**Author details**

Leema George1 , Swapna Upadhyay2 , Koustav Ganguly1 and Tobias Stoeger3\*

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

1 SRM Research Institute, SRM University, Chennai, India

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

KG; TS: Equal contribution

#### **References**


[5] Heymann F, Trautwein C, Tacke F. Monocytes and Macrophages as Cellular Targets in Liver Fibrosis. Inflammation and Allergy Drug Targets. 2009;8(4):307-318.

[19] Wynn T, Barron L. Macrophages: Master Regulators of Inflammation and Fibrosis.

Macrophage Polarization in Lung Biology and Diseases

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

45

[20] Homer R, Elias J, Lee C, Herzog E. Modern Concepts on the Role of Inflammation in Pulmonary Fibrosis. Archives of Pathology and Laboratory Medicine. 2011;135(6):

[21] Olsen HH, Grunewald J, Tornling G, Sköld CM, Eklund A. Bronchoalveolar Lavage Results Are Independent of Season, Age, Gender and Collection Site. PLoS One.

[22] van Furth R, Cohn ZA. The Origin and Kinetics of Mononuclear Phagocytes. Journal

[23] Auffray C, Sieweke MH, Geissmann F. Blood Monocytes: Development, Heterogene‐ ity, and Relationship with Dendritic Cells. Annual Review of Immunology.

[24] Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P, Figueiredo JL, Kohler RH, Chudnovskiy A, Waterman P, Aikawa E, Mempel TR, Libby P, Weissleder R, Pittet MJ. Identification of Splenic Reservoir Monocytes and

[25] Gordon S, Taylor PR. Monocyte and Macrophage Heterogeneity. Nature Reviews.

[26] Passlick B, Flieger D, Ziegler-Heitbrock HW. Identification and Characterization of a Novel Monocyte Subpopulation in Human Peripheral Blood. Blood. 1989;74(7):

[27] Geissmann F, Jung S, Littman DR. Blood Monocytes Consist of Two Principal Sub‐

[28] Sunderkotter C, Nikolic T, Dillon MJ, Van Rooijen N, Stehling M, Drevets DA, Lee‐ nen PJ. Subpopulations of Mouse Blood Monocytes Differ in Maturation Stage and

[29] Gordon S, Taylor P. Monocyte and Macrophage Heterogeneity. Nature reviews. Im‐

[30] Hashimoto D, Chow A, Noizat C, Teo P, Beasley MB, Leboeuf M, Becker CD, See P, Price J, Lucas D, Greter M, Mortha A, Boyer SW, Forsberg EC, Tanaka M, van Rooi‐ jen N, Garcia-Sastre A, Stanley ER, Ginhoux F, Frenette PS, Merad M. Tissue-Resi‐ dent Macrophages Self-Maintain Locally Throughout Adult Life with Minimal

[31] Sallusto F, Lanzavecchia A. Efficient Presentation of Soluble Antigen by Cultured Human Dendritic Cells Is Maintained by Granulocyte/Macrophage Colony-Stimulat‐

Contribution from Circulating Monocytes. Immunity. 2013;38(4):792-804.

Inflammatory Response. The Journal of Immunology. 2004;172(7):4410-4417.

sets with Distinct Migratory Properties. Immunity. 2003;19(1):71-82.

Their Deployment to Inflammatory Sites. Science. 2009;325(5940):612-616.

Seminars in liver disease. 2010;30(3):245-257.

of Experimental Medicine. 1968;128(3):415-435.

780-788.

2012;7(8):e43644.

2009;27:669-692.

2527-2534.

Immunology. 2005;5(12):953-964.

munology. 2005;5(12):953-964.


[19] Wynn T, Barron L. Macrophages: Master Regulators of Inflammation and Fibrosis. Seminars in liver disease. 2010;30(3):245-257.

[5] Heymann F, Trautwein C, Tacke F. Monocytes and Macrophages as Cellular Targets in Liver Fibrosis. Inflammation and Allergy Drug Targets. 2009;8(4):307-318.

[6] Sohn JJ, Schetter AJ, Yfantis HG, Ridnour LA, Horikawa I, Khan MA, Robles AI, Hussain SP, Goto A, Bowman ED, Hofseth LJ, Bartkova J, Bartek J, Wogan GN, Wink DA, Harris CC. Macrophages, Nitric Oxide and Micrornas Are Associated with DNA Damage Response Pathway and Senescence in Inflammatory Bowel Disease. PLoS

[7] Murray PJ, Wynn TA. Protective and Pathogenic Functions of Macrophage Subsets.

[8] Libby P, Ridker PM, Hansson GK. Progress and Challenges in Translating the Biolo‐

[9] Shalhoub J, Falck-Hansen MA, Davies AH, Monaco C. Innate Immunity and Mono‐ cyte-Macrophage Activation in Atherosclerosis. Journal of inflammation (London,

[10] Shapiro S. The Macrophage in Chronic Obstructive Pulmonary Disease. American

[11] Tetley TD. Macrophages and the Pathogenesis of Copd. Chest. 2002;121(5 Suppl):

[12] Barnes PJ. Mediators of Chronic Obstructive Pulmonary Disease. Pharmacological

[13] Brusselle G, Joos G, Bracke K. New Insights into the Immunology of Chronic Ob‐

[14] Balhara J, Gounni AS. The Alveolar Macrophages in Asthma: A Double-Edged

[15] Yang M, Kumar R, Hansbro P, Foster P. Emerging Roles of Pulmonary Macrophages in Driving the Development of Severe Asthma. Journal of Leukocyte Biology.

[16] Marc P-G. The Alveolar Macrophage. American Journal of Respiratory Cell and Mo‐

[17] Nuovo GJ, Hagood JS, Magro CM, Chin N, Kapil R, Davis L, Marsh CB, Folcik VA. The Distribution of Immunomodulatory Cells in the Lungs of Patients with Idiopath‐

[18] Rydell-Törmänen K, Andréasson K, Hesselstrand R, Risteli J, Heinegård D, Saxne T, Westergren-Thorsson G. Extracellular Matrix Alterations and Acute Inflammation; Developing in Parallel During Early Induction of Pulmonary Fibrosis. Laboratory In‐

Journal of Respiratory and Critical Care Medicine. 1999;160:S29-S32.

structive Pulmonary Disease. Lancet. 2011;378(9795):1015-1026.

ic Pulmonary Fibrosis. Modern Pathology. 2012;25(3):416-433.

Sword. Mucosal Immunology. 2012;5(6):605-609.

Nature Reviews Immunology. 2011;11(11):723-737.

gy of Atherosclerosis. Nature. 2011;473(7347):317-325.

One. 2012;7(9):e44156.

44 Lung Inflammation

England). 2011;8:9.

Reviews. 2004;56(4):515-548.

2012;91(4):557-569.

lecular Biology. 2004;31.

vestigation. 2012;92(6):917-925.

156S-159S.


ing Factor Plus Interleukin 4 and Downregulated by Tumor Necrosis Factor Alpha. Journal of Experimental Medicine. 1994;179(4):1109-1118.

cytes in Response to Endotoxin-Induced Lung Inflammation. American Journal of

Macrophage Polarization in Lung Biology and Diseases

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

47

[43] Spiteri MA, Clarke SW, Poulter LW. Isolation of Phenotypically and Functionally Distinct Macrophage Subpopulations from Human Bronchoalveolar Lavage. The Eu‐

[44] Guth AM, Janssen WJ, Bosio CM, Crouch EC, Henson PM, Dow SW. Lung Environ‐ ment Determines Unique Phenotype of Alveolar Macrophages. American Journal of

[45] Lohmann-Matthes ML, Steinmuller C, Franke-Ullmann G. Pulmonary Macrophages.

[46] Tighe RM, Liang J, Liu N, Jung Y, Jiang D, Gunn MD, Noble PW. Recruited Exuda‐ tive Macrophages Selectively Produce Cxcl10 after Noninfectious Lung Injury. Amer‐

[47] Lee HW, Choi HJ, Ha SJ, Lee KT, Kwon YG. Recruitment of Monocytes/Macrophages in Different Tumor Microenvironments. Biochimica et Biophysica Acta. 2013;1835(2):

[48] Mosser D, Edwards J. Exploring the Full Spectrum of Macrophage Activation. Na‐

[49] Geissmann F, Prost C, Monnet JP, Dy M, Brousse N, Hermine O. Transforming Growth Factor Beta1, in the Presence of Granulocyte/Macrophage Colony-Stimulat‐ ing Factor and Interleukin 4, Induces Differentiation of Human Peripheral Blood Monocytes into Dendritic Langerhans Cells. Journal of Experimental Medicine.

[50] Stein M, Keshav S, Harris N, Gordon S. Interleukin 4 Potently Enhances Murine Mac‐ rophage Mannose Receptor Activity: A Marker of Alternative Immunologic Macro‐

[51] Martinez FO, Helming L, Gordon S. Alternative Activation of Macrophages: An Im‐ munologic Functional Perspective. Annual Review of Immunology. 2009;27:451-483.

[52] Lambrecht BN. Alveolar Macrophage in the Driver's Seat. Immunity. 2006;24(4):

[53] Stout RD, Jiang C, Matta B, Tietzel I, Watkins SK, Suttles J. Macrophages Sequentially Change Their Functional Phenotype in Response to Changes in Microenvironmental

[54] Stout RD, Suttles J. Immunosenescence and Macrophage Functional Plasticity: Dysre‐ gulation of Macrophage Function by Age-Associated Microenvironmental Changes.

Influences. The Journal of Immunology. 2005;175(1):342-349.

Immunological Reviews. 2005;205:60-71.

phage Activation. Journal of Experimental Medicine. 1992;176(1):287-292.

ican Journal of Respiratory Cell and Molecular Biology. 2011;45(4):781-788.

Respiratory Cell and Molecular Biology. 2006;35(2):227-235.

Physiology Lung Cellular and Molecular Physiology. 2009;296.

The European Respiratory Journal. 1994;7(9):1678-1689.

ropean Respiratory Journal. 1992;5(6):717-726.

ture reviews. Immunology. 2008;8(12):958-969.

170-179.

366-368.

1998;187(6):961-966.


cytes in Response to Endotoxin-Induced Lung Inflammation. American Journal of Respiratory Cell and Molecular Biology. 2006;35(2):227-235.

[43] Spiteri MA, Clarke SW, Poulter LW. Isolation of Phenotypically and Functionally Distinct Macrophage Subpopulations from Human Bronchoalveolar Lavage. The Eu‐ ropean Respiratory Journal. 1992;5(6):717-726.

ing Factor Plus Interleukin 4 and Downregulated by Tumor Necrosis Factor Alpha.

[32] Geissmann F, Auffray C, Palframan R, Wirrig C, Ciocca A, Campisi L, Narni-Manci‐ nelli E, Lauvau G. Blood Monocytes: Distinct Subsets, How They Relate to Dendritic Cells, and Their Possible Roles in the Regulation of T-Cell Responses. Immunology

[33] Yona S, Kim KW, Wolf Y, Mildner A, Varol D, Breker M, Strauss-Ayali D, Viukov S, Guilliams M, Misharin A, Hume DA, Perlman H, Malissen B, Zelzer E, Jung S. Fate Mapping Reveals Origins and Dynamics of Monocytes and Tissue Macrophages un‐

[34] Guilliams M, De Kleer I, Henri S, Post S, Vanhoutte L, De Prijck S, Deswarte K, Ma‐ lissen B, Hammad H, Lambrecht BN. Alveolar Macrophages Develop from Fetal Monocytes That Differentiate into Long-Lived Cells in the First Week of Life Via Gm-

[35] Dijkstra CD, Van Vliet E, Dopp EA, van der Lelij AA, Kraal G. Marginal Zone Macro‐ phages Identified by a Monoclonal Antibody: Characterization of Immuno-and En‐ zyme-Histochemical Properties and Functional Capacities. Immunology. 1985;55(1):

[36] Kraal G, Janse M. Marginal Metallophilic Cells of the Mouse Spleen Identified by a

[37] Sica A, Larghi P, Mancino A, Rubino L, Porta C, Totaro MG, Rimoldi M, Biswas SK, Allavena P, Mantovani A. Macrophage Polarization in Tumour Progression. Semin

[38] Sica A, Mantovani A. Macrophage Plasticity and Polarization: In Vivo Veritas. The

[39] Careau E, Bissonnette EY. Adoptive Transfer of Alveolar Macrophages Abrogates Bronchial Hyperresponsiveness. American Journal of Respiratory Cell and Molecular

[40] Lensmar C, Elmberger G, Sandgren P, Skold CM, Eklund A. Leukocyte Counts and Macrophage Phenotypes in Induced Sputum and Bronchoalveolar Lavage Fluid from

[41] Liang J, Jung Y, Tighe R, Xie T, Liu N, Leonard M, Gunn M, Jiang D, Noble P. A Mac‐ rophage Subpopulation Recruited by Cc Chemokine Ligand-2 Clears Apoptotic Cells in Noninfectious Lung Injury. American Journal of Physiology. Lung Cellular and

[42] Maus U, Janzen S, Wall G, Srivastava M, Blackwell T, Christman J, Seeger W, Welte T, Lohmeyer J. Resident Alveolar Macrophages Are Replaced by Recruited Mono‐

Normal Subjects. The European Respiratory Journal. 1998;12(3):595-600.

Csf. Journal of Experimental Medicine. 2013;210(10):1977-1992.

Monoclonal Antibody. Immunology. 1986;58(4):665-669.

Journal of Clinical Investigation. 2012;122(3):787-795.

Cancer Biol. 2008;18(5):349-355.

Biology. 2004;31(1):22-27.

Molecular Physiology. 2012;302(9):40.

Journal of Experimental Medicine. 1994;179(4):1109-1118.

and Cell Biology. 2008;86(5):398-408.

23-30.

46 Lung Inflammation

der Homeostasis. Immunity. 2013;38(1):79-91.


[55] Goerdt S, Orfanos CE. Other Functions, Other Genes: Alternative Activation of Anti‐ gen-Presenting Cells. Immunity. 1999;10(2):137-142.

Phenotype and Function Are Improved by Treatment with Procysteine. American

Macrophage Polarization in Lung Biology and Diseases

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

49

[67] Ezekowitz RA, Gordon S. Alterations of Surface Properties by Macrophage Activa‐ tion: Expression of Receptors for Fc and Mannose-Terminal Glycoproteins and Dif‐ ferentiation Antigens. Contemporary Topics in Immunobiology. 1984;13:33-56.

[68] Doherty TM, Kastelein R, Menon S, Andrade S, Coffman RL. Modulation of Murine Macrophage Function by Il-13. The Journal of Immunology. 1993;151(12):7151-7160.

[69] Doyle AG, Herbein G, Montaner LJ, Minty AJ, Caput D, Ferrara P, Gordon S. Inter‐ leukin-13 Alters the Activation State of Murine Macrophages in Vitro: Comparison with Interleukin-4 and Interferon-Gamma. European Journal of Immunology.

[70] Murray P, Wynn T. Obstacles and Opportunities for Understanding Macrophage Po‐

[71] Taylor EL, Megson IL, Haslett C, Rossi AG. Nitric Oxide: A Key Regulator of Mye‐ loid Inflammatory Cell Apoptosis. Cell Death and Differentiation. 2003;10(4):418-430.

[72] Freire-de-Lima CG, Xiao YQ, Gardai SJ, Bratton DL, Schiemann WP, Henson PM. Apoptotic Cells, through Transforming Growth Factor-Beta, Coordinately Induce Anti-Inflammatory and Suppress Pro-Inflammatory Eicosanoid and No Synthesis in Murine Macrophages. The Journal of Biological Chemistry. 2006;281(50):38376-38384.

[73] Beck-Speier I, Karg E, Behrendt H, Stoeger T, Alessandrini F. Ultrafine Particles Af‐ fect the Balance of Endogenous Pro-and Anti-Inflammatory Lipid Mediators in the

[74] Johnston LK, Rims CR, Gill SE, McGuire JK, Manicone AM. Pulmonary Macrophage Subpopulations in the Induction and Resolution of Acute Lung Injury. American

[75] He C, Ryan AJ, Murthy S, Carter AB. Accelerated Development of Pulmonary Fibro‐ sis Via Cu,Zn-Superoxide Dismutase-Induced Alternative Activation of Macrophag‐

[76] Tschernig T, Pabst R. What Is the Clinical Relevance of Different Lung Compart‐

[77] Warner AE, Brain JD. The Cell Biology and Pathogenic Role of Pulmonary Intravas‐ cular Macrophages. American Journal of Physiology 1990;258(2 Pt 1):L1-12.

[78] Vanderbilt JN, Mager EM, Allen L, Sawa T, Wiener-Kronish J, Gonzalez R, Dobbs LG. Cxc Chemokines and Their Receptors Are Expressed in Type Ii Cells and Upre‐ gulated Following Lung Injury. American Journal of Respiratory Cell and Molecular

Lung: In-Vitro and in-Vivo Studies. Particle and Fibre Toxicology. 2012;9:27.

Journal of Respiratory Cell and Molecular Biology. 2012;47(4):417-426.

es. The Journal of Biological Chemistry 2013;288(28):20745-20757.

ments? BMC Pulmonary Medicine 2009;9:39.

Biology. 2003;29(6):661-668.

larization. Journal of leukocyte biology. 2011;89(4):557-563.

Journal of Respiratory Cell and Molecular Biology 2011;44(5):673-681.

1994;24(6):1441-1445.


Phenotype and Function Are Improved by Treatment with Procysteine. American Journal of Respiratory Cell and Molecular Biology 2011;44(5):673-681.

[67] Ezekowitz RA, Gordon S. Alterations of Surface Properties by Macrophage Activa‐ tion: Expression of Receptors for Fc and Mannose-Terminal Glycoproteins and Dif‐ ferentiation Antigens. Contemporary Topics in Immunobiology. 1984;13:33-56.

[55] Goerdt S, Orfanos CE. Other Functions, Other Genes: Alternative Activation of Anti‐

[56] Gratchev A, Kzhyshkowska J, Kothe K, Muller-Molinet I, Kannookadan S, Utikal J, Goerdt S. Mphi1 and Mphi2 Can Be Re-Polarized by Th2 or Th1 Cytokines, Respec‐ tively, and Respond to Exogenous Danger Signals. Immunobiology. 2006;211(6-8):

[57] Biswas SK, Sica A, Lewis CE. Plasticity of Macrophage Function During Tumor Pro‐ gression: Regulation by Distinct Molecular Mechanisms. The Journal of Immunology.

[58] Modolell M, Corraliza IM, Link F, Soler G, Eichmann K. Reciprocal Regulation of the Nitric Oxide Synthase/Arginase Balance in Mouse Bone Marrow-Derived Macro‐ phages by Th1 and Th2 Cytokines. European Journal of Immunology. 1995;25(4):

[59] Rutschman R, Lang R, Hesse M, Ihle JN, Wynn TA, Murray PJ. Cutting Edge: Stat6- Dependent Substrate Depletion Regulates Nitric Oxide Production. The Journal of

[60] Mylonas KJ, Nair MG, Prieto-Lafuente L, Paape D, Allen JE. Alternatively Activated Macrophages Elicited by Helminth Infection Can Be Reprogrammed to Enable Mi‐

[61] Buttari B, Segoni L, Profumo E, D'Arcangelo D, Rossi S, Facchiano F, Businaro R, Iu‐ liano L, Rigano R. 7-Oxo-Cholesterol Potentiates Pro-Inflammatory Signaling in Hu‐ man M1 and M2 Macrophages. Biochemical Pharmacology. 2013;86(1):130-137.

[62] Porta C, Rimoldi M, Raes G, Brys L, Ghezzi P, Di Liberto D, Dieli F, Ghisletti S, Nato‐ li G, De Baetselier P, Mantovani A, Sica A. Tolerance and M2 (Alternative) Macro‐ phage Polarization Are Related Processes Orchestrated by P50 Nuclear Factor Kappab. Proceedings of the National Academy of Sciences of the United States of

[63] Lawrence T, Natoli G. Transcriptional Regulation of Macrophage Polarization: Ena‐ bling Diversity with Identity. Nature Reviews Immunology. 2011;11(11):750-761.

[64] Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The Chemokine Sys‐ tem in Diverse Forms of Macrophage Activation and Polarization. Trends in immu‐

[65] Martinez F, Gordon S, Locati M, Mantovani A. Transcriptional Profiling of the Hu‐ man Monocyte-to-Macrophage Differentiation and Polarization: New Molecules and Patterns of Gene Expression. The Journal of immunology 2006;177(10):7303-7311.

[66] Hodge S, Matthews G, Mukaro V, Ahern J, Shivam A, Hodge G, Holmes M, Jers‐ mann H, Reynolds PN. Cigarette Smoke-Induced Changes to Alveolar Macrophage

crobial Killing. The Journal of Immunology. 2009;182(5):3084-3094.

gen-Presenting Cells. Immunity. 1999;10(2):137-142.

473-486.

48 Lung Inflammation

1101-1104.

2008;180(4):2011-2017.

Immunology. 2001;166(4):2173-2177.

America. 2009;106(35):14978-14983.

nology. 2004;25(12):677-686.


[79] Murphy J, Summer R, Wilson AA, Kotton DN, Fine A. The Prolonged Life-Span of Alveolar Macrophages. American Journal of Respiratory Cell and Molecular Biology. 2008;38(4):380-385.

Cells in Vivo by Resident Alveolar Macrophages. Journal of Experimental Medicine.

Macrophage Polarization in Lung Biology and Diseases

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

51

[91] Strickland D, Kees UR, Holt PG. Regulation of T-Cell Activation in the Lung: Isolated Lung T Cells Exhibit Surface Phenotypic Characteristics of Recent Activation Includ‐ ing Down-Modulated T-Cell Receptors, but Are Locked into the G0/G1 Phase of the

[92] Wilsher ML, Hughes DA, Haslam PL. Immunoregulatory Properties of Pulmonary Surfactant: Effect of Lung Lining Fluid on Proliferation of Human Blood Lympho‐

[93] Thepen T, Hoeben K, Breve J, Kraal G. Alveolar Macrophages Down-Regulate Local Pulmonary Immune Responses against Intratracheally Administered T-Cell-Depend‐

[94] Upham JW, Strickland DH, Bilyk N, Robinson BW, Holt PG. Alveolar Macrophages from Humans and Rodents Selectively Inhibit T-Cell Proliferation but Permit T-Cell

[95] Holt PG, Kees UR, Shon-Hegrad MA, Rose A, Ford J, Bilyk N, Bowman R, Robinson BW. Limiting-Dilution Analysis of T Cells Extracted from Solid Human Lung Tissue: Comparison of Precursor Frequencies for Proliferative Responses and Lymphokine Production between Lung and Blood T Cells from Individual Donors. Immunology.

[96] Fontenot JD, Gavin MA, Rudensky AY. Foxp3 Programs the Development and Func‐ tion of Cd4+Cd25+Regulatory T Cells. Nature Immunology 2003;4(4):330-336.

[97] Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. A Function for Interleukin 2 in Foxp3-Expressing Regulatory T Cells. Nature Immunology. 2005;6(11):1142-1151.

[98] Mathers C, Loncar D. Projections of Global Mortality and Burden of Disease from

[99] Russell RE, Thorley A, Culpitt SV, Dodd S, Donnelly LE, Demattos C, Fitzgerald M, Barnes PJ. Alveolar Macrophage-Mediated Elastolysis: Roles of Matrix Metalloprotei‐ nases, Cysteine, and Serine Proteases. American Journal of Physiology Lung Cellular

[100] Bracke K, Cataldo D, Maes T, Gueders M, Noel A, Foidart JM, Brusselle G, Pauwels RA. Matrix Metalloproteinase-12 and Cathepsin D Expression in Pulmonary Macro‐ phages and Dendritic Cells of Cigarette Smoke-Exposed Mice. International Archives

[101] Mocchegiani E, Giacconi R, Costarelli L. Metalloproteases/Anti-Metalloproteases Im‐ balance in Chronic Obstructive Pulmonary Disease: Genetic Factors and Treatment Implications. Current Opinion in Pulmonary Medicine. 2011;17 Suppl 1:S11-19.

ent, but Not T-Cell-Independent Antigens. Immunology. 1992;76(1):60-64.

Activation and Cytokine Secretion. Immunology. 1995;84(1):142-147.

1993;177(2):397-407.

1988;64(4):649-654.

2002 to 2030. PLoS Medicine. 2006;3(11).

and Molecular Physiology. 2002;283(4):L867-873.

of Allergy and Immunology. 2005;138(2):169-179.

Cell Cycle. Immunology. 1996;87(2):242-249.

cytes. Thorax. 1988;43(5):354-359.


Cells in Vivo by Resident Alveolar Macrophages. Journal of Experimental Medicine. 1993;177(2):397-407.

[91] Strickland D, Kees UR, Holt PG. Regulation of T-Cell Activation in the Lung: Isolated Lung T Cells Exhibit Surface Phenotypic Characteristics of Recent Activation Includ‐ ing Down-Modulated T-Cell Receptors, but Are Locked into the G0/G1 Phase of the Cell Cycle. Immunology. 1996;87(2):242-249.

[79] Murphy J, Summer R, Wilson AA, Kotton DN, Fine A. The Prolonged Life-Span of Alveolar Macrophages. American Journal of Respiratory Cell and Molecular Biology.

[80] Coleman MM, Ruane D, Moran B, Dunne PJ, Keane J, Mills KH. Alveolar Macro‐ phages Contribute to Respiratory Tolerance by Inducing Foxp3 Expression in Naive T Cells. American Journal of Respiratory Cell and Molecular Biology. 2013;48(6):

[81] Mantovani A, Sica A, Locati M. Macrophage Polarization Comes of Age. Immunity.

[82] Jaguin M, Houlbert N, Fardel O, Lecureur V. Polarization Profiles of Human M-Csf-Generated Macrophages and Comparison of M1-Markers in Classically Activated Macrophages from Gm-Csf and M-Csf Origin. Cellular Immunology. 2013;281(1):

[83] Ohmori Y, Hamilton TA. Requirement for Stat1 in Lps-Induced Gene Expression in

[84] Takeda K, Kamanaka M, Tanaka T, Kishimoto T, Akira S. Impaired Il-13-Mediated Functions of Macrophages in Stat6-Deficient Mice. The Journal of Immunology.

[85] Ito S, Ansari P, Sakatsume M, Dickensheets H, Vazquez N, Donnelly RP, Larner AC, Finbloom DS. Interleukin-10 Inhibits Expression of Both Interferon Alpha-and Inter‐ feron Gamma-Induced Genes by Suppressing Tyrosine Phosphorylation of Stat1.

[86] Richmond LJ, Alcorn MJ, Pearson C, Cameron G, Thomas T, Eaves CJ, Eaves AC, Holyoake TL. Cml Leukapheresis Products Can Be Enriched for Cd34+Cells and Si‐ multaneously Depleted of Cd15+Cells Using a Simple Ab Cocktail. Cytotherapy.

[87] Watanabe K, Jose PJ, Rankin SM. Eotaxin-2 Generation Is Differentially Regulated by Lipopolysaccharide and Il-4 in Monocytes and Macrophages. The Journal of Immu‐

[88] Bonecchi R, Sozzani S, Stine JT, Luini W, D'Amico G, Allavena P, Chantry D, Manto‐ vani A. Divergent Effects of Interleukin-4 and Interferon-Gamma on Macrophage-Derived Chemokine Production: An Amplification Circuit of Polarized T Helper 2

[89] Holt PG. Macrophage: Dendritic Cell Interaction in Regulation of the Ige Response in

[90] Holt PG, Oliver J, Bilyk N, McMenamin C, McMenamin PG, Kraal G, Thepen T. Downregulation of the Antigen Presenting Cell Function(S) of Pulmonary Dendritic

Macrophages. Journal of Leukocyte Biology. 2001;69(4):598-604.

2008;38(4):380-385.

2005;23(4):344-346.

1996;157(8):3220-3222.

2002;4(5):407-413.

Blood. 1999;93(5):1456-1463.

nology. 2002;168(4):1911-1918.

Responses. Blood. 1998;92(8):2668-2671.

Asthma. Clinical and Experimental Allergy. 1993;23(1):4-6.

773-780.

50 Lung Inflammation

51-61.


[102] Finlay GA, O'Driscoll LR, Russell KJ, D'Arcy EM, Masterson JB, FitzGerald MX, O'Connor CM. Matrix Metalloproteinase Expression and Production by Alveolar Macrophages in Emphysema. American Journal of Respiratory and Critical Care Medicine. 1997;156(1):240-247.

[114] Keatings VM, Collins PD, Scott DM, Barnes PJ. Differences in Interleukin-8 and Tu‐ mor Necrosis Factor-Alpha in Induced Sputum from Patients with Chronic Obstruc‐ tive Pulmonary Disease or Asthma. American Journal of Respiratory and Critical

Macrophage Polarization in Lung Biology and Diseases

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

53

[115] Bhowmik A, Seemungal TA, Sapsford RJ, Wedzicha JA. Relation of Sputum Inflam‐ matory Markers to Symptoms and Lung Function Changes in Copd Exacerbations.

[116] Bucchioni E, Kharitonov SA, Allegra L, Barnes PJ. High Levels of Interleukin-6 in the Exhaled Breath Condensate of Patients with Copd. Respiratory Medicine.

[117] Daldegan MB, Teixeira MM, Talvani A. Concentration of Ccl11, Cxcl8 and Tnf-Alpha in Sputum and Plasma of Patients Undergoing Asthma or Chronic Obstructive Pul‐ monary Disease Exacerbation. Brazilian Journal of Medical and Biological Research.

[118] Sapey E, Ahmad A, Bayley D, Newbold P, Snell N, Rugman P, Stockley RA. Imbalan‐ ces between Interleukin-1 and Tumor Necrosis Factor Agonists and Antagonists in

[119] Shaykhiev R, Krause A, Salit J, Strulovici-Barel Y, Harvey B-G, O'Connor T, Crystal R. Smoking-Dependent Reprogramming of Alveolar Macrophage Polarization: Im‐ plication for Pathogenesis of Chronic Obstructive Pulmonary Disease. The Journal of

[120] Rosell A, Monso E, Soler N, Torres F, Angrill J, Riise G, Zalacain R, Morera J, Torres A. Microbiologic Determinants of Exacerbation in Chronic Obstructive Pulmonary

[121] Kunz LI, Lapperre TS, Snoeck-Stroband JB, Budulac SE, Timens W, van Wijngaarden S, Schrumpf JA, Rabe KF, Postma DS, Sterk PJ, Hiemstra PS. Smoking Status and An‐ ti-Inflammatory Macrophages in Bronchoalveolar Lavage and Induced Sputum in

[122] Woodruff PG, Koth LL, Yang YH, Rodriguez MW, Favoreto S, Dolganov GM, Paquet AC, Erle DJ. A Distinctive Alveolar Macrophage Activation State Induced by Ciga‐ rette Smoking. American Journal of Respiratory and Critical Care Medicine.

[123] Churg A, Wang X, Wang RD, Meixner SC, Pryzdial EL, Wright JL. Alpha1-Antitryp‐ sin Suppresses Tnf-Alpha and Mmp-12 Production by Cigarette Smoke-Stimulated Macrophages. American Journal of Respiratory Cell and Molecular Biology.

Stable Copd. Journal of Clinical Immunology. 2009;29(4):508-516.

Disease. Archives of Internal Medicine. 2005;165(8):891-897.

Care Medicine 1996;153(2):530-534.

Thorax. 2000;55(2):114-120.

2003;97(12):1299-1302.

2005;38(9):1359-1365.

immunology. 2009;183(4):2867-2883.

Copd. Respiratory Research. 2011;12:34.

2005;172(11):1383-1392.

2007;37(2):144-151.


[114] Keatings VM, Collins PD, Scott DM, Barnes PJ. Differences in Interleukin-8 and Tu‐ mor Necrosis Factor-Alpha in Induced Sputum from Patients with Chronic Obstruc‐ tive Pulmonary Disease or Asthma. American Journal of Respiratory and Critical Care Medicine 1996;153(2):530-534.

[102] Finlay GA, O'Driscoll LR, Russell KJ, D'Arcy EM, Masterson JB, FitzGerald MX, O'Connor CM. Matrix Metalloproteinase Expression and Production by Alveolar Macrophages in Emphysema. American Journal of Respiratory and Critical Care

[103] Hogg JC, Senior RM. Chronic Obstructive Pulmonary Disease-Part 2: Pathology and

[104] Chapman HA, Riese RJ, Shi GP. Emerging Roles for Cysteine Proteases in Human Bi‐

[105] Snider GL. Emphysema: The First Two Centuries--and Beyond. A Historical Over‐ view, with Suggestions for Future Research: Part 1. The American Review of Respira‐

[106] Demedts IK, Morel-Montero A, Lebecque S, Pacheco Y, Cataldo D, Joos GF, Pauwels RA, Brusselle GG. Elevated Mmp-12 Protein Levels in Induced Sputum from Patients

[107] Chung KF, Adcock IM. Multifaceted Mechanisms in Copd: Inflammation, Immunity, and Tissue Repair and Destruction. The European Respiratory Journal. 2008;31(6):

[108] Smith JA, Gray AB, Pyne DB, Baker MS, Telford RD, Weidemann MJ. Moderate Exer‐ cise Triggers Both Priming and Activation of Neutrophil Subpopulations. The Amer‐

[109] Finkelstein R, Fraser RS, Ghezzo H, Cosio MG. Alveolar Inflammation and Its Rela‐ tion to Emphysema in Smokers. American Journal of Respiratory and Critical Care

[110] Jeffery PK. Structural and Inflammatory Changes in Copd: A Comparison with Asth‐

[111] Maestrelli P, Paska C, Saetta M, Turato G, Nowicki Y, Monti S, Formichi B, Miniati M, Fabbri LM. Decreased Haem Oxygenase-1 and Increased Inducible Nitric Oxide Synthase in the Lung of Severe Copd Patients. The European Respiratory Journal.

[112] Ichinose M, Sugiura H, Yamagata S, Koarai A, Shirato K. Increase in Reactive Nitro‐ gen Species Production in Chronic Obstructive Pulmonary Disease Airways. Ameri‐ can Journal of Respiratory and Critical Care Medicine 2000;162(2 Pt 1):701-706. [113] Seimetz M, Parajuli N, Pichl A, Veit F, Kwapiszewska G, Weisel FC, Milger K, Egem‐ nazarov B, Turowska A, Fuchs B, Nikam S, Roth M, Sydykov A, Medebach T, Klepet‐ ko W, Jaksch P, Dumitrascu R, Garn H, Voswinckel R, Kostin S, Seeger W, Schermuly RT, Grimminger F, Ghofrani HA, Weissmann N. Inducible Nos Inhibition Reverses Tobacco-Smoke-Induced Emphysema and Pulmonary Hypertension in Mice. Cell.

Biochemistry of Emphysema. Thorax. 2002;57(9):830-834.

ology. Annual Review of Physiology. 1997;59:63-88.

can Journal of Physiology 1996;270(4 Pt 2):R838-R845.

tory Disease. 1992;146(5 Pt 1):1334-1344.

with Copd. Thorax. 2006;61(3):196-201.

Medicine. 1995;152(5 Pt 1):1666-1672.

ma. Thorax. 1998;53(2):129-136.

2003;21(6):971-976.

2011;147(2):293-305.

1334-1356.

52 Lung Inflammation

Medicine. 1997;156(1):240-247.


[124] Ishii T, Abboud RT, Wallace AM, English JC, Coxson HO, Finley RJ, Shumansky K, Pare PD, Sandford AJ. Alveolar Macrophage Proteinase/Antiproteinase Expression and Lung Function/Emphysema. The European Respiratory Journal. 2013.

[134] Lauzon-Joset JF, Marsolais D, Langlois A, Bissonnette EY. Dysregulation of Alveolar Macrophages Unleashes Dendritic Cell-Mediated Mechanisms of Allergic Airway In‐

Macrophage Polarization in Lung Biology and Diseases

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

55

[135] Wynn TA. Integrating Mechanisms of Pulmonary Fibrosis. Journal of Experimental

[136] Sun L, Louie MC, Vannella KM, Wilke CA, LeVine AM, Moore BB, Shanley TP. New Concepts of Il-10-Induced Lung Fibrosis: Fibrocyte Recruitment and M2 Activation in a Ccl2/Ccr2 Axis. American Journal of Physiology Lung Cellular and Molecular

[137] Pechkovsky DV, Prasse A, Kollert F, Engel KM, Dentler J, Luttmann W, Friedrich K, Muller-Quernheim J, Zissel G. Alternatively Activated Alveolar Macrophages in Pul‐ monary Fibrosis-Mediator Production and Intracellular Signal Transduction. Clinical

[138] Mathai SK, Gulati M, Peng X, Russell TR, Shaw AC, Rubinowitz AN, Murray LA, Si‐ ner JM, Antin-Ozerkis DE, Montgomery RR, Reilkoff RA, Bucala RJ, Herzog EL. Cir‐ culating Monocytes from Systemic Sclerosis Patients with Interstitial Lung Disease Show an Enhanced Profibrotic Phenotype. Laboratory Investigation. 2010;90(6):

[139] Wynn TA. Fibrotic Disease and the T(H)1/T(H)2 Paradigm. Nature Reviews Immu‐

[140] Hardie WD, Glasser SW, Hagood JS. Emerging Concepts in the Pathogenesis of Lung

[141] Liu T, Jin H, Ullenbruch M, Hu B, Hashimoto N, Moore B, McKenzie A, Lukacs NW, Phan SH. Regulation of Found in Inflammatory Zone 1 Expression in Bleomycin-In‐ duced Lung Fibrosis: Role of Il-4/Il-13 and Mediation Via Stat-6. The Journal of Im‐

[142] Murray LA, Argentieri RL, Farrell FX, Bracht M, Sheng H, Whitaker B, Beck H, Tsui P, Cochlin K, Evanoff HL, Hogaboam CM, Das AM. Hyper-Responsiveness of Ipf/Uip Fibroblasts: Interplay between Tgfbeta1, Il-13 and Ccl2. International Journal

[143] Hashimoto S, Gon Y, Takeshita I, Matsumoto K, Maruoka S, Horie T. Transforming Growth Factor-Beta1 Induces Phenotypic Modulation of Human Lung Fibroblasts to Myofibroblast through a C-Jun-Nh2-Terminal Kinase-Dependent Pathway. Ameri‐

[144] Migliaccio CT, Buford MC, Jessop F, Holian A. The Il-4ralpha Pathway in Macro‐ phages and Its Potential Role in Silica-Induced Pulmonary Fibrosis. Journal of Leu‐

can Journal of Respiratory and Critical Care Medicine 2001;163(1):152-157.

Fibrosis. The American Journal of Pathology 2009;175(1):3-16.

of Biochemistry and Cell Biology. 2008;40(10):2174-2182.

flammation. Mucosal immunology. 2013.

Medicine. 2011;208(7):1339-1350.

Physiology. 2011;300(3):L341-353.

Immunology. 2010;137(1):89-101.

nology. 2004;4(8):583-594.

munology. 2004;173(5):3425-3431.

kocyte Biology. 2008;83(3):630-639.

812-823.


[134] Lauzon-Joset JF, Marsolais D, Langlois A, Bissonnette EY. Dysregulation of Alveolar Macrophages Unleashes Dendritic Cell-Mediated Mechanisms of Allergic Airway In‐ flammation. Mucosal immunology. 2013.

[124] Ishii T, Abboud RT, Wallace AM, English JC, Coxson HO, Finley RJ, Shumansky K, Pare PD, Sandford AJ. Alveolar Macrophage Proteinase/Antiproteinase Expression

[125] Pappas K, Papaioannou A, Kostikas K, Tzanakis N. The Role of Macrophages in Ob‐ structive Airways Disease: Chronic Obstructive Pulmonary Disease and Asthma. Cy‐

[126] Draijer C, Robbe P, Boorsma CE, Hylkema MN, Melgert BN. Characterization of Macrophage Phenotypes in Three Murine Models of House-Dust-Mite-Induced

[127] Bunting MM, Shadie AM, Flesher RP, Nikiforova V, Garthwaite L, Tedla N, Herbert C, Kumar RK. Interleukin-33 Drives Activation of Alveolar Macrophages and Air‐ way Inflammation in a Mouse Model of Acute Exacerbation of Chronic Asthma. Bi‐

[128] Moon K-A, Kim S, Kim T-B, Yun E, Park C-S, Cho Y, Moon H-B, Lee K-Y. Allergen-Induced Cd11b+Cd11c(Int) Ccr3+Macrophages in the Lung Promote Eosinophilic Airway Inflammation in a Mouse Asthma Model. International Immunology.

[129] Heaton T, Rowe J, Turner S, Aalberse R, de Klerk N, Suriyaarachchi D, Serralha M, Holt B, Hollams E, Yerkovich S, Holt K, Sly P, Goldblatt J, Le Souef P, Holt P. An Immunoepidemiological Approach to Asthma: Identification of in-Vitro T-Cell Re‐ sponse Patterns Associated with Different Wheezing Phenotypes in Children. Lancet.

[130] Kurowska-Stolarska M, Stolarski B, Kewin P, Murphy G, Corrigan CJ, Ying S, Pitman N, Mirchandani A, Rana B, van Rooijen N, Shepherd M, McSharry C, McInnes IB, Xu D, Liew FY. Il-33 Amplifies the Polarization of Alternatively Activated Macrophages That Contribute to Airway Inflammation. The Journal of Immunology. 2009;183(10):

[131] Simpson J, Gibson P, Yang I, Upham J, James A, Reynolds P, Hodge S, Group ASR. Impaired Macrophage Phagocytosis in Non-Eosinophilic Asthma. Clinical and exper‐ imental allergy : journal of the British Society for Allergy and Clinical Immunology.

[132] Gavala ML, Kelly EAB, Esnault S, Kukreja S, Evans MD, Bertics PJ, Chupp GL, Jar‐ jour NN. Segmental Allergen Challenge Enhances Chitinase Activity and Levels of Ccl18 in Mild Atopic Asthma. Clinical and Experimental Allergy. 2013;43(2):187-197.

[133] Siddiqui S, Secor ER, Jr., Silbart LK. Broncho-Alveolar Macrophages Express Chemo‐ kines Associated with Leukocyte Migration in a Mouse Model of Asthma. Cellular

and Lung Function/Emphysema. The European Respiratory Journal. 2013.

tokine. 2013;64(3):613-625.

54 Lung Inflammation

2007;19(12):1371-1381.

2005;365(9454):142-149.

6469-6477.

2013;43(1):29-35.

Immunology. 2013;281(2):159-169.

Asthma. Mediators of inflammation. 2013;2013:10.

oMed Research International. 2013;2013:250938.


[145] Bargagli E, Margollicci M, Luddi A, Nikiforakis N, Perari MG, Grosso S, Perrone A, Rottoli P. Chitotriosidase Activity in Patients with Interstitial Lung Diseases. Respi‐ ratory Medicine. 2007;101(10):2176-2181.

[155] Kang CM, Jang AS, Ahn MH, Shin JA, Kim JH, Choi YS, Rhim TY, Park CS. Interleu‐ kin-25 and Interleukin-13 Production by Alveolar Macrophages in Response to Parti‐ cles. American Journal of Respiratory Cell and Molecular Biology. 2005;33(3):290-296.

Macrophage Polarization in Lung Biology and Diseases

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

57

[156] Takenaka S, Möller W, Semmler-Behnke M, Karg E, Wenk A, Schmid O, Stoeger T, Jennen L, Aichler M, Walch A, Pokhrel S, Mädler L, Eickelberg O, Kreyling W. Effi‐ cient Internalization and Intracellular Translocation of Inhaled Gold Nanoparticles in Rat Alveolar Macrophages. Nanomedicine (London, England). 2012;7(6):855-865.


[155] Kang CM, Jang AS, Ahn MH, Shin JA, Kim JH, Choi YS, Rhim TY, Park CS. Interleu‐ kin-25 and Interleukin-13 Production by Alveolar Macrophages in Response to Parti‐ cles. American Journal of Respiratory Cell and Molecular Biology. 2005;33(3):290-296.

[145] Bargagli E, Margollicci M, Luddi A, Nikiforakis N, Perari MG, Grosso S, Perrone A, Rottoli P. Chitotriosidase Activity in Patients with Interstitial Lung Diseases. Respi‐

[146] Tercelj M, Salobir B, Simcic S, Wraber B, Zupancic M, Rylander R. Chitotriosidase Activity in Sarcoidosis and Some Other Pulmonary Diseases. Scandinavian Journal

[147] Everson MP, Chandler DB. Changes in Distribution, Morphology, and Tumor Ne‐ crosis Factor-Alpha Secretion of Alveolar Macrophage Subpopulations During the Development of Bleomycin-Induced Pulmonary Fibrosis. The American Journal of

[148] Gibbons MA, MacKinnon AC, Ramachandran P, Dhaliwal K, Duffin R, Phythian-Adams AT, van Rooijen N, Haslett C, Howie SE, Simpson AJ, Hirani N, Gauldie J, Iredale JP, Sethi T, Forbes SJ. Ly6chi Monocytes Direct Alternatively Activated Profi‐ brotic Macrophage Regulation of Lung Fibrosis. American Journal of Respiratory

[149] Cabrera S, Gaxiola M, Arreola JL, Ramirez R, Jara P, D'Armiento J, Richards T, Sel‐ man M, Pardo A. Overexpression of Mmp9 in Macrophages Attenuates Pulmonary Fibrosis Induced by Bleomycin. The International Journal of Biochemistry and Cell

[150] Donaldson K, Stone V, Clouter A, Renwick L, MacNee W. Ultrafine Particles. Occu‐

[151] Geiser M, Casaulta M, Kupferschmid B, Schulz H, Semmler-Behnke M, Kreyling W. The Role of Macrophages in the Clearance of Inhaled Ultrafine Titanium Dioxide Particles. American Journal of Respiratory Cell and Molecular Biology. 2008;38(3):

[152] Andre E, Stoeger T, Takenaka S, Bahnweg M, Ritter B, Karg E, Lentner B, Reinhard C, Schulz H, Wjst M. Inhalation of Ultrafine Carbon Particles Triggers Biphasic Pro-Inflammatory Response in the Mouse Lung. The European Respiratory Journal.

[153] Stoeger T, Reinhard C, Takenaka S, Schroeppel A, Karg E, Ritter B, Heyder J, Schulz H. Instillation of Six Different Ultrafine Carbon Particles Indicates a Surface Area Threshold Dose for Acute Lung Inflammation in Mice. Environmental Health Per‐

[154] Ganguly K, Upadhyay S, Irmler M, Takenaka S, Pukelsheim K, Beckers J, Hamel‐ mann E, Schulz H, Stoeger T. Pathway Focused Protein Profiling Indicates Differen‐ tial Function for Il-1b,-18 and Vegf During Initiation and Resolution of Lung Inflammation Evoked by Carbon Nanoparticle Exposure in Mice. Particle and Fibre

pational and Environmental Medicine. 2001;58(3):211-216, 199.

of Clinical and Laboratory Investigation. 2009;69(5):575-578.

ratory Medicine. 2007;101(10):2176-2181.

Pathology. 1992;140(2):503-512.

Biology. 2007;39(12):2324-2338.

371-376.

56 Lung Inflammation

2006;28(2):275-285.

Toxicology 2009;6:31.

spectives. 2006;114(3):328-333.

and Critical Care Medicine 2011;184(5):569-581.

[156] Takenaka S, Möller W, Semmler-Behnke M, Karg E, Wenk A, Schmid O, Stoeger T, Jennen L, Aichler M, Walch A, Pokhrel S, Mädler L, Eickelberg O, Kreyling W. Effi‐ cient Internalization and Intracellular Translocation of Inhaled Gold Nanoparticles in Rat Alveolar Macrophages. Nanomedicine (London, England). 2012;7(6):855-865.

**Chapter 3**

**The Role of MMPs in the Progression of Chronic Lung**

The alveolar extracellular matrix (ECM) and chronic lung inflammatory diseases, such as pulmonary fibrosis and chronic obstructive pulmonary disease (COPD), are closely connected. Pulmonary fibrosis is associated with ECM production, deposition and remodeling. In contrast, COPD is defined by a loss of the ECM. Matrix metalloproteinases (MMPs) regulate ECM remodeling, and therefore play an important role in the development of chronic lung diseases. MMPs constitute a family of endopeptidases that have a common zinc-based active site. In this chapter, the role of MMPs in pulmonary fibrosis and COPD are discussed, mainly based on the findings in animal models. The effects of MMPs inhibitor on chronic lung disease

MMPs constitute a family of endopeptidases with a zinc molecule in their active site and a dependency on Ca2+ for their activity. MMPs are thought to be responsible for the turnover and degradation of the ECM [1-3]. In the lungs, these proteinases are synthesized and secreted by diverse cell types, including mesenchymal cells, macrophages, polymorphonuclear cells, alveolar type II epithelial cells, fibroblasts, smooth muscle cells, the lung parenchyma and

The most commonly used classifications are based partly on the historical assessment of the substrate specificity of the MMPs, and partly on the cellularlocalization of the MMPs. They can be divided into two main groups based on their domain and compartment location: basic

> © 2014 The Author(s). Licensee InTech. 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.

**Inflammatory Diseases**

http://dx.doi.org/10.5772/57391

Additional information is available at the end of the chapter

Masaki Fujita

**1. Introduction**

are also herein discussed.

inflammatory cells [4].

*Classification*

**2. Overview**
