. Journal of Immunology. 2017;**198**:3815-3822

[74] Croston TL, Lemons AR, Beezhold DH, Green BJ. MicroRNA regulation of

#### *Asthma - Biological Evidences*

host immune responses following fungal exposure. Frontiers in Immunology. 2018;**9**:170

[75] Xiang Y, Eyers F, Herbert C, Tay HL, Foster PS, Yang M. MicroRNA-487b is a negative regulator of macrophage activation by targeting IL-33 production. Journal of Immunology. 2016;**196**:3421-3428

[76] Montagner S, Orlandi EM, Merante S, Monticelli S. The role of miRNAs in mast cells and other innate immune cells. Immunological Reviews. 2013;**253**:12-24

**123**

**Chapter 9**

**Abstract**

**1. Introduction**

of asthmatic patients.

**2. Saffron and asthma**

Nutritional Recommendations in

Asthma is a heterogeneous disease, and airway inflammation has an important

role in its pathogenesis. Some nutritional factors can influence the process of asthma. It is reported that saffron has anti-inflammatory, antioxidant, and muscle relaxant effects, and some animal and human studies showed that saffron and its active components (safranal and crocin) improved the asthma biomarkers and clinical symptoms. Some other nutritional factors also affect asthma; for example, magnesium can relax the muscles and thus has bronchodilatory effects. Curcumin is the major active component of turmeric which has a potent antioxidant, anti-inflammatory, and anti-allergic effects. Because some researchers suggested that intestinal microbial flora has an important role in allergy, probiotics can be a complementary supplement for asthmatic patients. Generally nutritional factors could be advised for asthmatic patients with the goal of reducing the needs for chemical drugs.

**Keywords:** asthma, inflammation, spirometry, nutritional recommendations

Asthma is usually associated with chronic inflammation of airway [1]. In asthmatic patients, bronchial hyper-responsiveness, airway inflammation, and also airway remodeling are the prominent features. This chronic respiratory disease affects over 300 million people worldwide, and it is estimated that it will probably become more than 400 million by 2020 [2]. The WHO has estimated that 15 million disability-adjusted life-years are lost annually due to asthma [3]. Asthma disease

Nutritional advices have an important role in the improvement of lung function

Saffron (*Crocus sativus* L.) has antioxidant [5], anti-inflammatory [6], and muscle relaxant effects [7] and so has beneficial effects on asthma. Results of our clinical trial showed that saffron supplementation (100 mg of dried saffron stigma in capsules) for 8 weeks in mild and moderate allergic asthmatic patients improved the lung function by increasing the forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and forced expiratory flow (FEF) 25-75 and decreased some inflammatory factors (anti-HSP 70 and hs-CRP) in comparison to placebo [8]. In this trial the clinical symptoms of patients (including

imposes many economic and social burdens [4].

Asthmatic Patients

*Marzie Zilaee and Seyed Ahmad Hosseini*

#### **Chapter 9**

*Asthma - Biological Evidences*

2018;**9**:170

host immune responses following fungal exposure. Frontiers in Immunology.

[75] Xiang Y, Eyers F, Herbert C, Tay HL, Foster PS, Yang M. MicroRNA-487b is a negative regulator of macrophage

production. Journal of Immunology.

activation by targeting IL-33

[76] Montagner S, Orlandi EM, Merante S, Monticelli S. The role of miRNAs in mast cells and other innate immune cells. Immunological Reviews.

2016;**196**:3421-3428

2013;**253**:12-24

**122**

## Nutritional Recommendations in Asthmatic Patients

*Marzie Zilaee and Seyed Ahmad Hosseini*

#### **Abstract**

Asthma is a heterogeneous disease, and airway inflammation has an important role in its pathogenesis. Some nutritional factors can influence the process of asthma. It is reported that saffron has anti-inflammatory, antioxidant, and muscle relaxant effects, and some animal and human studies showed that saffron and its active components (safranal and crocin) improved the asthma biomarkers and clinical symptoms. Some other nutritional factors also affect asthma; for example, magnesium can relax the muscles and thus has bronchodilatory effects. Curcumin is the major active component of turmeric which has a potent antioxidant, anti-inflammatory, and anti-allergic effects. Because some researchers suggested that intestinal microbial flora has an important role in allergy, probiotics can be a complementary supplement for asthmatic patients. Generally nutritional factors could be advised for asthmatic patients with the goal of reducing the needs for chemical drugs.

**Keywords:** asthma, inflammation, spirometry, nutritional recommendations

#### **1. Introduction**

Asthma is usually associated with chronic inflammation of airway [1]. In asthmatic patients, bronchial hyper-responsiveness, airway inflammation, and also airway remodeling are the prominent features. This chronic respiratory disease affects over 300 million people worldwide, and it is estimated that it will probably become more than 400 million by 2020 [2]. The WHO has estimated that 15 million disability-adjusted life-years are lost annually due to asthma [3]. Asthma disease imposes many economic and social burdens [4].

Nutritional advices have an important role in the improvement of lung function of asthmatic patients.

#### **2. Saffron and asthma**

Saffron (*Crocus sativus* L.) has antioxidant [5], anti-inflammatory [6], and muscle relaxant effects [7] and so has beneficial effects on asthma. Results of our clinical trial showed that saffron supplementation (100 mg of dried saffron stigma in capsules) for 8 weeks in mild and moderate allergic asthmatic patients improved the lung function by increasing the forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and forced expiratory flow (FEF) 25-75 and decreased some inflammatory factors (anti-HSP 70 and hs-CRP) in comparison to placebo [8]. In this trial the clinical symptoms of patients (including frequency of the shortness of breath during day- and nighttime, use of salbutamol spray, waking up due to asthma symptoms, and activity limitation) improved after saffron supplementation [9].

Some animal studies also investigated the effects of saffron on asthma. Active constituents of saffron (safranal and crocin) have antioxidant and antiinflammatory effects and so have beneficial effects on asthma. This is reported that saffron supplementation in animals with allergic asthma decreased eosinophils, basophils, and total white blood cells, and some of these effects were found to be equal to dexamethasone [10]. Saffron supplementation in guinea pig with allergic asthma decreased the serum level of endothelin1 (as an inflammatory index) [11]. Boskabady et al. reported that saffron had a potent relaxant effect on tracheal chains of guinea pigs which was comparable to or even higher than that of theophylline [7].

#### **3. Magnesium and asthma**

Insufficient magnesium (Mg) intake can influence the management of asthma [12, 13]. Some drugs used in the treatment of asthma reduce the body's magnesium storage [14]. For example, β2-receptor agonist drugs can increase urinary excretion of magnesium and thus lead to magnesium deficiency [15].

Magnesium has muscle relaxant effects and bronchodilator effects [16] because of physiologic calcium antagonist effects [17] or adenylyl cyclase activation action [18]. Results of a clinical trial on 112 patients with mild to moderate asthma suggested that 340 mg MgSO4 supplementation for 2 months had bronchodilation effects and improved the lung function and so can be used as an emergency treatment for asthma attack [19].

Alexandra et al. [20] surveyed the effect of magnesium in patients with mild to moderate asthma. They showed that 340 mg Mg supplementation for 6.5 months significantly increased the concentration of methacholine required to cause 20% drop in the forced expiratory volume in 1 minute (FEV1) and improved the peak expiratory flow rate (PEFR). Mg also improved the quality of life and asthma control in comparison to control group [20].

For children with moderate-to-severe asthma, magnesium seems to be beneficial. It is a safe drug to prescribe but has minor side effects reported, for example, pain and numbness at the infusion site, hypotension, epigastric or facial warmth, flushing, dry mouth, and malaise. Due to the anti-inflammatory and bronchodilating effects, magnesium can be considered as an adjuvant therapy in pediatric patients who do not respond to conventional treatment in severe manifestations of asthma. Future studies should investigate the best route of administration and the optimal dosage for most benefits [21].

Because of the difficulties in measurement and also interpretation of extracellular vs. intracellular forms of magnesium, the relationship between asthma and magnesium deficiency is unclear [15]. Some studies reported that low dietary magnesium intake (which is the major determinant in homeostasis of magnesium) may be involved in the etiology of chronic obstructive airway disease and asthma [15]. Britton et al. reported that 100 mg/d higher dietary magnesium intake was independently associated with higher FEV1 and lower bronchial hyperreactivity [22].

#### **4. Curcumin and asthma**

Curcumin is the yellow pigment of turmeric (*Curcuma longa*) (a spice) which has anti-inflammatory [23] and anti-allergic [24] and antiasthmatic [24] effects.

**125**

*Nutritional Recommendations in Asthmatic Patients DOI: http://dx.doi.org/10.5772/intechopen.86259*

adenosine molecules (ICAM-1) [27].

response) [25].

(without systemic side effects) for local use can be produced.

In a murine model of chronic asthma, it is reported that curcumin similar to dexamethasone improved histological changes of chronic asthma [23]. Subhashini et al. reported that curcumin via intranasal rout in asthmatic mice suppressed airway inflammation [24]. So, curcumin as a complementary drug in the nasal drop form

Chauhan et al. [25] reported that in murines with chronic asthma, curcumin

In a clinical trial, curcumin supplementation (1000 mg twice a day) in atopic asthmatic patients has no significant effect on FEV1, serum immunoglobulin E, dose of bronchodilator consumption, and asthma control in comparison to placebo [26]. Some anti-inflammatory mechanisms of curcumin include regulation of nuclear

factor kB (NF-kB) (as a transcription factor), cytokines (TNF-α and IL-6), and

**5. Macro- and micronutrients and other nutritional factors and asthma**

It is suggested that antioxidant supplementation can modulate the effects of airway injury in asthmatic patients who are exposed to air pollutants such as ozone. A clinical trial in Mexico City showed that supplementation of vitamins C and E in children with moderate-to-severe asthma reduced the loss of airway function [30]. Studies have also associated selenium deficiency with asthma [31]. A reverse relationship was seen between wheezing symptoms and insufficient vitamin E intake, but the association between asthma and vitamin E was not seen. Thus more studies must be done to understand the mechanism of vitamin E in the oxidation and inflammation of asthmatic patients [32, 33]. Nuts contain selenium and vitamin

It is reported that there is an association between asthma and low serum levels of carotenoids. Supplementation of omega-3 polyunsaturated fatty acids of fish oil in asthmatic children decreased the wheezing, but into later childhood this beneficial effect did not continue. It is reported that supplementation of zinc and vitamin C

Conflicting results on the benefits of vitamin D supplementation have been reported. In one study low serum levels (less than 30 ng/dL) of vitamin D were related to an increase in exacerbation of asthma [35]. In another study, high doses of vitamin D supplementation were not associated with any protective effect [36]. Children with a higher than desirable body mass index (BMI) have a significant

increase in the risk of development of asthma. In obese children with asthma, weight loss diets showed improvements in the lung function, control of asthma, and quality of life [37]. The effectiveness of inhaled corticosteroid drugs is low in

The nutritionists should train the overweight and obese patients about the role of weight management in asthma control, discuss about suitable energy intake and activity, and review the known food allergies. Also the nutritionist should provide

oxidative stress has a protective effect in children with asthma [29].

E and thus are a good choice for asthmatic patients [34].

also improves the lung function and asthma symptoms [29].

overweight and obese asthmatic patients [38].

Oxidative stress has an important role in the progress of asthma. There are some potent evidences that the oxidant-to-antioxidant ratio reduces in asthmatic patients. Oxygen and nitrogen active species have primary effect on the airway inflammation and are indicators of asthma severity [28]. So, supplementation of antioxidants in asthma has some beneficial effects on the progression and severity of disease. It seems that a diet rich in monounsaturated fats and antioxidants that counteract the

(without any side effects) reduced airway inflammation and remodeling. It decreased IgE, TNF-α, and Th2 responses and increased Th1 route (as a protective *Nutritional Recommendations in Asthmatic Patients DOI: http://dx.doi.org/10.5772/intechopen.86259*

*Asthma - Biological Evidences*

saffron supplementation [9].

**3. Magnesium and asthma**

ment for asthma attack [19].

control in comparison to control group [20].

optimal dosage for most benefits [21].

**4. Curcumin and asthma**

frequency of the shortness of breath during day- and nighttime, use of salbutamol spray, waking up due to asthma symptoms, and activity limitation) improved after

Insufficient magnesium (Mg) intake can influence the management of asthma [12, 13]. Some drugs used in the treatment of asthma reduce the body's magnesium storage [14]. For example, β2-receptor agonist drugs can increase urinary excretion

Magnesium has muscle relaxant effects and bronchodilator effects [16] because of physiologic calcium antagonist effects [17] or adenylyl cyclase activation action [18]. Results of a clinical trial on 112 patients with mild to moderate asthma suggested that 340 mg MgSO4 supplementation for 2 months had bronchodilation effects and improved the lung function and so can be used as an emergency treat-

Alexandra et al. [20] surveyed the effect of magnesium in patients with mild to moderate asthma. They showed that 340 mg Mg supplementation for 6.5 months significantly increased the concentration of methacholine required to cause 20% drop in the forced expiratory volume in 1 minute (FEV1) and improved the peak expiratory flow rate (PEFR). Mg also improved the quality of life and asthma

For children with moderate-to-severe asthma, magnesium seems to be beneficial. It is a safe drug to prescribe but has minor side effects reported, for example, pain and numbness at the infusion site, hypotension, epigastric or facial warmth, flushing, dry mouth, and malaise. Due to the anti-inflammatory and bronchodilating effects, magnesium can be considered as an adjuvant therapy in pediatric patients who do not respond to conventional treatment in severe manifestations of asthma. Future studies should investigate the best route of administration and the

Because of the difficulties in measurement and also interpretation of extracellular vs. intracellular forms of magnesium, the relationship between asthma and magnesium deficiency is unclear [15]. Some studies reported that low dietary magnesium intake (which is the major determinant in homeostasis of magnesium) may be involved in the etiology of chronic obstructive airway disease and asthma [15]. Britton et al. reported that 100 mg/d higher dietary magnesium intake was independently associated with higher FEV1 and lower bronchial hyperreactivity [22].

Curcumin is the yellow pigment of turmeric (*Curcuma longa*) (a spice) which has anti-inflammatory [23] and anti-allergic [24] and antiasthmatic [24] effects.

of magnesium and thus lead to magnesium deficiency [15].

Some animal studies also investigated the effects of saffron on asthma. Active constituents of saffron (safranal and crocin) have antioxidant and antiinflammatory effects and so have beneficial effects on asthma. This is reported that saffron supplementation in animals with allergic asthma decreased eosinophils, basophils, and total white blood cells, and some of these effects were found to be equal to dexamethasone [10]. Saffron supplementation in guinea pig with allergic asthma decreased the serum level of endothelin1 (as an inflammatory index) [11]. Boskabady et al. reported that saffron had a potent relaxant effect on tracheal chains of guinea pigs which was comparable to or even higher than that of theophylline [7].

**124**

In a murine model of chronic asthma, it is reported that curcumin similar to dexamethasone improved histological changes of chronic asthma [23]. Subhashini et al. reported that curcumin via intranasal rout in asthmatic mice suppressed airway inflammation [24]. So, curcumin as a complementary drug in the nasal drop form (without systemic side effects) for local use can be produced.

Chauhan et al. [25] reported that in murines with chronic asthma, curcumin (without any side effects) reduced airway inflammation and remodeling. It decreased IgE, TNF-α, and Th2 responses and increased Th1 route (as a protective response) [25].

In a clinical trial, curcumin supplementation (1000 mg twice a day) in atopic asthmatic patients has no significant effect on FEV1, serum immunoglobulin E, dose of bronchodilator consumption, and asthma control in comparison to placebo [26].

Some anti-inflammatory mechanisms of curcumin include regulation of nuclear factor kB (NF-kB) (as a transcription factor), cytokines (TNF-α and IL-6), and adenosine molecules (ICAM-1) [27].

#### **5. Macro- and micronutrients and other nutritional factors and asthma**

Oxidative stress has an important role in the progress of asthma. There are some potent evidences that the oxidant-to-antioxidant ratio reduces in asthmatic patients. Oxygen and nitrogen active species have primary effect on the airway inflammation and are indicators of asthma severity [28]. So, supplementation of antioxidants in asthma has some beneficial effects on the progression and severity of disease. It seems that a diet rich in monounsaturated fats and antioxidants that counteract the oxidative stress has a protective effect in children with asthma [29].

It is suggested that antioxidant supplementation can modulate the effects of airway injury in asthmatic patients who are exposed to air pollutants such as ozone. A clinical trial in Mexico City showed that supplementation of vitamins C and E in children with moderate-to-severe asthma reduced the loss of airway function [30].

Studies have also associated selenium deficiency with asthma [31]. A reverse relationship was seen between wheezing symptoms and insufficient vitamin E intake, but the association between asthma and vitamin E was not seen. Thus more studies must be done to understand the mechanism of vitamin E in the oxidation and inflammation of asthmatic patients [32, 33]. Nuts contain selenium and vitamin E and thus are a good choice for asthmatic patients [34].

It is reported that there is an association between asthma and low serum levels of carotenoids. Supplementation of omega-3 polyunsaturated fatty acids of fish oil in asthmatic children decreased the wheezing, but into later childhood this beneficial effect did not continue. It is reported that supplementation of zinc and vitamin C also improves the lung function and asthma symptoms [29].

Conflicting results on the benefits of vitamin D supplementation have been reported. In one study low serum levels (less than 30 ng/dL) of vitamin D were related to an increase in exacerbation of asthma [35]. In another study, high doses of vitamin D supplementation were not associated with any protective effect [36].

Children with a higher than desirable body mass index (BMI) have a significant increase in the risk of development of asthma. In obese children with asthma, weight loss diets showed improvements in the lung function, control of asthma, and quality of life [37]. The effectiveness of inhaled corticosteroid drugs is low in overweight and obese asthmatic patients [38].

The nutritionists should train the overweight and obese patients about the role of weight management in asthma control, discuss about suitable energy intake and activity, and review the known food allergies. Also the nutritionist should provide

high-quality protein, vitamins, and minerals in the form of small meals to reduce the risk of infection [34].

Exposure to food allergens, especially an immunoglobulin E-mediated reaction to a food protein, can cause bronchoconstriction. Complete removal of the allergenic food protein is the only dietary advice which is currently available for food allergies. Some sulfites, such as sodium and potassium sulfides (in processed foods), have been found to be a trigger for patients with asthma [39]. Some common food allergens for children include eggs, milk, seafood, peanuts, tree nuts, fish, soy, or wheat and for adults include peanuts, tree nuts, shellfish, and fish [34].

Percentage of energy intake from fat in asthmatic patients must be high, because the respiratory quotient (RQ ) of fats is lower than carbohydrate and protein [33].

Prostanoid production may be affected by dietary fat composition. Observational studies (from the 1960s and 1970s) reported that in population whose diets were rich in fish oil, the incidence of asthma was low [40]. Some studies demonstrated the fish oil anti-inflammatory effects (reduced leukocyte chemotaxis and leukotriene production) in asthmatic patients [41], but results of a systematic review showed that there is no consistent effect of fish oil on lung function, asthma medication use, bronchial hyperreactivity, and asthma symptoms [40]. A review covering 26 studies (randomized, placebo-controlled, and others) reported that the effect of w-3 fatty acid supplements could not be conclusive [42].

When the immune system of infants is immature, breastfeeding protects the immunological system and in early childhood provides a modest protective effect from wheeze [43, 44]. If the duration of breastfeeding could be longer, the protective effects seem to be more. Supplementation the diet of lactating women with fish oil could be related with alteration in the immune response of neonates to allergens, and insufficient intake of zinc and vitamins D and E during pregnancy is related to increased wheezing and asthma in children up to age of 5 years old [45]. Maternal intake of vitamins E and D can modify the development of the lung of neonates [45]. It is reported that insufficient serum level of vitamin D is an index for severity of asthma in childhood [46].

Theobromine in cocoa leads to increase blood flow to the brain and so reduces coughing and is a good food choice for asthmatic patients. It is better that these patients consume less sodium in their diet. In 5–20% of asthmatics patients who are sensitive to aspirin, salicylate sensitivity is common. Some vegetables and many fruits contain salicylates. Quercetin in pears, apples, onions, berries, and oranges should be encouraged in an amount of five or more servings per week [34].

#### **6. Botanicals, herbs, and supplements**


**127**

*Nutritional Recommendations in Asthmatic Patients DOI: http://dx.doi.org/10.5772/intechopen.86259*

**7. Probiotics and asthma**

Staphylococcus aureu [56, 57].

prevention of allergy in:

effects of these should be evaluated [34].

• Licorice, stinging nettle, gingko, and anise have not shown efficacy, and side

• *Boswellia serrata* extract has anti-inflammatory effects due to the triterpene compounds [50]. The mechanism of anti-inflammatory properties of boswellic acids is inhibition of proteases (cathepsin G), lipoxygenases (enzyme which is

It is reported that the intestinal flora can affect the mucosal immunity and so may be an effective factor for allergic disease [52]. Exposure to microbial flora in early childhood can lead to a change in the Th1/Th2 ratio toward the Th1 response. Some studies suggested that the content of intestinal flora can be different in patients with allergic disease and also in individuals who live in industrialized countries (where the prevalence of allergic disease is higher) [53–55]; patients with allergic disease have less Bifidobacteria and Lactobacilli and more Clostridia and

The World Allergy Organization in 2015 recommended the use of probiotics for

Results of a meta-analysis demonstrated that there is no evidence for protective effect of perinatal probiotic administration and childhood wheeze or asthma. So there is insufficient evidence for supplementation of probiotics for the prevention of allergic disorders and asthma, and more studies are required to explore the

Generally, probiotic consumption for prevention of asthma and allergy is based on the little evidences, and more studies are needed for exact evaluation of the role of microflora in allergic disease and for determination of the best type of probiotic

a.Pregnant women who have children with high risk of allergy

b.Mothers lactating infants with high risk of developing allergy

c.Infants who have risk of progressing allergies [58]

potential relationship between probiotic and asthma [59].

for supplementation in allergic disease [60].

responsible for the synthesis of leukotrienes), and NF-kB [51].


### **7. Probiotics and asthma**

*Asthma - Biological Evidences*

the risk of infection [34].

conclusive [42].

of asthma in childhood [46].

**6. Botanicals, herbs, and supplements**

the seaweed is used [48].

high-quality protein, vitamins, and minerals in the form of small meals to reduce

Exposure to food allergens, especially an immunoglobulin E-mediated reaction to a food protein, can cause bronchoconstriction. Complete removal of the allergenic food protein is the only dietary advice which is currently available for food allergies. Some sulfites, such as sodium and potassium sulfides (in processed foods), have been found to be a trigger for patients with asthma [39]. Some common food allergens for children include eggs, milk, seafood, peanuts, tree nuts, fish, soy, or wheat and for adults include peanuts, tree nuts, shellfish, and fish [34].

Percentage of energy intake from fat in asthmatic patients must be high, because the respiratory quotient (RQ ) of fats is lower than carbohydrate and protein [33]. Prostanoid production may be affected by dietary fat composition. Observational studies (from the 1960s and 1970s) reported that in population whose diets were rich in fish oil, the incidence of asthma was low [40]. Some studies demonstrated the fish oil anti-inflammatory effects (reduced leukocyte chemotaxis and leukotriene production) in asthmatic patients [41], but results of a systematic review showed that there is no consistent effect of fish oil on lung function, asthma medication use, bronchial hyperreactivity, and asthma symptoms [40]. A review covering 26 studies (randomized, placebo-controlled, and others) reported that the effect of w-3 fatty acid supplements could not be

When the immune system of infants is immature, breastfeeding protects the immunological system and in early childhood provides a modest protective effect from wheeze [43, 44]. If the duration of breastfeeding could be longer, the protective effects seem to be more. Supplementation the diet of lactating women with fish oil could be related with alteration in the immune response of neonates to allergens, and insufficient intake of zinc and vitamins D and E during pregnancy is related to increased wheezing and asthma in children up to age of 5 years old [45]. Maternal intake of vitamins E and D can modify the development of the lung of neonates [45]. It is reported that insufficient serum level of vitamin D is an index for severity

Theobromine in cocoa leads to increase blood flow to the brain and so reduces coughing and is a good food choice for asthmatic patients. It is better that these patients consume less sodium in their diet. In 5–20% of asthmatics patients who are sensitive to aspirin, salicylate sensitivity is common. Some vegetables and many fruits contain salicylates. Quercetin in pears, apples, onions, berries, and oranges should be encouraged in an amount of five or more servings per week [34].

• ASHMI, a combination of three herbal extracts (*Ganoderma lucidum* (fungal), *Sophora flavescens*, and *Glycyrrhiza uralensis* (Fabaceae species)), is used in China for antiasthma intervention [47], and in oriental cultures and Vietnam,

• Gamma linolenic acid (GLA; borage oil) as a dietary fatty acid without any side

• *Ephedra* has bronchodilator effects, but it has some side effects such as significantly increasing blood pressure and heart rate, arrhythmias, and problems with blood glucose. This has been removed from the market by the Food and

effects can modulate the endogenous inflammatory mediators [49].

Drug Administration (FDA), but some forms are available.

**126**

It is reported that the intestinal flora can affect the mucosal immunity and so may be an effective factor for allergic disease [52]. Exposure to microbial flora in early childhood can lead to a change in the Th1/Th2 ratio toward the Th1 response.

Some studies suggested that the content of intestinal flora can be different in patients with allergic disease and also in individuals who live in industrialized countries (where the prevalence of allergic disease is higher) [53–55]; patients with allergic disease have less Bifidobacteria and Lactobacilli and more Clostridia and Staphylococcus aureu [56, 57].

The World Allergy Organization in 2015 recommended the use of probiotics for prevention of allergy in:


Results of a meta-analysis demonstrated that there is no evidence for protective effect of perinatal probiotic administration and childhood wheeze or asthma. So there is insufficient evidence for supplementation of probiotics for the prevention of allergic disorders and asthma, and more studies are required to explore the potential relationship between probiotic and asthma [59].

Generally, probiotic consumption for prevention of asthma and allergy is based on the little evidences, and more studies are needed for exact evaluation of the role of microflora in allergic disease and for determination of the best type of probiotic for supplementation in allergic disease [60].

*Asthma - Biological Evidences*

### **Author details**

Marzie Zilaee1,2 and Seyed Ahmad Hosseini1,2\*

1 Nutrition and Metabolic Diseases Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

2 Nutrition Department, Faculty of Paramedicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

\*Address all correspondence to: seyedahmadhosseini@yahoo.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**129**

*Nutritional Recommendations in Asthmatic Patients DOI: http://dx.doi.org/10.5772/intechopen.86259*

> [8] Hosseini SA, Zilaee M, Shoushtari MH. An evaluation of the effect of saffron supplementation on the antibody titer to heat-shock protein (HSP) 70, hsCRP and spirometry test in patients with mild and moderate persistent allergic asthma: A triple-blind, randomized placebo-controlled trial. Respiratory

> [9] Zilaee M, Hosseini SA, Jafarirad S, Abolnezhadian F, Cheraghian B, Namjoyan F, et al. An evaluation of the effects of saffron supplementation on the asthma clinical symptoms and asthma severity in patients with mild and moderate persistent allergic asthma: a double-blind, randomized placebocontrolled trial. Respiratory Research.

[10] Boskabady MH, Farkhondeh T. Antiinflammatory, antioxidant, and immunomodulatory effects of *Crocus sativus* L. and its main constituents. Phytotherapy Research.

[11] Gholamnezhad Z, Koushyar H, Byrami G, Boskabady MH. The extract of *Crocus sativus* and its constituent safranal, affect serum levels of endothelin and total protein in sensitized guinea pigs. Iranian Journal of Basic Medical Sciences. 2013;**16**(9):1022

[12] Fogarty A, Lewis S, Scrivener S, Antoniak M, Pacey S, Pringle M, et al. Oral magnesium and vitamin C supplements in asthma: A parallel group randomized placebo-controlled trial. Clinical and Experimental Allergy.

[13] Fawcett W, Haxby E, Male D. Magnesium: Physiology and pharmacology. British Journal of Anaesthesia. 1999;**83**(2):302-320

[14] Alamoudi OS. Electrolyte

disturbances in patients with chronic,

Medicine. 2018;**145**:28-34

2019;**20**(1):39

2016;**30**(7):1072-1094

2003;**33**(10):1355-1359

[1] Bateman ED, Hurd S, Barnes P, Bousquet J, Drazen J, FitzGerald M, et al. Global strategy for asthma management and prevention: GINA executive summary. The European Respiratory Journal. 2008;**31**(1):143-178

[2] Pelaia G, Vatrella A, Busceti MT, Gallelli L, Calabrese C, Terracciano R, et al. Cellular mechanisms underlying eosinophilic and neutrophilic airway inflammation in asthma. Mediators of

[3] Pachter LM, Weller SC, Baer RD, Garcia de Alba Garcia JE, Trotter RT, Glazer M, et al. Variation in asthma beliefs and practices among mainland Puerto Ricans, Mexican-Americans, Mexicans, and Guatemalans. The Journal of Asthma. 2002;**39**(2):119-134

[4] Rabe KF, Adachi M, Lai CK, Soriano JB, Vermeire PA, Weiss KB, et al. Worldwide severity and control of asthma in children and adults: the global asthma insights and reality surveys. The Journal of Allergy and Clinical Immunology. 2004;**114**(1):40-47

[5] Escribano J, Alonso G-L, Coca-Prados M, Fernández J-A. Crocin, safranal and picrocrocin from saffron (*Crocus sativus* L.) inhibit the growth of human cancer cells in vitro. Cancer

Letters. 1996;**100**(1-2):23-30

2012;**19**(10):904-911

2006;**58**(10):1385-1390

[6] Boskabady M, Tabatabaee A, Byrami G. The effect of the extract of *Crocus sativus* and its constituent safranal, on lung pathology and lung inflammation of ovalbumin sensitized guinea-pigs. Phytomedicine.

[7] Boskabady MA, Aslani M. Relaxant effect of *Crocus sativus* (saffron) on guinea-pig tracheal chains and its possible mechanisms. The Journal of Pharmacy and Pharmacology.

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*Nutritional Recommendations in Asthmatic Patients DOI: http://dx.doi.org/10.5772/intechopen.86259*

#### **References**

*Asthma - Biological Evidences*

**128**

**Author details**

provided the original work is properly cited.

Marzie Zilaee1,2 and Seyed Ahmad Hosseini1,2\*

of Medical Sciences, Ahvaz, Iran

Medical Sciences, Ahvaz, Iran

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: seyedahmadhosseini@yahoo.com

1 Nutrition and Metabolic Diseases Research Center, Ahvaz Jundishapur University

2 Nutrition Department, Faculty of Paramedicine, Ahvaz Jundishapur University of

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[3] Pachter LM, Weller SC, Baer RD, Garcia de Alba Garcia JE, Trotter RT, Glazer M, et al. Variation in asthma beliefs and practices among mainland Puerto Ricans, Mexican-Americans, Mexicans, and Guatemalans. The Journal of Asthma. 2002;**39**(2):119-134

[4] Rabe KF, Adachi M, Lai CK, Soriano JB, Vermeire PA, Weiss KB, et al. Worldwide severity and control of asthma in children and adults: the global asthma insights and reality surveys. The Journal of Allergy and Clinical Immunology. 2004;**114**(1):40-47

[5] Escribano J, Alonso G-L, Coca-Prados M, Fernández J-A. Crocin, safranal and picrocrocin from saffron (*Crocus sativus* L.) inhibit the growth of human cancer cells in vitro. Cancer Letters. 1996;**100**(1-2):23-30

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[9] Zilaee M, Hosseini SA, Jafarirad S, Abolnezhadian F, Cheraghian B, Namjoyan F, et al. An evaluation of the effects of saffron supplementation on the asthma clinical symptoms and asthma severity in patients with mild and moderate persistent allergic asthma: a double-blind, randomized placebocontrolled trial. Respiratory Research. 2019;**20**(1):39

[10] Boskabady MH, Farkhondeh T. Antiinflammatory, antioxidant, and immunomodulatory effects of *Crocus sativus* L. and its main constituents. Phytotherapy Research. 2016;**30**(7):1072-1094

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**132**

## *Edited by Celso Pereira*

Asthma is a prevalent disease in all age groups that results from different pathogenic mechanisms, cells, and mediators engaged in innumerous clinical phenotypes and endotypes. This book exhaustively and didactically explores the biological expression of numerous cells and mediators involved in bronchial inflammation. The information provided aims at identifying the diversity and complexity of the interrelationships between the different players, drawing attention to critical mechanisms in asthma. It also highlights the requirement of new tools to identify strong biomarkers absolutely critical for managing asthma.

Published in London, UK © 2019 IntechOpen © vitanovski / iStock

Asthma - Biological Evidences

Asthma

Biological Evidences

*Edited by Celso Pereira*