**2. Therapeutic potential of polyunsaturated fatty acids in inflammatory diseases**

The intervention of cellular functions by bioactive lipids from the diet offers an attractive tool to modify or to prevent many pathophysiological processes of inflammatory diseases including bronchitis, conjunctivitis, COPD, hepatitis, IBD, psoriasis, RA and rhinitis. Dietary n-3 PUFA act via several mechanisms, which they primarily conduct by substituting phospholipid pools containing arachidonic acid (AA) with EPA and DHA. The enhanced physiological levels of EPA and DHA, suppress cyclooxygenase and lipoxygenase and lower synthesis of the inflammatory eicosanoids, thromboxane (TXA2) and leukotriene B4 (LTB4) from 20:4 in platelets and macrophages. Anti-inflammatory effects of n-3 PUFA can also be apart from eicosanoid pathway by affecting the expression pattern of cell surface adhesion molecules which participate in interactions between leukocytes and endothelial cells, thereby facilitating the infiltration of leukocytes into sites of inflammation [17]. Understanding the influence of dietary n-3 PUFA on the modulation of inflammatory complication is hence crucial if they need to be exploited as an adjunct therapy in treating many of these diseases.

**199**

*Modulatory Potentials of n-3 Polyunsaturated Fatty Acids in Inflammatory Diseases*

Chronic bronchitis is associated with high morbidity and mortality worldwide and has a diverse range of associated factors, including occupational, economic, and educational status [18]. The inflammation observed in chronic bronchitis is marked by airway eosinophilia, activated T-lymphocytes, rise in the amount of TNF-α-positive cells and neutrophils in the bronchial mucosa [1]. The advanced stage of the disease also shows similar signs, accompanied by hypertrophy of goblet cells, purulent bronchitis, and dilatation (diffuse or localized). The rise in eosinophils in bronchitis (caused by allergens, chemicals or drugs, etc.) is characterized by asthma and chronic cough and currently treated with anti-inflammatory drugs like inhaled corticosteroids. Although a shortcoming of this treatment is that it is most helpful only in those respiratory illnesses where eosinophils are elevated, and not in

Moreover, acute bronchitis which is generally treated with antibiotics has several reported undesired side-effects associated with their use- nausea, vomiting or diarrhea, headaches, skin rash, and vaginitis, apart from population-level harm from antibiotic resistance [20]. Concerning the chronic form of the disease as seen in smokers, etc., rampant use of prophylactic antibiotics does not seem to have a considerable effect [21]. In such a scenario, having an effective treatment option for bronchitis, that eliminates any adverse effects and can always be effective despite widespread and prolonged use, is welcome. Some essential nutrients have proven benefits in this regard. A randomized self-controlled study was done using n-3 PUFA, vitamin C, and Zn supplementation in asthmatic children showed that nutritional intervention could lower the severity of inflammatory diseases. This was confirmed by testing the pulmonary function and inflammatory markers present in the sputum, where a remarkable improvement was seen in results of those on a diet supplemented with n-3 PUFA, vitamin C, and Zn [22]. When n-3 PUFA are considered individually, it was established from a study that daily ingestion of 3 g of n-3 PUFA for a month by atopic patients, showed reduced bronchial hyperactivity and improved responsiveness towards the ultrasonically nebulized distilled water [23]. To validate the connection between dietary fats and bronchitis, the pathophysiology of this condition needs to be addressed. The inflammation is related to altered level in membrane fatty acid composition of erythrocytes and an imbalance in the precursor of a pro to anti-inflammatory eicosanoid ratio [24]. A comparative assessment of the impact of n-3 and n-6 PUFA on respiratory function was done, by supplementation of the diet of asthmatic patients with perilla oil (n-3) or corn oil (n-6). The study revealed that, leucocytes from the corn oil supplemented group generated a greater amount of LTB4 and LTC4 than the perilla oil supplemented group, and the anti-inflammatory benefits in the latter were also reflected through their improved respiratory function parameters of peak expiratory flow (PEF) in the mornings, forced expiratory volume (FEV) and forced vital capacity (FVC) [25]. On deeper investigation of the mechanisms of n-3 fatty acid-mediated actions, it was found that mice exposed to cigarette smoke to mimic lung injury caused by smoke and pulmonary toxicants, on treatment with the resolvin RvD1, exhibited potent anti-inflammatory and resolution of inflammation in the lungs when supplied after the final smoke exposure. The same study also made use of blood monocytes, small airway epithelial cells, and primary human lung fibroblasts, which were treated with cytokine IL-1β or an extract of cigarette smoke along with RvD1 in in vitro. RvD1 inhibits the release of pro-inflammatory mediators by primary human cells in a dose-dependent manner, attenuates neutrophilic lung inflammation and release of pro-inflammatory cytokines, along with the upregulation of the anti-inflammatory cytokine IL-10 [26]. Lipoxins and resolvins serve as

*DOI: http://dx.doi.org/10.5772/intechopen.88394*

other types of bronchitis [19].

**2.1 Bronchitis**

*Modulatory Potentials of n-3 Polyunsaturated Fatty Acids in Inflammatory Diseases DOI: http://dx.doi.org/10.5772/intechopen.88394*

#### **2.1 Bronchitis**

*Apolipoproteins, Triglycerides and Cholesterol*

derived from EPA and DHA [12].

tis, rhinitis, hepatitis, conjunctivitis, etc.

**diseases**

many common conditions and diseases. Bronchitis, conjunctivitis, chronic obstructive pulmonary disease (COPD), hepatitis, irritable bowel disease (IBD), psoriasis, rheumatoid arthritis (RA), and rhinitis are known to have a critical link with eicosanoids productions that eventually leads inflammation [1–8]. Even though effective pharmaceutical interventions are available to treat as well as manage these complications, adjunct therapies involving dietary management is mostly recommended [9, 10]. Nutraceutical intervention in the management of these inflammatory complications is gaining importance due to convenience, safety, and the low-cost attached in it Investigations have pointed out that n-3 polyunsaturated fatty acids (n-3 PUFA) positively alter inflammatory pathways. Their actions aid in reduced levels of eicosanoids (20 carbon lipid-derived molecules) and other inflammatory biomarkers, such as interleukin-1b (IL-1b), IL-6, and tumor necrosis factor-α (TNF- α) in plasma and urine, by serving as secondary messengers or modifying the transcriptional regulation of particular genes involved in inflammation [11]. In contrast, a high intake of dietary n-6 polyunsaturated fatty acids (n-6 PUFA) is associated with increased synthesis of proinflammatory eicosanoids synthesized from arachidonic acid metabolism, which include leukotrienes, lipoxins, thromboxanes, prostaglandins, and hydroxy

fatty acids, and suppresses the synthesis of anti-inflammatory eicosanoids

The modern (mostly western) diet is a poor source of n-3 PUFA, with an abysmal n-3:n-6 fatty acid ratio of 1:15–20, which is in sharp contrast to that found in the diet followed by our ancestors-1:1 [13, 14]. Both n-3 and n-6 PUFA consumed in the diet compete for the same enzymes and also regulate many transcription factors which impact cellular and tissue metabolism, and, a skewed ratio of n-3:n-6 PUFA result in the altered equilibrium in composition and fluidity of cell membrane as well as the functionality of organs [15, 16]. Evidence is accumulating that these physiological changes have led to interactions between constituents of the diet and genes, culminating in the rise of local and systemic inflammation. It is coupled with the disruption of immune/defense mechanism leading to rheumatoid arthritis, chronic obstructive pulmonary disease, irritable bowel diseases, psoriasis, bronchi-

**2. Therapeutic potential of polyunsaturated fatty acids in inflammatory** 

The intervention of cellular functions by bioactive lipids from the diet offers an attractive tool to modify or to prevent many pathophysiological processes of inflammatory diseases including bronchitis, conjunctivitis, COPD, hepatitis, IBD, psoriasis, RA and rhinitis. Dietary n-3 PUFA act via several mechanisms, which they primarily conduct by substituting phospholipid pools containing arachidonic acid (AA) with EPA and DHA. The enhanced physiological levels of EPA and DHA, suppress cyclooxygenase and lipoxygenase and lower synthesis of the inflammatory eicosanoids, thromboxane (TXA2) and leukotriene B4 (LTB4) from 20:4 in platelets and macrophages. Anti-inflammatory effects of n-3 PUFA can also be apart from eicosanoid pathway by affecting the expression pattern of cell surface adhesion molecules which participate in interactions between leukocytes and endothelial cells, thereby facilitating the infiltration of leukocytes into sites of inflammation [17]. Understanding the influence of dietary n-3 PUFA on the modulation of inflammatory complication is hence crucial if they need to be exploited as an adjunct therapy in treating many of

**198**

these diseases.

Chronic bronchitis is associated with high morbidity and mortality worldwide and has a diverse range of associated factors, including occupational, economic, and educational status [18]. The inflammation observed in chronic bronchitis is marked by airway eosinophilia, activated T-lymphocytes, rise in the amount of TNF-α-positive cells and neutrophils in the bronchial mucosa [1]. The advanced stage of the disease also shows similar signs, accompanied by hypertrophy of goblet cells, purulent bronchitis, and dilatation (diffuse or localized). The rise in eosinophils in bronchitis (caused by allergens, chemicals or drugs, etc.) is characterized by asthma and chronic cough and currently treated with anti-inflammatory drugs like inhaled corticosteroids. Although a shortcoming of this treatment is that it is most helpful only in those respiratory illnesses where eosinophils are elevated, and not in other types of bronchitis [19].

Moreover, acute bronchitis which is generally treated with antibiotics has several reported undesired side-effects associated with their use- nausea, vomiting or diarrhea, headaches, skin rash, and vaginitis, apart from population-level harm from antibiotic resistance [20]. Concerning the chronic form of the disease as seen in smokers, etc., rampant use of prophylactic antibiotics does not seem to have a considerable effect [21]. In such a scenario, having an effective treatment option for bronchitis, that eliminates any adverse effects and can always be effective despite widespread and prolonged use, is welcome. Some essential nutrients have proven benefits in this regard. A randomized self-controlled study was done using n-3 PUFA, vitamin C, and Zn supplementation in asthmatic children showed that nutritional intervention could lower the severity of inflammatory diseases. This was confirmed by testing the pulmonary function and inflammatory markers present in the sputum, where a remarkable improvement was seen in results of those on a diet supplemented with n-3 PUFA, vitamin C, and Zn [22]. When n-3 PUFA are considered individually, it was established from a study that daily ingestion of 3 g of n-3 PUFA for a month by atopic patients, showed reduced bronchial hyperactivity and improved responsiveness towards the ultrasonically nebulized distilled water [23]. To validate the connection between dietary fats and bronchitis, the pathophysiology of this condition needs to be addressed. The inflammation is related to altered level in membrane fatty acid composition of erythrocytes and an imbalance in the precursor of a pro to anti-inflammatory eicosanoid ratio [24]. A comparative assessment of the impact of n-3 and n-6 PUFA on respiratory function was done, by supplementation of the diet of asthmatic patients with perilla oil (n-3) or corn oil (n-6). The study revealed that, leucocytes from the corn oil supplemented group generated a greater amount of LTB4 and LTC4 than the perilla oil supplemented group, and the anti-inflammatory benefits in the latter were also reflected through their improved respiratory function parameters of peak expiratory flow (PEF) in the mornings, forced expiratory volume (FEV) and forced vital capacity (FVC) [25]. On deeper investigation of the mechanisms of n-3 fatty acid-mediated actions, it was found that mice exposed to cigarette smoke to mimic lung injury caused by smoke and pulmonary toxicants, on treatment with the resolvin RvD1, exhibited potent anti-inflammatory and resolution of inflammation in the lungs when supplied after the final smoke exposure. The same study also made use of blood monocytes, small airway epithelial cells, and primary human lung fibroblasts, which were treated with cytokine IL-1β or an extract of cigarette smoke along with RvD1 in in vitro. RvD1 inhibits the release of pro-inflammatory mediators by primary human cells in a dose-dependent manner, attenuates neutrophilic lung inflammation and release of pro-inflammatory cytokines, along with the upregulation of the anti-inflammatory cytokine IL-10 [26]. Lipoxins and resolvins serve as

natural agonists in resolution of pulmonary inflammation. Briefly, lipoxins are arachidonic acid derivatives generated via multistep enzymatic reactions mediated by lipoxygenases to produce trihydroxy-tetraene-containing eicosanoids. On the other hand, resolvins are endogenous autacoids, derived from EPA and DHA as E-series (RvE) and D-series (RvD) resolvins, respectively. The intracellular signaling pathways resolvins adopt to bring about their actions, involve NF-Ƙβ and kinases. Resolvins can control the NF-Ƙβ signaling pathway, for e.g. RvE1 is an agonist in the signal transduction mechanism to inhibit TNF-α induced activation of NF-Ƙβ in a concentration-dependent manner. It can also suppress pro-inflammatory LTB4-mediated BLT1 signaling by lowering activation of NF-Ƙβ. The mechanism of NF-Ƙβ repression is relevant for resolution of inflammation in pulmonary diseases, as it induces granulocyte apoptosis. With respect to kinases, the pro-inflammatory reactions involved in chronic inflammatory lung diseases, are mainly regulated by phosphatidylinositol 3-kinase (PI3-K) and the MAPK family member extracellular signal regulated kinase (ERK). *In vitro*, RvE1 increases phosphorylation of kinases, which has a protective effect of controlling apoptotic programs in cells. RvE1 also mitigates attenuates inflammatory pain by indirectly inhibiting the ERK signaling pathway [27].

### **2.2 Irritable bowel disease (IBD)**

Inflammatory/irritable bowel disease is a broader term used to describe the disorders that involve the inflammation of the gastrointestinal tract. Crohn's disease (CD) and ulcerative colitis (UC) are both related to IBD and result from interactions between gene, environment, and gut microbiota. Crohn's disease is characterized by chronic inflammation which relapses and remits, ultimately affecting the entire gastrointestinal tract, whereas ulcerative colitis inflammation is mostly confined to the colon-rectum junction. The pathogenesis of the disease mostly involves predisposing genetic, environmental, and immunologic factors [28, 29]. More than 200 gene regions have been identified that confer risk for Crohn's disease or ulcerative colitis in the European population [30]. The currently available drugs to treat IBD work by targeting receptors of T-cell activation (e.g., visilizumab, abatacept), prebiotics, probiotics targeting the intestinal flora antibiotics, adhesion molecule blockers (e.g., MLN-02, alicaforsen, natalizumab), cytokines (e.g., interleukin 10) [31]. Despite the advent of new therapeutic agents in recent years, current treatments are modestly successful with notable side effects [32]. Also, epidemiologic studies reported that increased animal fat/n-6 PUFA intake with the prevalence of both CD [33, 34] and UC [35]. Hence it is necessary to understand the role of n-3 PUFA and its metabolites in disease prevention of IBD. The potential role of n-3 PUFA in inflammation has garnered interest in fatty acid profiling in various metabolic and inflammatory diseases. Like other diseases, the inflammatory state in IBD is a result of the eicosanoid pathway with elevated levels of LTB4, LTC4, and thromboxanes (A1 and A2) in the inflamed intestinal mucosa [4]. Many clinical studies conducted with fish oil or EPA supplementation reported the inhibitory effect on inflammatory molecules production [36–38]. Animal model studies are in line with results of clinical studies concluded that n-3 PUFA ameliorated the intestinal inflammation [39–41]. The immunomodulatory and anti-inflammatory effects of n-3 PUFA are reported either directly [42, 43] or indirectly by the generation of PUFA metabolites containing hydroxyl groups i.e. resolvins, hydroxy fatty acids etc. [44]. Although there is a reasonable amount of data available on anti-inflammatory effect of n-3 PUFA, limited reports available in their use on IBD patients; hence deeper research in the aspects of dose, and mechanistic understanding is needed to replace or enhance the effect of currently available drugs along with nutritional intervention.

**201**

*Modulatory Potentials of n-3 Polyunsaturated Fatty Acids in Inflammatory Diseases*

genesis and potential of RvE1 as an adjuvant in the psoriatic therapy [51].

COPD is a chronic inflammatory lung disease triggered by exposure to toxic particles and gases, especially, cigarette smoke. Some of the predominant characteristics of COPD include parenchymal destruction, poorly reversible, persistent airflow limitation, and chronic bronchitis. A COPD patient shows some visible symptoms like cough, chest tightness dyspnoea, excess sputum production, and wheezing [52]. COPD is coordinated by a complex network of inflammatory mediators, such as inflammatory enzymes, lipid mediators (eicosanoids, namely prostanoids and leukotrienes, LTs), interleukins (ILs), and adhesion molecules, which may moderate airway inflammation through chemotactic and autocrine or paracrine effects [3]. Eicosanoids are produced by cells resident in the lung and airways, such as fibroblasts, epithelial cells, myofibroblasts, and smooth muscle cells, also by inflammatory cells that have migrated from the circulation to the airways, such as macrophages, mast cells, neutrophils, platelets, eosinophils, and T-lymphocytes [53]. Activated macrophages release cytokines such as IL-8, IL-6, IL-10, TNF-α, and LTB4, which can attract and activate various inflammatory cells.

**2.4 Chronic obstructive pulmonary disease (COPD)**

Psoriasis is an inflammatory skin disease, affecting about 2% of the general population, characterized by hyperproliferation and poor differentiation of keratinocytes, increased vascularization of the skin, leukocyte infiltration and fibroblast activation [45]. It is a skin disease considered to be resulting from T-cell-mediated inflammation, wherein the inflammatory reaction is controlled by diet, lifestyle, and environmental cues such as infections and stress. Although the etiology remains unknown, accumulating evidence indicates that cytokines, mainly tumor necrosis factor α (TNF-α), IL-17 and IL-23, play essential roles in the development [6]. In the psoriatic lesions, inflammatory dermal dendritic cells (DCs) produce IL-23 that enhances the production of T cytotoxic 17 cells (Tc17) or IL-17 from T helper 17 cells (Th17) in the skin, leading to epithelial hyperplasia and inflammatory cell infiltration [46]. A documented and conclusive cure for psoriasis does not exist, some of the commonly used treatments to reduce the severity of disease and lessen the impact are phototherapy, topical and systemic therapies in moderate-tosevere psoriasis and drugs are corticosteroids, methotrexate, tar, cyclosporine, and emollients. Nevertheless, almost all the mentioned treatments are accompanied by major adverse effects [47]. Among nutritional components regulating the pathophysiology of psoriasis, PUFAs proved to be promising in the treatment of many skin diseases as safe, including psoriasis [48]. Calorie restriction or weight loss may also influence the severity of the disease. However randomized control trial study conducted by Guida et al. concluded that calorie restriction (20 kcal/kg/day) along with n-3 PUFA (2.6 g/day) enriched diet improved the clinical response of immunemodulating drugs in obese psoriatic patients [49]. Many clinical studies have demonstrated that the administration of fish oil or n-3 PUFA ethyl esters in psoriatic animal model/patients ameliorated the degree of skin inflammation [ 44–48, 50]. However, the reports on the exact mechanism are limited. A recent study conducted by Sawada et al. using metabolite produced by n-3 PUFA such as resolvinE1 (RvE1) in imiquimod (IMQ )-induced murine psoriasis mouse model concluded that RvE1 remarkably suppressed the epidermal hyperplasia and inflammatory cell infiltration in the psoriatic skin. These suppressive effects are due to the antagonistic effect of RvE1 on BLT1 production, a receptor of LTB4 and decrease in mRNA expression of cytokines (IL-17 and IL-23) indicating the novel mechanism of psoriatic patho-

*DOI: http://dx.doi.org/10.5772/intechopen.88394*

**2.3 Psoriasis**

*Modulatory Potentials of n-3 Polyunsaturated Fatty Acids in Inflammatory Diseases DOI: http://dx.doi.org/10.5772/intechopen.88394*
