**12. Asthma**

Asthma is characterized by airway inflammation and airway hyperresponsiveness (AHR). Macrophages also contribute significantly to the development of asthma [125]. The inflam‐ matory process of asthma is dominated by Th2 inflammation, but there is also involvement of both types M1 and M2 macrophages [14]. The balance between different phenotypes of macrophages changes with the severity of asthma [126]. In case of acute exacerbation of chronic asthma, AMs are found to significantly enhance the expression of AAM markers along with pro-inflammatory cytokines (IFNγ and TNFα) and cell surface proteins. Ironically, the cell surface proteins associated with antigen presentation are M1 inducers [127, 128]. Elevated serum IFNγ correlates with the severity of airway inflammation in atopic asthma, and IFNγ has been linked to mechanisms inducing AHR [129]. It was demonstrated that IL33/ST2 plays a significant role in the amplification of AAM polarization and chemokine production which contribute to innate and Ag-induced airway inflammation [130].

The ability of AMs to phagocytose apoptotic cells is known as efferocytosis. Macrophage efferocytosis is impaired in non-eosinophilic asthma to a similar degree as in COPD [131]. In mice with less severe asthma, M1 macrophage numbers were higher and correlated negatively with M2 macrophage counts. Lower numbers of M2-like macrophages were found in mice exposed to house dust mites. The balance between macrophage phenotypes changes as the severity of allergic airway inflammation increases. Influencing this imbalanced relationship could be a novel approach to treat asthma [126]. CCL18 and YKL40 (chitinase 3-like 1) levels and CHIT1 (chitinase 1) activity are enhanced in allergic airway inflammation and thus may contribute to airway remodelling in asthma [132]. M2 macrophages play a role in eosinophil and potentially other leukocyte migration patterns into asthmatic airways [133]. Dysregulation of alveolar macrophage function results in dendritic cell-mediated mechanisms of allergic airway inflammation [134]. AMs can also contribute to the genetic susceptibility to allergic asthma [39].

#### **13. Pulmonary fibrosis**

Fibrosis is the result of persistent or dysregulated wound healing, usually in response to some type of repeated injury. It is often associated with chronic inflammation, alveolar epithelial hyperplasia and excessive deposition of ECM [135]. Lung macrophages and circulating monocytes play an important role during pulmonary fibrosis. AMs are involved in the removal of accumulated collagen. AAM play an important role in the development and resolution of lung fibrosis after injury, but their growth promoting activity raise the intriguing possibility that persistent M2 activity might contribute to the failure in resolving fibrosis in IPF patients. Sun and coworkers [136] reported that increased numbers of AAMs induced by over expres‐ sion of IL10 results in induction of lung fibrosis in mice. Accordingly increased expression of CD206 (another marker of AAM) and IL4 is observed in patients with IPF and systemic sclerosis [137, 138]. Secretion of IL4 and IL13 by T cells is required for fibroblast migration and proliferation and their subsequent differentiation into myofibroblasts. IFNγ, in contrast, attenuates the fibrotic response and induces collagen degradation [139]. Paired immunoglo‐ bulin like receptor beta (PIRB) contributes to the pathogenesis of pulmonary fibrosis via the negative regulation of macrophage effector function and fibrogenic mediator expression. PIRB negatively regulates IL4-induced macrophage activation. Various studies have also demon‐ strated the role of AAM production in pulmonary fibrosis [140]. Relmα, a hallmark M2 macrophage marker is upregulated in pulmonary fibrosis which is controlled by IL4/ IL13-and STAT6-dependent pathways [141].

[122-124]. It could be considered that COPD pathogenesis is largely contributed by dysfunction

Asthma is characterized by airway inflammation and airway hyperresponsiveness (AHR). Macrophages also contribute significantly to the development of asthma [125]. The inflam‐ matory process of asthma is dominated by Th2 inflammation, but there is also involvement of both types M1 and M2 macrophages [14]. The balance between different phenotypes of macrophages changes with the severity of asthma [126]. In case of acute exacerbation of chronic asthma, AMs are found to significantly enhance the expression of AAM markers along with pro-inflammatory cytokines (IFNγ and TNFα) and cell surface proteins. Ironically, the cell surface proteins associated with antigen presentation are M1 inducers [127, 128]. Elevated serum IFNγ correlates with the severity of airway inflammation in atopic asthma, and IFNγ has been linked to mechanisms inducing AHR [129]. It was demonstrated that IL33/ST2 plays a significant role in the amplification of AAM polarization and chemokine production which

The ability of AMs to phagocytose apoptotic cells is known as efferocytosis. Macrophage efferocytosis is impaired in non-eosinophilic asthma to a similar degree as in COPD [131]. In mice with less severe asthma, M1 macrophage numbers were higher and correlated negatively with M2 macrophage counts. Lower numbers of M2-like macrophages were found in mice exposed to house dust mites. The balance between macrophage phenotypes changes as the severity of allergic airway inflammation increases. Influencing this imbalanced relationship could be a novel approach to treat asthma [126]. CCL18 and YKL40 (chitinase 3-like 1) levels and CHIT1 (chitinase 1) activity are enhanced in allergic airway inflammation and thus may contribute to airway remodelling in asthma [132]. M2 macrophages play a role in eosinophil and potentially other leukocyte migration patterns into asthmatic airways [133]. Dysregulation of alveolar macrophage function results in dendritic cell-mediated mechanisms of allergic airway inflammation [134]. AMs can also contribute to the genetic susceptibility to allergic

Fibrosis is the result of persistent or dysregulated wound healing, usually in response to some type of repeated injury. It is often associated with chronic inflammation, alveolar epithelial hyperplasia and excessive deposition of ECM [135]. Lung macrophages and circulating monocytes play an important role during pulmonary fibrosis. AMs are involved in the removal of accumulated collagen. AAM play an important role in the development and resolution of lung fibrosis after injury, but their growth promoting activity raise the intriguing possibility that persistent M2 activity might contribute to the failure in resolving fibrosis in IPF patients.

of macrophages rather than a single subset of AMs.

contribute to innate and Ag-induced airway inflammation [130].

**12. Asthma**

40 Lung Inflammation

asthma [39].

**13. Pulmonary fibrosis**

The Th2 cytokines IL4 and IL13, like TGFβ1, directly stimulate collagen synthesis in mouse and human fibroblasts [142]. They also promote the development of the classic myofibroblast phenotype in human lung fibroblasts [143]. Macrophages accumulate in areas of fibrotic injury but their role remains incompletely understood. A study using silica-induced model of lung fibrosis found that the IL4Rα-dependent differentiation of AAM is critical for the induction and maintenance of the CD4+ Th2 response required to trigger fibrosis [144]. Chitotriosidase, an enzyme especially expressed by M2 macrophages is also overexpressed in patients with IPF, especially in a progressing stage suggesting that this enzyme plays a role in the patho‐ genesis of diffuse lung disease-associated fibrosis [145, 146].

Polarization of macrophages to the M1 phenotype attenuates pulmonary fibrosis [65]. Fibrosis may be independent of monocyte and lung macrophage activity during the inflammation phase of bleomycin injury, a frequently used animal model for IPF. The depletion of lung macrophages during the inflammatory phase of bleomycin injury has no effect on the early as well as peak stage of lung fibrosis. However, during the progressive phase, lung macrophage depletion reduces the degree of pulmonary fibrosis. Depletion of lung macrophages during the resolution phase of bleomycin induced lung fibrosis slowed down the process [147]. Macrophages may promote resolution during the reversible phase of bleomycin induced pulmonary fibrosis [148]. Overexpression of MMP9 by AMs has the capability to attenuate the fibrosis induced by bleomycin [149]. ExMacs are recruited to the lung after noninfectious injury by bleomycin and are the major source of macrophages derived CXCL10 [46]. ExMacs are CD11c+ , MHCIIin Gr-1 int and are separated from resident AMs by high expression of both CD11b and CX3CR1. Everson and colleagues [147] separated AMs into 18 density defined subpopulations. Bleomycin altered the proportions of these subpopulations and enhanced the production of TNFα production in these specific subpopulations. Bleomycin-treated *Pirb(-/-)* mice displayed an increased expression of collagen and IL4 associated profibrogenic markers Relmα, MMP12, TIMP1, and osteopontin, which were localized to AMs. Thus, macrophages may have a role in resolution during the reversible phase of bleomycin induced pulmonary fibrosis [148].

#### **14. Environmental exposure to particle inhalation**

Epidemiologic and occupational studies show that exposure to high concentrations of ambient particulate matter cause cardiopulmonary health effects, including exacerbation of preexisting lung disease as well as the development of respiratory infections. Particle related oxidative stress and inflammatory responses are considered to be key for the subsequent health effects, but the precise mechanism how inhaled poorly soluble, sterile, endotoxin free particle induce pulmonary inflammation is not well understood [150]. Since the size of the inhaled material determines their penetration depth into the lungs, smaller particle (<100nm) cause higher alveolar lung burden than bigger sized particles. Lung surface macrophages (i.e. AMs) do not efficiently phagocytose small, sub-100nm sized, so called ultrafine particles (UFP) or nanoparticles (NP), but take them up in a rather sporadic and unspecific way [151]. But the evidence that UFP bypass the most important clearance mechanism for particles deposited in the alveoli, namely phagocytic uptake by macrophages, requires further clarification as to whether these results are specific for the material, the size or other characteristics of the particles. A rethinking of clearance pathways for inhaled UFP is therefore considered neces‐ sary [151].

functionality. Various factors of the lung microenvironment define the polarization of macrophages. The temporal changes in the polarization of macrophages during chronic pulmonary diseases help in the regulation of tissue repair and remodeling. Thus understand‐ ing of the molecular mechanisms and microenvironment biology of macrophage polarization is a crucial step in evolving novel therapeutic strategies for treating chronic respiratory

, Koustav Ganguly1

2 Department of Biotechnology, Indian Institute of Technology, Madras, Chennai, India

3 Institute of Lung Biology and Disease, Comprehensive Pneumology Center, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Munich, Germany

[1] Occupational and Enviromental Health. Fifth edition ed. Levy BS, Wegman DH, Bar‐

[2] Hubeau C, Puchelle E, Gaillard D. Distinct Pattern of Immune Cell Population in the Lung of Human Fetuses with Cystic Fibrosis. Journal of Allergy and Clinical Immu‐

[3] Gordon S, Martinez F. Alternative Activation of Macrophages: Mechanism and Func‐

[4] Grom AA, Mellins ED. Macrophage Activation Syndrome: Advances Towards Un‐ derstanding Pathogenesis. Current Opinion in Rheumatology. 2010;22(5):561-566.

on SL, Sokas RK, editors: Lippincott Williams and Wilkins; 2006.

\*Address all correspondence to: tobias.stoeger@helmholtz-muenchen.de

and Tobias Stoeger3\*

Macrophage Polarization in Lung Biology and Diseases

http://dx.doi.org/10.5772/57567

43

diseases.

**Acknowledgements**

**Author details**

KG; TS: Equal contribution

nology. 2001;108(4):524-529.

tions. Immunity. 2010;32(5):593-604.

**References**

Leema George1

(S.U.) CSIR-SRA (13-8553A)-2012/POOL

, Swapna Upadhyay2

1 SRM Research Institute, SRM University, Chennai, India

Inhalation of ultrafine carbon particles triggers a biphasic pro-inflammatory process in the lung, involving the activation of macrophages and the upregulation of immunomodulatory proteins [152]. Higher doses cause a distinct inflammatory response characterized by the release of pro-inflammatory cytokines and accumulation of inflammatory leukocytes [153]. A single exposure to these carbon particles however causes only a transient inflammatory response, which resolves within one week after treatment [154]. Black carbon laden AMs however are observed even at much later time points when no inflammatory stimulation in the lungs is detectable. Whether the immunological activity of these long-living tissue macrophages gets changed remains unknown. In animal experiments, when lung inflamma‐ tion for example is induced by titanium di oxide (TiO2) particles in rats, AMs induce the production of IL-13 and IL-25 production. This in turn modulates the inflammatory response [155]. When exposed to gold NPs, it is found that AMs efficiently internalize NPs by endocy‐ tosis, and rearrangements of vesicles and of NPs within the vesicles of macrophages occurred [156]. The uptake of gold particles by AMs is limited, though to a low degree, systemic particle translocation is reported. To summarise, inhaled NPs or UFPs pose high burden to the integrity of lungs as these particles penetrate into the susceptible alveolar region due to the ineffective clearance mechanisms. Whether an activation of lung macrophages, potentially caused by particle-cell interactions, results in a change of their immunological properties thereby increasing the susceptibility for secondary infection warrants further investigations.

#### **15. Conclusion**

Macrophages are essential to host defense mechanism. The alveolar macrophages exhibit unique properties, including uncharacteristic phenotypic features, remarkable plasticity and functionality. Various factors of the lung microenvironment define the polarization of macrophages. The temporal changes in the polarization of macrophages during chronic pulmonary diseases help in the regulation of tissue repair and remodeling. Thus understand‐ ing of the molecular mechanisms and microenvironment biology of macrophage polarization is a crucial step in evolving novel therapeutic strategies for treating chronic respiratory diseases.
