Cellular and molecular mechanisms of fibrosis

Fibrosis is defined by the overgrowth, hardening, and/or scarring of various tissues and is attributed to excess deposition of extracellular matrix components including collagen. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli including persistent infections, autoimmune reactions, allergic responses, chemical insults, radiation, and tissue injury. Although current treatments for fibrotic diseases such as idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis typically target the inflammatory response, there is accumulating evidence that the mechanisms driving fibrogenesis are distinct from those regulating inflammation. In fact, some studies have suggested that ongoing inflammation is needed to reverse established and progressive fibrosis. The key cellular mediator of fibrosis is the myofibroblast, which when activated serves as the primary collagen‐producing cell. Myofibroblasts are generated from a variety of sources including resident mesenchymal cells, epithelial and endothelial cells in processes termed epithelial/endothelial‐mesenchymal (EMT/EndMT) transition, as well as from circulating fibroblast‐like cells called fibrocytes that are derived from bone‐marrow stem cells. Myofibroblasts are activated by a variety of mechanisms, including paracrine signals derived from lymphocytes and macrophages, autocrine factors secreted by myofibroblasts, and pathogen‐associated molecular patterns (PAMPS) produced by pathogenic organisms that interact with pattern recognition receptors (i.e. TLRs) on fibroblasts. Cytokines (IL‐13, IL‐21, TGF‐β1), chemokines (MCP‐1, MIP‐1β), angiogenic factors (VEGF), growth factors (PDGF), peroxisome proliferator‐activated receptors (PPARs), acute phase proteins (SAP), caspases, and components of the renin–angiotensin–aldosterone system (ANG II) have been identified as important regulators of fibrosis and are being investigated as potential targets of antifibrotic drugs. This review explores our current understanding of the cellular and molecular mechanisms of fibrogenesis. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

[1]  D. Lovett,et al.  Gelatinase A (MMP-2) is necessary and sufficient for renal tubular cell epithelial-mesenchymal transformation. , 2003, The American journal of pathology.

[2]  B. Schnyder,et al.  The interleukin-4/interleukin-13 receptor of human synovial fibroblasts: overexpression of the nonsignaling interleukin-13 receptor alpha2. , 1998, Laboratory investigation; a journal of technical methods and pathology.

[3]  M. Kitaichi,et al.  In vitro production of B cell growth factor and B cell differentiation factor by peripheral blood mononuclear cells and bronchoalveolar lavage T lymphocytes from patients with idiopathic pulmonary fibrosis , 1990, Clinical and experimental immunology.

[4]  B. Stripp,et al.  Phenotypic and physiologic characterization of transgenic mice expressing interleukin 4 in the lung: lymphocytic and eosinophilic inflammation without airway hyperreactivity. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Minghua Wu,et al.  Increased Bleomycin-Induced Skin Fibrosis in Mice Lacking the Th1-Specific Transcription Factor T-bet , 2007, Pathobiology.

[6]  R. Gomer,et al.  Bone marrow-derived fibroblast precursors mediate ischemic cardiomyopathy in mice , 2006, Proceedings of the National Academy of Sciences.

[7]  R. Homer,et al.  Airway remodeling in asthma. , 1999, The Journal of clinical investigation.

[8]  R. Rippe,et al.  Expression of Interleukin-10 by in Vitro and in Vivo Activated Hepatic Stellate Cells* , 1998, The Journal of Biological Chemistry.

[9]  D. Lamb,et al.  A type 2 (Th2‐like) pattern of immune response predominates in the pulmonary interstitium of patients with cryptogenic fibrosing alveolitis (CFA) , 1995, Clinical and experimental immunology.

[10]  A. Sher,et al.  IL-10 regulates liver pathology in acute murine Schistosomiasis mansoni but is not required for immune down-modulation of chronic disease. , 1998, Journal of immunology.

[11]  J. Fallowfield,et al.  Spontaneous recovery from micronodular cirrhosis: evidence for incomplete resolution associated with matrix cross-linking. , 2004, Gastroenterology.

[12]  B. Kahaleh,et al.  Association between enhanced type I collagen expression and epigenetic repression of the FLI1 gene in scleroderma fibroblasts. , 2006, Arthritis and rheumatism.

[13]  徳田 敦子.  Pivotal role of CCR1-positive leukocytes in bleomycin-induced lung fibrosis in mice , 2001 .

[14]  M. Burdick,et al.  Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. , 2004, The Journal of clinical investigation.

[15]  R. Puri,et al.  IL-13 signaling through the IL-13α2 receptor is involved in induction of TGF-β1 production and fibrosis , 2006, Nature Medicine.

[16]  David G. Morris,et al.  Global analysis of gene expression in pulmonary fibrosis reveals distinct programs regulating lung inflammation and fibrosis. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[17]  N. Khalil,et al.  Plasmin regulates the activation of cell-associated latent TGF-beta 1 secreted by rat alveolar macrophages after in vivo bleomycin injury. , 1996, American journal of respiratory cell and molecular biology.

[18]  John C. Lee,et al.  SB 239063, a p38 MAPK inhibitor, reduces neutrophilia, inflammatory cytokines, MMP-9, and fibrosis in lung. , 2000, American journal of physiology. Lung cellular and molecular physiology.

[19]  C. Heldin,et al.  Non-Smad TGF-β signals , 2005, Journal of Cell Science.

[20]  D D Donaldson,et al.  The murine IL-13 receptor alpha 2: molecular cloning, characterization, and comparison with murine IL-13 receptor alpha 1. , 1998, Journal of immunology.

[21]  T. Williams,et al.  The eosinophil enigma. , 2004, The Journal of clinical investigation.

[22]  E. Pearce,et al.  Differential Regulation of Nitric Oxide Synthase-2 and Arginase-1 by Type 1/Type 2 Cytokines In Vivo: Granulomatous Pathology Is Shaped by the Pattern of l-Arginine Metabolism1 , 2001, The Journal of Immunology.

[23]  R. Egan,et al.  The role of IL‐5 in bleomycin‐induced pulmonary fibrosis , 1998, Journal of leukocyte biology.

[24]  T. Moore,et al.  Protection from Fluorescein Isothiocyanate-Induced Fibrosis in IL-13-Deficient, but Not IL-4-Deficient, Mice Results from Impaired Collagen Synthesis by Fibroblasts1 , 2004, The Journal of Immunology.

[25]  R. Lund,et al.  Human embryonic stem cell-derived cells rescue visual function in dystrophic RCS rats. , 2006, Cloning and stem cells.

[26]  J. Korn,et al.  Biology of the scleroderma fibroblast. , 1998, Current opinion in rheumatology.

[27]  J. Fallowfield,et al.  Reversal of fibrosis: no longer a pipe dream? , 2006, Clinics in liver disease.

[28]  Olivia T. Abar,et al.  A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C , 2007, Hepatology.

[29]  D. Sheppard,et al.  Transforming Growth Factor-β-Dependent and -Independent Pathways of Induction of Tubulointerstitial Fibrosis in β6−/− Mice , 2003 .

[30]  T. Wynn,et al.  Regulation and Function of the Interleukin 13 Receptor α 2 During a T Helper Cell Type 2–dominant Immune Response , 2003, The Journal of experimental medicine.

[31]  T. Moore,et al.  Protection from Pulmonary Fibrosis in the Absence of CCR2 Signaling1 , 2001, The Journal of Immunology.

[32]  A. Wangoo,et al.  Interleukin‐10‐ and corticosteroid‐induced reduction in type I procollagen in a human ex vivo scar culture , 1997, International journal of experimental pathology.

[33]  F Verrecchia,et al.  [Cellular and molecular mechanisms of fibrosis]. , 2006, Annales de pathologie.

[34]  M. Burdick,et al.  Production and function of murine macrophage inflammatory protein-1 alpha in bleomycin-induced lung injury. , 1994, Journal of immunology.

[35]  D. Kasper,et al.  Cellular mechanism of intraabdominal abscess formation by Bacteroides fragilis. , 1998, Journal of immunology.

[36]  J D Malley,et al.  Studies of murine schistosomiasis reveal interleukin‐13 blockade as a treatment for established and progressive liver fibrosis , 2001, Hepatology.

[37]  G. Zurawski,et al.  Receptors for interleukin‐13 and interleukin‐4 are complex and share a novel component that functions in signal transduction. , 1993, The EMBO journal.

[38]  H. Minamiguchi,et al.  Hematopoietic origins of fibroblasts: II. In vitro studies of fibroblasts, CFU-F, and fibrocytes. , 2006, Experimental hematology.

[39]  M. Burdick,et al.  IL-12 attenuates bleomycin-induced pulmonary fibrosis. , 2001, American journal of physiology. Lung cellular and molecular physiology.

[40]  James B. Mitchell,et al.  Mice lacking Smad3 are protected against cutaneous injury induced by ionizing radiation. , 2002, The American journal of pathology.

[41]  E. Gelfand,et al.  The Role of IL-13 in Established Allergic Airway Disease1 , 2002, The Journal of Immunology.

[42]  S. Rosenkranz,et al.  Alterations of β-adrenergic signaling and cardiac hypertrophy in transgenic mice overexpressing TGF-β1 , 2002 .

[43]  佐藤 三佐子.  Targeted disruption of TGF-β1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction , 2005 .

[44]  Wei Wu,et al.  Interleukin‐10 controls neutrophilic infiltration, hepatocyte proliferation, and liver fibrosis induced by carbon tetrachloride in mice , 1998, Hepatology.

[45]  T. Wynn,et al.  An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2-dominated inflammatory response. , 1999, The Journal of clinical investigation.

[46]  R. Coffman,et al.  Interleukin-10 and the interleukin-10 receptor. , 2001, Annual review of immunology.

[47]  M. Fujimoto,et al.  Pathogenesis of systemic sclerosis: altered B cell function is the key linking systemic autoimmunity and tissue fibrosis. , 2005, Journal of dermatological science.

[48]  G. Davis,et al.  Long‐term interleukin 10 therapy in chronic hepatitis C patients has a proviral and anti‐inflammatory effect , 2003, Hepatology.

[49]  T. Wynn,et al.  Interleukin-5 (IL-5) Augments the Progression of Liver Fibrosis by Regulating IL-13 Activity , 2006, Infection and Immunity.

[50]  T. Wynn,et al.  IL-13 receptor alpha 2 down-modulates granulomatous inflammation and prolongs host survival in schistosomiasis. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[51]  W. Williams,et al.  Overexpression of transforming growth factor-beta1 and insulin-like growth factor-I in patients with idiopathic hypertrophic cardiomyopathy. , 1997, Circulation.

[52]  R. Flavell,et al.  Transforming growth factor-β in T-cell biology , 2002, Nature Reviews Immunology.

[53]  C. Bertrand,et al.  IL‐5 deficiency abolishes aspects of airway remodelling in a murine model of lung inflammation , 2001, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[54]  R. Homer,et al.  Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. , 1999, The Journal of clinical investigation.

[55]  D. Podolsky,et al.  Intestinal myofibroblasts in innate immune responses of the intestine. , 2003, Gastroenterology.

[56]  G. Canonica,et al.  Interleukin (IL) 4 and IL-13 act on human lung fibroblasts. Implication in asthma. , 1998, The Journal of clinical investigation.

[57]  B. Willis,et al.  Epithelial origin of myofibroblasts during fibrosis in the lung. , 2006, Proceedings of the American Thoracic Society.

[58]  T. Wynn,et al.  The IL-21 receptor augments Th2 effector function and alternative macrophage activation. , 2006, The Journal of clinical investigation.

[59]  S. Phan,et al.  Eosinophils and T Lymphocytes Possess Distinct Roles in Bleomycin-Induced Lung Injury and Fibrosis 1 , 2003, The Journal of Immunology.

[60]  Christopher J. Parsons,et al.  Molecular mechanisms of hepatic fibrogenesis , 2007, Journal of gastroenterology and hepatology.

[61]  T. Standiford,et al.  A role for C‐C chemokines in fibrotic lung disease , 1995, Journal of leukocyte biology.

[62]  M. Burdick,et al.  Interaction of IL-13 and C10 in the pathogenesis of bleomycin-induced pulmonary fibrosis. , 2002, American journal of respiratory cell and molecular biology.

[63]  B. Berk,et al.  Angiotensin II and the Endothelium: Diverse Signals and Effects , 2005, Hypertension.

[64]  Xueli Yuan,et al.  Endothelial-to-mesenchymal transition contributes to cardiac fibrosis , 2007, Nature Medicine.

[65]  E. Rieber,et al.  Local production of interleukin-4 during radiation-induced pneumonitis and pulmonary fibrosis in rats: macrophages as a prominent source of interleukin-4. , 1997, American journal of respiratory cell and molecular biology.

[66]  P. Foster,et al.  Antigen‐specific production of interleukin (IL)‐13 and IL‐5 cooperate to mediate IL‐4Rα‐independent airway hyperreactivity , 2003, European journal of immunology.

[67]  B. Ma,et al.  The C10/CCL6 Chemokine and CCR1 Play Critical Roles in the Pathogenesis of IL-13-Induced Inflammation and Remodeling1 , 2004, The Journal of Immunology.

[68]  P. Foster,et al.  Intrinsic Defect in T Cell Production of Interleukin (IL)-13 in the Absence of Both IL-5 and Eotaxin Precludes the Development of Eosinophilia and Airways Hyperreactivity in Experimental Asthma , 2002, The Journal of experimental medicine.

[69]  D. Dunne,et al.  Morbidity in schistosomiasis: an update , 2001, Current opinion in infectious diseases.

[70]  A. Roberts,et al.  Targeted disruption of TGF-beta1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction. , 2003, The Journal of clinical investigation.

[71]  T. Wynn,et al.  Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. , 2007, The Journal of clinical investigation.

[72]  G. McKenzie,et al.  Impaired development of Th2 cells in IL-13-deficient mice. , 1998, Immunity.

[73]  J. Fallowfield,et al.  Interleukin‐10 expression and function in experimental murine liver inflammation and fibrosis , 1998, Hepatology.

[74]  B. Vaillant,et al.  Regulation of Hepatic Fibrosis and Extracellular Matrix Genes by the Th Response: New Insight into the Role of Tissue Inhibitors of Matrix Metalloproteinases , 2001, Journal of Immunology.

[75]  R. Hammer,et al.  Hepatic fibrosis, glomerulosclerosis, and a lipodystrophy-like syndrome in PEPCK-TGF-beta1 transgenic mice. , 1997, The Journal of clinical investigation.

[76]  Anita B. Roberts,et al.  REGULATION OF IMMUNE RESPONSES BY TGF-β* , 1998 .

[77]  R. Puri,et al.  Stat6-deficient mice develop airway hyperresponsiveness and peribronchial fibrosis during chronic fungal asthma. , 2002, The American journal of pathology.

[78]  G. Sempowski,et al.  Subsets of murine lung fibroblasts express membrane-bound and soluble IL-4 receptors. Role of IL-4 in enhancing fibroblast proliferation and collagen synthesis. , 1994, Journal of immunology.

[79]  M. Rugge,et al.  A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis. , 2004, Gastroenterology.

[80]  D. Cohen,et al.  Bleomycin‐induced pulmonary fibrosis is independent of eosinophils , 2000, Journal of leukocyte biology.

[81]  G. Gabbiani,et al.  Interferon-γ inhibits experimental renal fibrosis , 1999 .

[82]  J. Varga,et al.  Scleroderma: from cell and molecular mechanisms to disease models. , 2005, Trends in immunology.

[83]  P. Foster,et al.  Role of interleukin‐13 in eosinophil accumulation and airway remodelling in a mouse model of chronic asthma , 2002, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[84]  N. Kaminski,et al.  The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. , 1999, Cell.

[85]  R. Schwabe,et al.  NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis. , 2003, The Journal of clinical investigation.

[86]  A. Sher,et al.  Anti-IL-4 treatment of Schistosoma mansoni-infected mice inhibits development of T cells and non-B, non-T cells expressing Th2 cytokines while decreasing egg-induced hepatic fibrosis. , 1994, Journal of immunology.

[87]  T. Wynn.  Fibrotic disease and the TH1/TH2 paradigm , 2004, Nature Reviews Immunology.

[88]  R. Bucala,et al.  Circulating Fibrocytes Define a New Leukocyte Subpopulation That Mediates Tissue Repair , 1994, Molecular medicine.

[89]  H. Broxmeyer,et al.  Impaired Host Defense, Hematopoiesis, Granulomatous Inflammation and Type 1–Type 2 Cytokine Balance in Mice Lacking CC Chemokine Receptor 1 , 1997, The Journal of experimental medicine.

[90]  R. Homer,et al.  Interleukin-13 Induces Tissue Fibrosis by Selectively Stimulating and Activating Transforming Growth Factor β1 , 2001, The Journal of experimental medicine.

[91]  S. Forbes,et al.  Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. , 2005, The Journal of clinical investigation.

[92]  R. Strieter,et al.  The role of CXC chemokines in pulmonary fibrosis. , 2007, The Journal of clinical investigation.

[93]  T. Wynn.  IL-13 effector functions. , 2003, Annual review of immunology.

[94]  Anita B. Roberts,et al.  Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response , 1999, Nature Cell Biology.

[95]  S. Phan,et al.  Lung interleukin-5 expression in murine bleomycin-induced pulmonary fibrosis. , 1997, American journal of respiratory cell and molecular biology.

[96]  L. Lichtenstein,et al.  Interleukin-13 modulates collagen homeostasis in human skin and keloid fibroblasts. , 2000, The Journal of pharmacology and experimental therapeutics.

[97]  W. Strober,et al.  Transforming Growth Factor (TGF)-β1–producing Regulatory T Cells Induce Smad-mediated Interleukin 10 Secretion That Facilitates Coordinated Immunoregulatory Activity and Amelioration of TGF-β1–mediated Fibrosis , 2003, The Journal of experimental medicine.

[98]  T. Wynn.  Fibrotic disease and the T(H)1/T(H)2 paradigm. , 2004, Nature reviews. Immunology.

[99]  T. Colby,et al.  Coexpression of IL-5 and Eotaxin-2 in Mice Creates an Eosinophil-Dependent Model of Respiratory Inflammation with Characteristics of Severe Asthma1 , 2007, The Journal of Immunology.

[100]  R. Flavell,et al.  IL-13Ralpha2 and IL-10 coordinately suppress airway inflammation, airway-hyperreactivity, and fibrosis in mice. , 2007, The Journal of clinical investigation.

[101]  P. Sommer,et al.  Lysyl oxidase-like protein localizes to sites of de novo fibrinogenesis in fibrosis and in the early stromal reaction of ductal breast carcinomas. , 1998, Laboratory investigation; a journal of technical methods and pathology.

[102]  T. Wynn,et al.  IL-10 and the Dangers of Immune Polarization: Excessive Type 1 and Type 2 Cytokine Responses Induce Distinct Forms of Lethal Immunopathology in Murine Schistosomiasis , 2000, The Journal of Immunology.

[103]  J. Devière,et al.  Endogenous interleukin-10 modulates fibrosis and regeneration in experimental chronic pancreatitis. , 2002, American journal of physiology. Gastrointestinal and liver physiology.

[104]  R. Hirschberg,et al.  BMP7 antagonizes TGF-β-dependent fibrogenesis in mesangial cells , 2003 .

[105]  F. Jirik,et al.  A role for T helper 2 cells in mediating skin fibrosis in tight-skin mice. , 1999, Cellular immunology.

[106]  E. Neilson,et al.  Mechanisms of tubulointerstitial fibrosis. , 2010, Journal of the American Society of Nephrology : JASN.

[107]  R. Kalluri,et al.  Epithelial-mesenchymal transition and its implications for fibrosis. , 2003, The Journal of clinical investigation.

[108]  B. Hinz,et al.  Myofibroblasts and mechano-regulation of connective tissue remodelling , 2002, Nature Reviews Molecular Cell Biology.

[109]  G. Gurujeyalakshmi,et al.  Molecular mechanisms of antifibrotic effect of interferon gamma in bleomycin-mouse model of lung fibrosis: downregulation of TGF-beta and procollagen I and III gene expression. , 1995, Experimental lung research.

[110]  B. Ma,et al.  Overlapping and enzyme-specific contributions of matrix metalloproteinases-9 and -12 in IL-13-induced inflammation and remodeling. , 2002, The Journal of clinical investigation.

[111]  B. Ma,et al.  IL-13-Induced Chemokine Responses in the Lung: Role of CCR2 in the Pathogenesis of IL-13-Induced Inflammation and Remodeling1 , 2002, The Journal of Immunology.

[112]  D. Edwards,et al.  TIMP-1 deficiency does not attenuate interstitial fibrosis in obstructive nephropathy. , 2001, Journal of the American Society of Nephrology : JASN.

[113]  G. McKenzie,et al.  Schistosome Infection of Transgenic Mice Defines Distinct and Contrasting Pathogenic Roles for IL-4 and IL-13: IL-13 Is a Profibrotic Agent1 , 2000, The Journal of Immunology.

[114]  T. Hunt,et al.  Multiple Organ Engraftment by Bone‐Marrow‐Derived Myofibroblasts and Fibroblasts in Bone‐Marrow‐Transplanted Mice , 2003, Stem cells.

[115]  T. Wynn,et al.  NOS-2 mediates the protective anti-inflammatory and antifibrotic effects of the Th1-inducing adjuvant, IL-12, in a Th2 model of granulomatous disease. , 2000, The American journal of pathology.

[116]  M. Washington,et al.  TGF-ß Signaling in Fibroblasts Modulates the Oncogenic Potential of Adjacent Epithelia , 2004, Science.

[117]  R. Coffman,et al.  Interleukin 5 is required for the blood and tissue eosinophilia but not granuloma formation induced by infection with Schistosoma mansoni. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[118]  J. Iredale.  Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. , 2007, The Journal of clinical investigation.

[119]  R. Kiss,et al.  Critical roles for IL-4, IL-5, and eosinophils in chronic skin allograft rejection. , 1999, The Journal of clinical investigation.

[120]  Jeremy Nathans,et al.  Macular degeneration: recent advances and therapeutic opportunities , 2006, Nature Reviews Neuroscience.

[121]  David Abraham,et al.  Systemic sclerosis: a prototypic multisystem fibrotic disorder. , 2007, The Journal of clinical investigation.

[122]  Vinay Kumar,et al.  Tissue Renewal and Repair: Regeneration, Healing, and Fibrosis , 2010 .

[123]  J. Iredale,et al.  Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cells and enhances the resolution of liver fibrosis in rats. , 2001, Gastroenterology.

[124]  A. Gabrielli,et al.  Bone marrow endothelial progenitors are defective in systemic sclerosis. , 2006, Arthritis and rheumatism.

[125]  M. Kurrer,et al.  IL-21 receptor signaling is integral to the development of Th2 effector responses in vivo. , 2007, Blood.

[126]  S. Sanjar,et al.  Airway subepithelial fibrosis in a murine model of atopic asthma: suppression by dexamethasone or anti-interleukin-5 antibody. , 2000, American journal of respiratory cell and molecular biology.

[127]  P. Foster,et al.  IL-13 Induces Airways Hyperreactivity Independently of the IL-4Rα Chain in the Allergic Lung1 , 2001, The Journal of Immunology.

[128]  C. Daniels,et al.  Imatinib mesylate inhibits the profibrogenic activity of TGF-beta and prevents bleomycin-mediated lung fibrosis. , 2004, The Journal of clinical investigation.

[129]  P. Carmeliet,et al.  Loss or inhibition of uPA or MMP-9 attenuates LV remodeling and dysfunction after acute pressure overload in mice. , 2005, The American journal of pathology.

[130]  L. Glimcher,et al.  Transcription factor T-bet regulates skin sclerosis through its function in innate immunity and via IL-13 , 2007, Proceedings of the National Academy of Sciences.

[131]  R. Poulsom,et al.  Bone marrow derivation of pericryptal myofibroblasts in the mouse and human small intestine and colon , 2002, Gut.

[132]  E. Ruoslahti,et al.  Natural inhibitor of transforming growth factor-β protects against scarring in experimental kidney disease , 1992, Nature.

[133]  N. Kabatereine,et al.  Periportal Fibrosis in Human Schistosoma mansoni Infection Is Associated with Low IL-10, Low IFN-γ, High TNF-α, or Low RANTES, Depending on Age and Gender 1 , 2004, The Journal of Immunology.

[134]  R. Bucala,et al.  The role of circulating fibrocytes in fibrosis , 2006, Current rheumatology reports.

[135]  J. Iredale,et al.  Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. , 1998, The Journal of clinical investigation.

[136]  A. Abbas,et al.  The enemy within: keeping self-reactive T cells at bay in the periphery , 2002, Nature Reviews Immunology.

[137]  Richard A Flavell,et al.  Transforming growth factor-beta regulation of immune responses. , 2006, Annual review of immunology.

[138]  Airway Remodelling in Asthma , 2006, Archivos de bronconeumologia.

[139]  M. Friedlander.  Fibrosis and diseases of the eye. , 2007, The Journal of clinical investigation.

[140]  S. Rosenkranz.  TGF-β1 and angiotensin networking in cardiac remodeling , 2004 .

[141]  S. Friedman,et al.  Mechanisms of Disease: mechanisms of hepatic fibrosis and therapeutic implications , 2004, Nature Clinical Practice Gastroenterology &Hepatology.

[142]  Shizuo Akira,et al.  Toll-like receptor signalling , 2004, Nature Reviews Immunology.

[143]  C. Hogaboam,et al.  Infectious disease, the innate immune response, and fibrosis. , 2007, The Journal of clinical investigation.

[144]  A. Caplan,et al.  Mesenchymal stem cells as trophic mediators , 2006, Journal of cellular biochemistry.

[145]  M. Neeman,et al.  Lysyl oxidase-related protein-1 promotes tumor fibrosis and tumor progression in vivo. , 2003, Cancer research.

[146]  F. Jirik,et al.  Anti‐IL‐4 treatment prevents dermal collagen deposition in the tight‐skin mouse model of scleroderma , 1998, European journal of immunology.

[147]  M. Hatano,et al.  Blockade of Transforming Growth Factor β/Smad Signaling in T Cells by Overexpression of Smad7 Enhances Antigen-Induced Airway Inflammation and Airway Reactivity , 2000, The Journal of experimental medicine.

[148]  J. Westwick,et al.  Therapeutic Effect of IL-13 Immunoneutralization During Chronic Experimental Fungal Asthma1 , 2001, The Journal of Immunology.

[149]  T. Moore,et al.  CCR2-mediated recruitment of fibrocytes to the alveolar space after fibrotic injury. , 2005, The American journal of pathology.

[150]  Michael J. Grusby,et al.  Enhanced Interleukin (IL)-13 Responses in Mice Lacking IL-13 Receptor α 2 , 2003, The Journal of experimental medicine.

[151]  D. Salant,et al.  RANTES and Monocyte Chemoattractant Protein–1 (MCP-1) Play an Important Role in the Inflammatory Phase of Crescentic Nephritis, but Only MCP-1 Is Involved in Crescent Formation and Interstitial Fibrosis , 1997, The Journal of experimental medicine.

[152]  Y. Kaneda,et al.  Introduction of the interleukin-10 gene into mice inhibited bleomycin-induced lung injury in vivo. , 2000, American journal of physiology. Lung cellular and molecular physiology.

[153]  D. Broide,et al.  Inhibition of airway remodeling in IL-5-deficient mice. , 2004, The Journal of clinical investigation.

[154]  S. Seki,et al.  Proteome analysis of rat hepatic stellate cells , 2000, Hepatology.

[155]  C. Page,et al.  Airway remodelling in asthma , 2002 .

[156]  T. Standiford,et al.  Airway Remodeling Is Absent in CCR1−/− Mice During Chronic Fungal Allergic Airway Disease1 , 2000, The Journal of Immunology.

[157]  R. Coffman,et al.  Immunostimulatory oligonucleotides block allergic airway inflammation by inhibiting Th2 cell activation and IgE-mediated cytokine induction , 2005, The Journal of experimental medicine.

[158]  F. Martinez,et al.  Mechanisms of pulmonary fibrosis. , 2004, Annual review of medicine.

[159]  John N. Weinstein,et al.  High-Throughput GoMiner, an 'industrial-strength' integrative gene ontology tool for interpretation of multiple-microarray experiments, with application to studies of Common Variable Immune Deficiency (CVID) , 2005, BMC Bioinformatics.

[160]  L. Wakefield,et al.  IL-13 Activates a Mechanism of Tissue Fibrosis That Is Completely TGF-β Independent , 2004, The Journal of Immunology.

[161]  M. Burdick,et al.  Critical role for the chemokine MCP-1/CCR2 in the pathogenesis of bronchiolitis obliterans syndrome. , 2001, The Journal of clinical investigation.

[162]  K. Csaky,et al.  Adenovector-mediated gene transfer of active transforming growth factor-beta1 induces prolonged severe fibrosis in rat lung. , 1997, The Journal of clinical investigation.

[163]  J. Munger.  The integrin αvβ6 binds and activates latent TGFβ1 : A mechanism for regulating pulmonary inflammation and fibrosis , 1999 .

[164]  K. Fujiwara,et al.  ECM remodeling in hypertensive heart disease. , 2007, The Journal of clinical investigation.

[165]  K. Takatsu,et al.  Role of interleukin-5 and eosinophils in allergen-induced airway remodeling in mice. , 2004, American journal of respiratory cell and molecular biology.

[166]  J. Egido,et al.  Angiotensin II and renal fibrosis. , 2001, Hypertension.

[167]  G. Berry,et al.  CD4(+) T helper cells engineered to produce latent TGF-beta1 reverse allergen-induced airway hyperreactivity and inflammation. , 2000, The Journal of clinical investigation.

[168]  Luca Mascitelli,et al.  Viral hepatitis C , 2004, The Lancet.

[169]  J. Dong,et al.  The 72-kilodalton IE-1 protein of human cytomegalovirus (HCMV) is a potent inducer of connective tissue growth factor (CTGF) in human dermal fibroblasts. , 2004, Clinical and experimental rheumatology.

[170]  S. Kunkel,et al.  Chemokines provide the sustained inflammatory bridge between innate and acquired immunity. , 2005, Cytokine & growth factor reviews.

[171]  A. Sher,et al.  An IL-12-based vaccination method for preventing fibrosis induced by schistosome infection , 1995, Nature.

[172]  S. Forbes,et al.  The bone marrow functionally contributes to liver fibrosis. , 2006, Gastroenterology.

[173]  J. Banchereau,et al.  Interleukin-4 stimulates collagen synthesis by normal and scleroderma fibroblasts in dermal equivalents. , 1992, Cellular and molecular biology.

[174]  C. Cohen,et al.  A chemokine receptor CCR-1 antagonist reduces renal fibrosis after unilateral ureter ligation. , 2002, The Journal of clinical investigation.

[175]  K. Flanders,et al.  Smad3: A Key Player in Pathogenetic Mechanisms Dependent on TGF‐β , 2003, Annals of the New York Academy of Sciences.

[176]  M. Selman,et al.  Matrix metalloproteases in aberrant fibrotic tissue remodeling. , 2006, Proceedings of the American Thoracic Society.

[177]  J. Wilkinson-Berka.  Angiotensin and diabetic retinopathy. , 2006, The international journal of biochemistry & cell biology.

[178]  D. Schuppan,et al.  Matrix as a modulator of hepatic fibrogenesis. , 2001, Seminars in liver disease.

[179]  P. Meltzer,et al.  Disease fingerprinting with cDNA microarrays reveals distinct gene expression profiles in lethal type‐1 and type‐2 cytokine‐mediated inflammatory reactions , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.