CoChat
Sign Up
Cited by 4,495TGF-β signaling in diseasesInterstitial Lung Diseases and Idiopathic Pulmonary FibrosisLiver physiology and pathology

Cellular and molecular mechanisms of fibrosis

Open access
Wynn, TA·2008·The Journal of Pathology
DOI 10.1002/path.2277PMC PMC2693329
Open this paper in CoChat — free account

Abstract

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1002/path.2277

Cites

14 of 14 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Several cell types contribute to liver fibrosis, including hepatic stellate cells (HSCs) and other fibroblasts, liver sinusoidal endothelial cells (LSECs), and hepatocytes; the immune system also plays key roles.

    “Several cell types contribute to liver fibrosis, including hepatic stellate cells (HSCs) and other fibroblasts, liver sinusoidal endothelial cells (LSECs), and hepatocytes; however, the immune system also plays key roles (2, 6).”

    From Targeting macrophages in liver fibrosis (2026) · cites this paper as [6]

    The Introduction identifies hepatic stellate cells as the primary source of myofibroblasts in liver fibrosis and describes a prominent role for CD4+ T cells in a model of liver fibrosis. It discusses epithelial and endothelial cells as possible sources of myofibroblasts in fibrosis generally, but does not identify hepatocytes or liver sinusoidal endothelial cells specifically as contributors to liver fibrosis. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Prolonged inflammation and remodeling can lead to fibrosis or hypertrophic scar formation due to dysregulation of the default healing process.

    “In some cases, as will be discussed in further detail, prolonged inflammation and remodeling leading to fibrosis or hypertrophic scar formation may occur due to dysregulation of the default healing process [32,86,101,102].”

    From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [102]

  • Macrophages regulate fibrosis through production of cytokines that activate fibroblasts (TGF-β, PDGF, IGF-1), production of MMPs and TIMPs that drive ECM remodeling, and M1 factors (IL-1b) that drive feed-forward inflammation.

    “Briefly, macrophages regulate the process of fibrosis through the production of cytokines which directly activate fibroblasts (TGF-β, PDGF, insulin like growth factor (IGF)-1), the production of MMPs and TIMPs which drive ECM remodeling, and M1 factors which drive a “feed-forward” state of inflammation and remodeling (IL-1b) [102].”

    From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [102]

  • Macrophages can also regulate or reverse fibrosis through secretion of matrix degrading MMPs and M2 factors (IL-10, RELMα, Arg-1) that suppress fibrosis.

    “Macrophages, however, can also regulate or reverse fibrosis through the secretion of matrix degrading MMPs and other M2 factors that have been shown to suppress fibrosis (IL-10, RELMα, Arg-1) [102,138–140].”

    From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [102]

  • Persistent or dysregulated inflammation can result in fibrosis following tissue injury or infection.

    “Persistent or dysregulated inflammation can result in fibrosis following tissue injury or in the setting of infection [101,102].”

    From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [102]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 160

  1. [1]Wynn TA. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest. 2007;117(3):524–529. doi: 10.1172/JCI31487. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  2. [3]Friedman SL. Mechanisms of disease: mechanisms of hepatic fibrosis and therapeutic implications. Nat Clin Pract Gastroenterol Hepatol. 2004;1(2):98–105. doi: 10.1038/ncpgasthep0055. [DOI] [PubMed] [Google Scholar] · DOI
  3. [4]Schuppan D, Ruehl M, Somasundaram R, Hahn EG. Matrix as a modulator of hepatic fibrogenesis. Semin Liver Dis. 2001;21(3):351–372. doi: 10.1055/s-2001-17556. [DOI] [PubMed] [Google Scholar] · DOI
  4. [5]Kumar V, Abbas AK, Fausto N. Tissue renewal and repair: regeneration, healing, and fibrosis. In: Kumar V, Abbas AK, Fausto N, editors. Pathologic Basis of Disease. Elsevier Saunders; Philadelphia, PA: 2005. pp. 87–118. [Google Scholar]
  5. [6]Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol. 2006;24:99–146. doi: 10.1146/annurev.immunol.24.021605.090737. [DOI] [PubMed] [Google Scholar] · DOI
  6. [7]Wynn TA. IL-13 effector functions. Annu Rev Immunol. 2003;21:425–456. doi: 10.1146/annurev.immunol.21.120601.141142. [DOI] [PubMed] [Google Scholar] · DOI
  7. [8]Parsons CJ, Takashima M, Rippe RA. Molecular mechanisms of hepatic fibrogenesis. J Gastroenterol Hepatol. 2007;22(suppl 1):S79–84. doi: 10.1111/j.1440-1746.2006.04659.x. [DOI] [PubMed] [Google Scholar] · DOI
  8. [10]Quan TE, Cowper SE, Bucala R. The role of circulating fibrocytes in fibrosis. Curr Rheumatol Rep. 2006;8(2):145–150. doi: 10.1007/s11926-006-0055-x. [DOI] [PubMed] [Google Scholar] · DOI
  9. [11]Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E, et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med. 2007;13(8):952–961. doi: 10.1038/nm1613. Epub: 29 July 2007. [DOI] [PubMed] [Google Scholar] · DOI
  10. [12]Willis BC, du Bois RM, Borok Z. Epithelial origin of myofibroblasts during fibrosis in the lung. Proc Am Thorac Soc. 2006;3(4):377–382. doi: 10.1513/pats.200601-004TK. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  11. [13]Kalluri R, Neilson EG. Epithelial–mesenchymal transition and its implications for fibrosis. J Clin Invest. 2003;112(12):1776–1784. doi: 10.1172/JCI20530. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  12. [14]Bucala R, Spiegel LA, Chesney J, Hogan M, Cerami A. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol Med. 1994;1(1):71–81. [PMC free article] [PubMed] [Google Scholar]
  13. [15]Ebihara Y, Masuya M, Larue AC, Fleming PA, Visconti RP, Minamiguchi H, et al. Hematopoietic origins of fibroblasts: II. In vitro studies of fibroblasts, CFU-F, and fibrocytes. Exp Hematol. 2006;34(2):219–229. doi: 10.1016/j.exphem.2005.10.008. [DOI] [PubMed] [Google Scholar] · DOI
  14. [16]Brittan M, Hunt T, Jeffery R, Poulsom R, Forbes SJ, Hodivala-Dilke K, et al. Bone marrow derivation of pericryptal myofibroblasts in the mouse and human small intestine and colon. Gut. 2002;50(6):752–757. doi: 10.1136/gut.50.6.752. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  15. [17]Direkze NC, Forbes SJ, Brittan M, Hunt T, Jeffery R, Preston SL, et al. Multiple organ engraftment by bone-marrow-derived myofibroblasts and fibroblasts in bone-marrow-transplanted mice. Stem Cells. 2003;21(5):514–520. doi: 10.1634/stemcells.21-5-514. [DOI] [PubMed] [Google Scholar] · DOI
  16. [18]Forbes SJ, Russo FP, Rey V, Burra P, Rugge M, Wright NA, et al. A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis. Gastroenterology. 2004;126(4):955–963. doi: 10.1053/j.gastro.2004.02.025. [DOI] [PubMed] [Google Scholar] · DOI
  17. [19]Russo FP, Alison MR, Bigger BW, Amofah E, Florou A, Amin F, et al. The bone marrow functionally contributes to liver fibrosis. Gastroenterology. 2006;130(6):1807–1821. doi: 10.1053/j.gastro.2006.01.036. [DOI] [PubMed] [Google Scholar] · DOI
  18. [20]Phillips RJ, Burdick MD, Hong K, Lutz MA, Murray LA, Xue YY, et al. Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. J Clin Invest. 2004;114(3):438–446. doi: 10.1172/JCI20997. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  19. [21]Moore BB, Kolodsick JE, Thannickal VJ, Cooke K, Moore TA, Hogaboam C, et al. CCR2-mediated recruitment of fibrocytes to the alveolar space after fibrotic injury. Am J Pathol. 2005;166(3):675–684. doi: 10.1016/S0002-9440(10)62289-4. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  20. [22]Haudek SB, Xia Y, Huebener P, Lee JM, Carlson S, Craw-ford JR, et al. Bone marrow-derived fibroblast precursors mediate ischemic cardiomyopathy in mice. Proc Natl Acad Sci USA. 2006;103(48):18284–18289. doi: 10.1073/pnas.0608799103. Epub: 17 November 2006. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  21. [23]Meneghin MD, Hogaboam C. Infectious disease, the innate immune response, and fibrosis. J Clin Invest. 2007;117(3):530–538. doi: 10.1172/JCI30595. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  22. [26]Coelho AL, Hogaboam CM, Kunkel SL. Chemokines provide the sustained inflammatory bridge between innate and acquired immunity. Cytokine Growth Factor Rev. 2005;16(6):553–560. doi: 10.1016/j.cytogfr.2005.03.004. Epub: 20 June 2005. [DOI] [PubMed] [Google Scholar] · DOI
  23. [27]Strehlow D, Korn JH. Biology of the scleroderma fibroblast. Curr Opin Rheumatol. 1998;10(6):572–578. doi: 10.1097/00002281-199811000-00011. [DOI] [PubMed] [Google Scholar] · DOI
  24. [28]Abraham DJ, Varga J. Scleroderma: from cell and molecular mechanisms to disease models. Trends Immunol. 2005;26(11):587–595. doi: 10.1016/j.it.2005.09.004. Epub: 15 September 2005. [DOI] [PubMed] [Google Scholar] · DOI
  25. [29]Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest. 2007;117(3):557–567. doi: 10.1172/JCI31139. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  26. [31]Moustakas A, Heldin CH. Non-Smad TGFβ signals. J Cell Sci. 2005;118(16):3573–3584. doi: 10.1242/jcs.02554. [DOI] [PubMed] [Google Scholar] · DOI
  27. [32]Markiewicz M, Smith EA, Rubinchik S, Dong JY, Trojanowska M, LeRoy EC. The 72-kDa IE-1 protein of human cytomegalovirus (HCMV) is a potent inducer of connective tissue growth factor (CTGF) in human dermal fibroblasts. Clin Exp Rheumatol. 2004;22(3 suppl 33):S31–34. [PubMed] [Google Scholar]
  28. [33]Wang Y, Fan PS, Kahaleh B. Association between enhanced type I collagen expression and epigenetic repression of the FLI1 gene in scleroderma fibroblasts. Arthritis Rheum. 2006;54(7):2271–2279. doi: 10.1002/art.21948. [DOI] [PubMed] [Google Scholar] · DOI
  29. [34]Hasegawa M, Fujimoto M, Takehara K, Sato S. Pathogenesis of systemic sclerosis: altered B cell function is the key linking systemic autoimmunity and tissue fibrosis. J Dermatol Sci. 2005;39(1):1–7. doi: 10.1016/j.jdermsci.2005.03.013. [DOI] [PubMed] [Google Scholar] · DOI
  30. [36]Ong CJ, Ip S, Teh SJ, Wong C, Jirik FR, Grusby MJ, et al. A role for T helper 2 cells in mediating skin fibrosis in tight-skin mice. Cell Immunol. 1999;196(1):60–68. doi: 10.1006/cimm.1999.1537. [DOI] [PubMed] [Google Scholar] · DOI
  31. [37]Lakos G, Melichian D, Wu M, Varga J. Increased bleomycin-induced skin fibrosis in mice lacking the Th1-specific transcription factor T-bet. Pathobiology. 2006;73(5):224–237. doi: 10.1159/000098208. [DOI] [PubMed] [Google Scholar] · DOI
  32. [38]Aliprantis AO, Wang J, Fathman JW, Lemaire R, Dorfman DM, Lafyatis R, et al. Transcription factor T-bet regulates skin sclerosis through its function in innate immunity and via IL-13. Proc Natl Acad Sci USA. 2007;104(8):2827–2830. doi: 10.1073/pnas.0700021104. Epub: 16 February 2007. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  33. [39]Smith RE, Strieter RM, Phan SH, Lukacs NW, Huffnagle GB, Wilke CA, et al. Production and function of murine macrophage inflammatory protein-1α in bleomycin-induced lung injury. J Immunol. 1994;153(10):4704–4712. [PubMed] [Google Scholar]
  34. [40]Smith RE, Strieter RM, Zhang K, Phan SH, Standiford TJ, Lukacs NW, et al. A role for C–C chemokines in fibrotic lung disease. J Leukoc Biol. 1995;57(5):782–787. doi: 10.1002/jlb.57.5.782. [DOI] [PubMed] [Google Scholar] · DOI
  35. [41]Lloyd CM, Minto AW, Dorf ME, Proudfoot A, Wells TN, Salant DJ, 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. J Exp Med. 1997;185(7):1371–1380. doi: 10.1084/jem.185.7.1371. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  36. [42]Belperio JA, Keane MP, Burdick MD, Lynch JP, III, Xue YY, Berlin A, et al. Critical role for the chemokine MCP-1/CCR2 in the pathogenesis of bronchiolitis obliterans syndrome. J Clin Invest. 2001;108(4):547–556. doi: 10.1172/JCI12214. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  37. [43]Tokuda A, Itakura M, Onai N, Kimura H, Kuriyama T, Matsushima K. Pivotal role of CCR1-positive leukocytes in bleomycin-induced lung fibrosis in mice. J Immunol. 2000;164(5):2745–2751. doi: 10.4049/jimmunol.164.5.2745. [DOI] [PubMed] [Google Scholar] · DOI
  38. [44]Blease K, Mehrad B, Standiford TJ, Lukacs NW, Kunkel SL, Chensue SW, et al. Airway remodelling is absent in CCR1−/− mice during chronic fungal allergic airway disease. J Immunol. 2000;165(3):1564–1572. doi: 10.4049/jimmunol.165.3.1564. [DOI] [PubMed] [Google Scholar] · DOI
  39. [45]Anders HJ, Vielhauer V, Frink M, Linde Y, Cohen CD, Blattner SM, et al. A chemokine receptor CCR-1 antagonist reduces renal fibrosis after unilateral ureter ligation. J Clin Invest. 2002;109(2):251–259. doi: 10.1172/JCI14040. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  40. [46]Moore BB, Paine R, III, Christensen PJ, Moore TA, Sitterding S, Ngan R, et al. Protection from pulmonary fibrosis in the absence of CCR2 signalling. J Immunol. 2001;167(8):4368–4377. doi: 10.4049/jimmunol.167.8.4368. [DOI] [PubMed] [Google Scholar] · DOI
  41. [47]Zhu Z, Ma B, Zheng T, Homer RJ, Lee CG, Charo IF, et al. IL-13-induced chemokine responses in the lung: role of CCR2 in the pathogenesis of IL-13-induced inflammation and remodelling. J Immunol. 2002;168(6):2953–2962. doi: 10.4049/jimmunol.168.6.2953. [DOI] [PubMed] [Google Scholar] · DOI
  42. [48]Gao JL, Wynn TA, Chang Y, Lee EJ, Broxmeyer HE, Cooper S, et al. Impaired host defence, hematopoiesis, granulomatous inflammation and type 1-type 2 cytokine balance in mice lacking CC chemokine receptor 1. J Exp Med. 1997;185(11):1959–1968. doi: 10.1084/jem.185.11.1959. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  43. [49]Belperio JA, Dy M, Burdick MD, Xue YY, Li K, Elias JA, et al. Interaction of IL-13 and C10 in the pathogenesis of bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol. 2002;27(4):419–427. doi: 10.1165/rcmb.2002-0009OC. [DOI] [PubMed] [Google Scholar] · DOI
  44. [50]Ma B, Zhu Z, Homer RJ, Gerard C, Strieter R, Elias JA. The C10/CCL6 chemokine and CCR1 play critical roles in the pathogenesis of IL-13-induced inflammation and remodelling. J Immunol. 2004;172(3):1872–1881. doi: 10.4049/jimmunol.172.3.1872. [DOI] [PubMed] [Google Scholar] · DOI
  45. [51]Wynn TA, Cheever AW, Jankovic D, Poindexter RW, Caspar P, Lewis FA, et al. An IL-12-based vaccination method for preventing fibrosis induced by schistosome infection. Nature. 1995;376(6541):594–596. doi: 10.1038/376594a0. [DOI] [PubMed] [Google Scholar] · DOI
  46. [52]Cheever AW, Williams ME, Wynn TA, Finkelman FD, Seder RA, Cox TM, 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. J Immunol. 1994;153(2):753–759. [PubMed] [Google Scholar]
  47. [53]Chiaramonte MG, Donaldson DD, Cheever AW, Wynn TA. An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2-dominated inflammatory response. J Clin Invest. 1999;104(6):777–785. doi: 10.1172/JCI7325. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  48. [54]Pesce J, Kaviratne M, Ramalingam TR, Thompson RW, Urban JF, Jr, Cheever AW, et al. The IL-21 receptor augments Th2 effector function and alternative macrophage activation. J Clin Invest. 2006;116(7):2044–2055. doi: 10.1172/JCI27727. Epub: 15 June 2006. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  49. [55]Reiman RM, Thompson RW, Feng CG, Hari D, Knight R, Cheever AW, et al. Interleukin-5 (IL-5) augments the progression of liver fibrosis by regulating IL-13 activity. Infect Immun. 2006;74(3):1471–1479. doi: 10.1128/IAI.74.3.1471-1479.2006. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  50. [56]Gurujeyalakshmi G, Giri SN. Molecular mechanisms of antifibrotic effect of interferon-γ in bleomycin-mouse model of lung fibrosis: downregulation of TGFβ and procollagen I and III gene expression. Exp Lung Res. 1995;21(5):791–808. doi: 10.3109/01902149509050842. [DOI] [PubMed] [Google Scholar] · DOI
  51. [58]Oldroyd SD, Thomas GL, Gabbiani G, El Nahas AM. Interferon-γ inhibits experimental renal fibrosis. Kidney Int. 1999;56(6):2116–2127. doi: 10.1046/j.1523-1755.1999.00775.x. [DOI] [PubMed] [Google Scholar] · DOI
  52. [59]Poynard T, Yuen MF, Ratziu V, Lai CL. Viral hepatitis C. Lancet. 2003;362(9401):2095–2100. doi: 10.1016/s0140-6736(03)15109-4. [DOI] [PubMed] [Google Scholar] · DOI
  53. [60]Hesse M, Cheever AW, Jankovic D, Wynn TA. NOS-2 mediates the protective anti-inflammatory and antifibrotic effects of the Th1-inducing adjuvant, IL-12, in a Th2 model of granulomatous disease. Am J Pathol. 2000;157(3):945–955. doi: 10.1016/S0002-9440(10)64607-X. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  54. [61]Hessel EM, Chu M, Lizcano JO, Chang B, Herman N, Kell SA, et al. Immunostimulatory oligonucleotides block allergic airway inflammation by inhibiting Th2 cell activation and IgE-mediated cytokine induction. J Exp Med. 2005;202(11):1563–1573. doi: 10.1084/jem.20050631. Epub: 28 November 2005. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  55. [62]Hoffmann KF, McCarty TC, Segal DH, Chiaramonte M, Hesse M, Davis EM, et al. Disease fingerprinting with cDNA microarrays reveals distinct gene expression profiles in lethal type 1 and type 2 cytokine-mediated inflammatory reactions. FASEB J. 2001;15(13):2545–2547. doi: 10.1096/fj.01-0306fje. [DOI] [PubMed] [Google Scholar] · DOI
  56. [63]Sandler NG, Mentink-Kane MM, Cheever AW, Wynn TA. Global gene expression profiles during acute pathogen-induced pulmonary inflammation reveal divergent roles for Th1 and Th2 responses in tissue repair. J Immunol. 2003;171(7):3655–3667. doi: 10.4049/jimmunol.171.7.3655. [DOI] [PubMed] [Google Scholar] · DOI
  57. [64]Zeeberg BR, Qin H, Narasimhan S, Sunshine M, Cao H, Kane DW, 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) BMC Bioinformat. 2005;6:168. doi: 10.1186/1471-2105-6-168. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  58. [65]Walker LS, Abbas AK. The enemy within: keeping self-reactive T cells at bay in the periphery. Nat Rev Immunol. 2002;2(1):11–19. doi: 10.1038/nri701. [DOI] [PubMed] [Google Scholar] · DOI
  59. [66]Hesse M, Modolell M, La Flamme AC, Schito M, Fuentes JM, Cheever AW, 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 metabolism. J Immunol. 2001;167(11):6533–6544. doi: 10.4049/jimmunol.167.11.6533. [DOI] [PubMed] [Google Scholar] · DOI
  60. [67]Decitre M, Gleyzal C, Raccurt M, Peyrol S, Aubert-Foucher E, Csiszar K, 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. Lab Invest. 1998;78(2):143–151. [PubMed] [Google Scholar]
  61. [68]Akiri G, Sabo E, Dafni H, Vadasz Z, Kartvelishvily Y, Gan N, et al. Lysyl oxidase-related protein-1 promotes tumor fibrosis and tumor progression in vivo. Cancer Res. 2003;63(7):1657–1666. [PubMed] [Google Scholar]
  62. [69]Wang S, Hirschberg R. BMP7 antagonizes TGFβ-dependent fibrogenesis in mesangial cells. Am J Physiol Renal Physiol. 2003;284(5):F1006–1013. doi: 10.1152/ajprenal.00382.2002. [DOI] [PubMed] [Google Scholar] · DOI
  63. [70]Cheng S, Lovett DH. Gelatinase A (MMP-2) is necessary and sufficient for renal tubular cell epithelial–mesenchymal transformation. Am J Pathol. 2003;162(6):1937–1949. doi: 10.1016/S0002-9440(10)64327-1. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  64. [71]Underwood DC, Osborn RR, Bochnowicz S, Webb EF, Rieman DJ, Lee JC, et al. SB 239063, a p38 MAPK inhibitor, reduces neutrophilia, inflammatory cytokines, MMP-9, and fibrosis in lung. Am J Physiol Lung Cell Mol Physiol. 2000;279(5):L895–902. doi: 10.1152/ajplung.2000.279.5.L895. [DOI] [PubMed] [Google Scholar] · DOI
  65. [72]Heymans S, Lupu F, Terclavers S, Vanwetswinkel B, Herbert JM, Baker A, et al. Loss or inhibition of uPA or MMP-9 attenuates LV remodelling and dysfunction after acute pressure overload in mice. Am J Pathol. 2005;166(1):15–25. doi: 10.1016/S0002-9440(10)62228-6. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  66. [73]Kim H, Oda T, Lopez-Guisa J, Wing D, Edwards DR, Soloway PD, et al. TIMP-1 deficiency does not attenuate interstitial fibrosis in obstructive nephropathy. J Am Soc Nephrol. 2001;12(4):736–748. doi: 10.1681/ASN.V124736. [DOI] [PubMed] [Google Scholar] · DOI
  67. [74]Vaillant B, Chiaramonte MG, Cheever AW, Soloway PD, Wynn TA. Regulation of hepatic fibrosis and extracellular matrix genes by the Th response: New insight into the role of tissue inhibitors of matrix metalloproteinases. J Immunol. 2001;167(12):7017–7026. doi: 10.4049/jimmunol.167.12.7017. [DOI] [PubMed] [Google Scholar] · DOI
  68. [75]Kaminski N, Allard JD, Pittet JF, Zuo F, Griffiths MJ, Morris D, et al. Global analysis of gene expression in pulmonary fibrosis reveals distinct programs regulating lung inflammation and fibrosis. Proc Natl Acad Sci USA. 2000;97(4):1778–1783. doi: 10.1073/pnas.97.4.1778. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  69. [76]Kristensen DB, Kawada N, Imamura K, Miyamoto Y, Tateno C, Seki S, et al. Proteome analysis of rat hepatic stellate cells. Hepatology. 2000;32(2):268–277. doi: 10.1053/jhep.2000.9322. [DOI] [PubMed] [Google Scholar] · DOI
  70. [77]Emura M, Nagai S, Takeuchi M, Kitaichi M, Izumi T, Nishimura K, 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. Clin Exp Immunol. 1990;82(1):133–139. doi: 10.1111/j.1365-2249.1990.tb05416.x. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  71. [78]Wallace WA, Ramage EA, Lamb D, Howie SE. A type 2 (Th2-like) pattern of immune response predominates in the pulmonary interstitium of patients with cryptogenic fibrosing alveolitis (CFA) Clin Exp Immunol. 1995;101(3):436–441. doi: 10.1111/j.1365-2249.1995.tb03131.x. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  72. [79]Booth M, Mwatha JK, Joseph S, Jones FM, Kadzo H, Ireri E, et al. Periportal fibrosis in human Schistosoma mansoni infection is associated with low IL-10, low IFNγ, high TNFα, or low RANTES, depending on age and gender. J Immunol. 2004;172(2):1295–1303. doi: 10.4049/jimmunol.172.2.1295. [DOI] [PubMed] [Google Scholar] · DOI
  73. [80]Buttner C, Skupin A, Reimann T, Rieber EP, Unteregger G, Geyer P, et al. Local production of interleukin-4 during radiation-induced pneumonitis and pulmonary fibrosis in rats: macrophages as a prominent source of interleukin-4. Am J Respir Cell Mol Biol. 1997;17(3):315–325. doi: 10.1165/ajrcmb.17.3.2279. [DOI] [PubMed] [Google Scholar] · DOI
  74. [81]Fertin C, Nicolas JF, Gillery P, Kalis B, Banchereau J, Maquart FX. Interleukin-4 stimulates collagen synthesis by normal and scleroderma fibroblasts in dermal equivalents. Cell Mol Biol. 1991;37(8):823–829. [PubMed] [Google Scholar]
  75. [82]Letterio JJ, Roberts AB. Regulation of immune responses by TGFβ. Annu Rev Immunol. 1998;16:137–161. doi: 10.1146/annurev.immunol.16.1.137. [DOI] [PubMed] [Google Scholar] · DOI
  76. [83]Sempowski GD, Beckmann MP, Derdak S, Phipps RP. Subsets of murine lung fibroblasts express membrane-bound and soluble IL-4 receptors. Role of IL-4 in enhancing fibroblast proliferation and collagen synthesis. J Immunol. 1994;152(7):3606–3614. [PubMed] [Google Scholar]
  77. [84]Doucet C, Brouty-Boye D, Pottin-Clemenceau C, Canonica GW, Jasmin C, Azzarone B. Interleukin (IL)-4 and IL-13 act on human lung fibroblasts. Implication in asthma. J Clin Invest. 1998;101(10):2129–2139. doi: 10.1172/JCI741. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  78. [85]Ong C, Wong C, Roberts CR, Teh HS, Jirik FR. Anti-IL-4 treatment prevents dermal collagen deposition in the tight-skin mouse model of scleroderma. Eur J Immunol. 1998;28(9):2619–2629. doi: 10.1002/(SICI)1521-4141(199809)28:09<2619::AID-IMMU2619>3.0.CO;2-M. [DOI] [PubMed] [Google Scholar] · DOI
  79. [86]Le Moine A, Flamand V, Demoor FX, Noel JC, Surquin M, Kiss R, et al. Critical roles for IL-4, IL-5, and eosinophils in chronic skin allograft rejection. J Clin Invest. 1999;103(12):1659–1667. doi: 10.1172/JCI5504. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  80. [87]Zurawski SM, Vega F, Jr, Huyghe B, Zurawski G. Receptors for interleukin-13 and interleukin-4 are complex and share a novel component that functions in signal transduction. EMBO J. 1993;12(7):2663–2670. doi: 10.1002/j.1460-2075.1993.tb05927.x. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  81. [88]McKenzie GJ, Emson CL, Bell SE, Anderson S, Fallon P, Zurawski G, et al. Impaired development of Th2 cells in IL-13-deficient mice. Immunity. 1998;9(3):423–432. doi: 10.1016/s1074-7613(00)80625-1. [DOI] [PubMed] [Google Scholar] · DOI
  82. [89]Zhu Z, Homer RJ, Wang Z, Chen Q, Geba GP, Wang J, et al. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest. 1999;103(6):779–788. doi: 10.1172/JCI5909. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  83. [90]Donaldson DD, Whitters MJ, Fitz LJ, Neben TY, Finnerty H, Henderson SL, et al. The murine IL-13 receptor α2: molecular cloning, characterization, and comparison with murine IL-13 receptor α1. J Immunol. 1998;161(5):2317–2324. [PubMed] [Google Scholar]
  84. [91]Blease K, Jakubzick C, Westwick J, Lukacs N, Kunkel SL, Hogaboam CM. Therapeutic effect of IL-13 immunoneutralization during chronic experimental fungal asthma. J Immunol. 2001;166(8):5219–5224. doi: 10.4049/jimmunol.166.8.5219. [DOI] [PubMed] [Google Scholar] · DOI
  85. [92]Kumar RK, Herbert C, Yang M, Koskinen AM, McKenzie AN, Foster PS. Role of interleukin-13 in eosinophil accumulation and airway remodelling in a mouse model of chronic asthma. Clin Exp Allergy. 2002;32(7):1104–1111. doi: 10.1046/j.1365-2222.2002.01420.x. [DOI] [PubMed] [Google Scholar] · DOI
  86. [93]Keane MP, Gomperts BN, Weigt S, Xue YY, Burdick MD, Nakamura H, et al. IL-13 is pivotal in the fibro-obliterative process of bronchiolitis obliterans syndrome. J Immunol. 2007;178(1):511–519. doi: 10.4049/jimmunol.178.1.511. [DOI] [PubMed] [Google Scholar] · DOI
  87. [94]Kolodsick JE, Toews GB, Jakubzick C, Hogaboam C, Moore TA, McKenzie A, et al. Protection from fluorescein isothiocyanate-induced fibrosis in IL-13-deficient, but not IL-4-deficient, mice results from impaired collagen synthesis by fibroblasts. J Immunol. 2004;172(7):4068–4076. doi: 10.4049/jimmunol.172.7.4068. [DOI] [PubMed] [Google Scholar] · DOI
  88. [95]Chiaramonte MG, Cheever AW, Malley JD, Donaldson DD, Wynn TA. Studies of murine schistosomiasis reveal interleukin-13 blockade as a treatment for established and progressive liver fibrosis. Hepatology. 2001;34(2):273–282. doi: 10.1053/jhep.2001.26376. [DOI] [PubMed] [Google Scholar] · DOI
  89. [96]Fallon PG, Richardson EJ, McKenzie GJ, McKenzie AN. Schistosome infection of transgenic mice defines distinct and contrasting pathogenic roles for IL-4 and IL-13: IL-13 is a profibrotic agent. J Immunol. 2000;164(5):2585–2591. doi: 10.4049/jimmunol.164.5.2585. [DOI] [PubMed] [Google Scholar] · DOI
  90. [97]Rankin JA, Picarella DE, Geba GP, Temann UA, Prasad B, DiCosmo B, et al. Phenotypic and physiologic characterization of transgenic mice expressing interleukin 4 in the lung: lymphocytic and eosinophilic inflammation without airway hyperreactivity. Proc Natl Acad Sci USA. 1996;93(15):7821–7825. doi: 10.1073/pnas.93.15.7821. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  91. [98]Webb DC, Mahalingam S, Cai Y, Matthaei KI, Donaldson DD, Foster PS. Antigen-specific production of interleukin (IL)-13 and IL-5 cooperate to mediate IL-4Rα-independent airway hyperreactivity. Eur J Immunol. 2003;33(12):3377–3385. doi: 10.1002/eji.200324178. [DOI] [PubMed] [Google Scholar] · DOI
  92. [99]Blease K, Schuh JM, Jakubzick C, Lukacs NW, Kunkel SL, Joshi BH, et al. Stat6-deficient mice develop airway hyperresponsiveness and peribronchial fibrosis during chronic fungal asthma. Am J Pathol. 2002;160(2):481–490. doi: 10.1016/S0002-9440(10)64867-5. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  93. [100]Fichtner-Feigl S, Strober W, Kawakami K, Puri RK, Kitani A. IL-13 signalling through the IL-13α2 receptor is involved in induction of TGFβ1 production and fibrosis. Nat Med. 2006;12(1):99–106. doi: 10.1038/nm1332. Epub: 4 December 2005. [DOI] [PubMed] [Google Scholar] · DOI
  94. [101]Wood N, Whitters MJ, Jacobson BA, Witek J, Sypek JP, Kasaian M, et al. Enhanced interleukin (IL)-13 responses in mice lacking IL-13 receptor α2. J Exp Med. 2003;197(6):703–709. doi: 10.1084/jem.20020906. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  95. [102]Gharaee-Kermani M, Phan SH. Lung interleukin-5 expression in murine bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol. 1997;16(4):438–447. doi: 10.1165/ajrcmb.16.4.9115755. [DOI] [PubMed] [Google Scholar] · DOI
  96. [103]Ochkur SI, Jacobsen EA, Protheroe CA, Biechele TL, Pero RS, McGarry MP, et al. Coexpression of IL-5 and eotaxin-2 in mice creates an eosinophil-dependent model of respiratory inflammation with characteristics of severe asthma. J Immunol. 2007;178(12):7879–7889. doi: 10.4049/jimmunol.178.12.7879. [DOI] [PubMed] [Google Scholar] · DOI
  97. [104]Williams TJ. The eosinophil enigma. J Clin Invest. 2004;113(4):507–509. doi: 10.1172/JCI21073. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  98. [105]Sher A, Coffman RL, Heiny S, Scott P, Cheever AW. Interleukin 5 is required for the blood and tissue eosinophilia but not granuloma formation induced by infection with Schistosoma mansoni. Proc Natl Acad Sci USA. 1990;87:61–64. doi: 10.1073/pnas.87.1.61. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  99. [106]Hao H, Cohen DA, Jennings CD, Bryson JS, Kaplan AM. Bleomycin-induced pulmonary fibrosis is independent of eosinophils. J Leukoc Biol. 2000;68(4):515–521. [PubMed] [Google Scholar]
  100. [107]Gharaee-Kermani M, McGarry B, Lukacs N, Huffnagle G, Egan RW, Phan SH. The role of IL-5 in bleomycin-induced pulmonary fibrosis. J Leukoc Biol. 1998;64(5):657–666. doi: 10.1002/jlb.64.5.657. [DOI] [PubMed] [Google Scholar] · DOI
  101. [108]Blyth DI, Wharton TF, Pedrick MS, Savage TJ, Sanjar S. Airway subepithelial fibrosis in a murine model of atopic asthma: suppression by dexamethasone or anti-interleukin-5 antibody. Am J Respir Cell Mol Biol. 2000;23(2):241–246. doi: 10.1165/ajrcmb.23.2.3999. [DOI] [PubMed] [Google Scholar] · DOI
  102. [109]Cho JY, Miller M, Baek KJ, Han JW, Nayar J, Lee SY, et al. Inhibition of airway remodelling in IL-5-deficient mice. J Clin Invest. 2004;113(4):551–560. doi: 10.1172/JCI19133. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  103. [110]Trifilieff A, Fujitani Y, Coyle AJ, Kopf M, Bertrand C. IL-5 deficiency abolishes aspects of airway remodelling in a murine model of lung inflammation. Clin Exp Allergy. 2001;31(6):934–942. doi: 10.1046/j.1365-2222.2001.01084.x. [DOI] [PubMed] [Google Scholar] · DOI
  104. [111]Huaux F, Liu T, McGarry B, Ullenbruch M, Xing Z, Phan SH. Eosinophils and T lymphocytes possess distinct roles in bleomycin-induced lung injury and fibrosis. J Immunol. 2003;171(10):5470–5481. doi: 10.4049/jimmunol.171.10.5470. [DOI] [PubMed] [Google Scholar] · DOI
  105. [112]Mattes J, Yang M, Mahalingam S, Kuehr J, Webb DC, Simson L, 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. J Exp Med. 2002;195(11):1433–1444. doi: 10.1084/jem.20020009. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  106. [113]Tanaka H, Komai M, Nagao K, Ishizaki M, Kajiwara D, Takatsu K, et al. Role of IL-5 and eosinophils in allergen-induced airway remodelling in mice. Am J Respir Cell Mol Biol. 2004;19:19. doi: 10.1165/rcmb.2003-0305OC. [DOI] [PubMed] [Google Scholar] · DOI
  107. [114]Frohlich A, Marsland BJ, Sonderegger I, Kurrer M, Hodge MR, Harris NL, et al. IL-21 receptor signalling is integral to the development of Th2 effector responses in vivo. Blood. 2007;109(5):2023–2031. doi: 10.1182/blood-2006-05-021600. Epub: 31 October 2006. [DOI] [PubMed] [Google Scholar] · DOI
  108. [115]Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M, Vuthoori S, et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest. 2005;115(1):56–65. doi: 10.1172/JCI22675. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  109. [116]Sato M, Muragaki Y, Saika S, Roberts AB, Ooshima A. Targeted disruption of TGFβ1/Smad3 signalling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction. J Clin Invest. 2003;112(10):1486–1494. doi: 10.1172/JCI19270. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  110. [117]Border WA, Noble NA, Yamamoto T, Harper JR, Yamaguchi Y, Pierschbacher MD, et al. Natural inhibitor of transforming growth factor-β protects against scarring in experimental kidney disease. Nature. 1992;360(6402):361–364. doi: 10.1038/360361a0. [DOI] [PubMed] [Google Scholar] · DOI
  111. [118]Clouthier DE, Comerford SA, Hammer RE. Hepatic fibrosis, glomerulosclerosis, and a lipodystrophy-like syndrome in PEPCK-TGFβ1 transgenic mice. J Clin Invest. 1997;100(11):2697–2713. doi: 10.1172/JCI119815. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  112. [119]Sime PJ, Xing Z, Graham FL, Csaky KG, Gauldie J. Adeno-vector-mediated gene transfer of active transforming growth factor-β1 induces prolonged severe fibrosis in rat lung. J Clin Invest. 1997;100(4):768–776. doi: 10.1172/JCI119590. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  113. [121]Munger JS, Huang X, Kawakatsu H, Griffiths MJ, Dalton SL, Wu J, et al. The integrin αvβ6 binds and activates latent TGFβ1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell. 1999;96(3):319–328. doi: 10.1016/s0092-8674(00)80545-0. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  114. [122]Roberts AB, Russo A, Felici A, Flanders KC. Smad3: a key player in pathogenetic mechanisms dependent on TGFβ. Ann NY Acad Sci. 2003;995:1–10. doi: 10.1111/j.1749-6632.2003.tb03205.x. [DOI] [PubMed] [Google Scholar] · DOI
  115. [123]Flanders KC, Sullivan CD, Fujii M, Sowers A, Anzano MA, Arabshahi A, et al. Mice lacking Smad3 are protected against cutaneous injury induced by ionizing radiation. Am J Pathol. 2002;160(3):1057–1068. doi: 10.1016/S0002-9440(10)64926-7. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  116. [125]Khalil N, Corne S, Whitman C, Yacyshyn H. Plasmin regulates the activation of cell-associated latent TGFβ1 secreted by rat alveolar macrophages after in vivo bleomycin injury. Am J Respir Cell Mol Biol. 1996;15(2):252–259. doi: 10.1165/ajrcmb.15.2.8703482. [DOI] [PubMed] [Google Scholar] · DOI
  117. [126]Ma LJ, Yang H, Gaspert A, Carlesso G, Barty MM, Davidson JM, et al. Transforming growth factor-β-dependent and-independent pathways of induction of tubulointerstitial fibrosis in β6−/− mice. Am J Pathol. 2003;163(4):1261–1273. doi: 10.1016/s0002-9440(10)63486-4. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  118. [127]Ashcroft GS, Yang X, Glick AB, Weinstein M, Letterio JL, Mizel DE, et al. Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat Cell Biol. 1999;1(5):260–266. doi: 10.1038/12971. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  119. [129]Lanone S, Zheng T, Zhu Z, Liu W, Lee CG, Ma B, et al. Overlapping and enzyme-specific contributions of matrix metalloproteinases-9 and-12 in IL-13-induced inflammation and remodelling. J Clin Invest. 2002;110(4):463–474. doi: 10.1172/JCI14136. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  120. [130]Elias JA, Zhu Z, Chupp G, Homer RJ. Airway remodelling in asthma. J Clin Invest. 1999;104(8):1001–1006. doi: 10.1172/JCI8124. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  121. [131]Nakao A, Miike S, Hatano M, Okumura K, Tokuhisa T, Ra C, et al. Blockade of transforming growth factor beta/Smad signalling in T cells by overexpression of Smad7 enhances antigen-induced airway inflammation and airway reactivity. J Exp Med. 2000;192(2):151–158. doi: 10.1084/jem.192.2.151. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  122. [132]Hansen G, McIntire JJ, Yeung VP, Berry G, Thorbecke GJ, Chen L, et al. CD4+ T helper cells engineered to produce latent TGFβ1 reverse allergen-induced airway hyperreactivity and inflammation. J Clin Invest. 2000;105(1):61–70. doi: 10.1172/JCI7589. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  123. [133]Kitani A, Fuss I, Nakamura K, Kumaki F, Usui T, Strober W. Transforming growth factor (TGF)-β1-producing regulatory T cells induce Smad-mediated interleukin 10 secretion that facilitates coordinated immunoregulatory activity and amelioration of TGFβ1-mediated fibrosis. J Exp Med. 2003;198(8):1179–1188. doi: 10.1084/jem.20030917. Epub: 13 October 2003. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  124. [134]Daniels CE, Wilkes MC, Edens M, Kottom TJ, Murphy SJ, Limper AH, et al. Imatinib mesylate inhibits the profibrogenic activity of TGFβ and prevents bleomycin-mediated lung fibrosis. J Clin Invest. 2004;114(9):1308–1316. doi: 10.1172/JCI19603. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  125. [136]Del Papa N, Quirici N, Soligo D, Scavullo C, Cortiana M, Borsotti C, et al. Bone marrow endothelial progenitors are defective in systemic sclerosis. Arthritis Rheum. 2006;54(8):2605–2615. doi: 10.1002/art.22035. [DOI] [PubMed] [Google Scholar] · DOI
  126. [137]Wilkinson-Berka JL. Angiotensin and diabetic retinopathy. Int J Biochem Cell Biol. 2006;38(5–6):752–765. doi: 10.1016/j.biocel.2005.08.002. Epub: 1 September 2005. [DOI] [PubMed] [Google Scholar] · DOI
  127. [138]Rattner A, Nathans J. Macular degeneration: recent advances and therapeutic opportunities. Nat Rev Neurosci. 2006;7(11):860–872. doi: 10.1038/nrn2007. Epub: 11 October 2006. [DOI] [PubMed] [Google Scholar] · DOI
  128. [139]Friedlander M. Fibrosis and diseases of the eye. J Clin Invest. 2007;117(3):576–586. doi: 10.1172/JCI31030. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  129. [140]Strieter RM, Gomperts BN, Keane MP. The role of CXC chemokines in pulmonary fibrosis. J Clin Invest. 2007;117(3):549–556. doi: 10.1172/JCI30562. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  130. [141]Watanabe T, Barker TA, Berk BC. Angiotensin II and the endothelium: diverse signals and effects. Hypertension. 2005;45(2):163–169. doi: 10.1161/01.HYP.0000153321.13792.b9. Epub: 3 January 2005. [DOI] [PubMed] [Google Scholar] · DOI
  131. [142]Mezzano SA, Ruiz-Ortega M, Egido J. Angiotensin II and renal fibrosis. Hypertension. 2001;38(3 Pt 2):635–638. doi: 10.1161/hy09t1.094234. [DOI] [PubMed] [Google Scholar] · DOI
  132. [143]Rosenkranz S. TGFβ1 and angiotensin networking in cardiac remodelling. Cardiovasc Res. 2004;63(3):423–432. doi: 10.1016/j.cardiores.2004.04.030. [DOI] [PubMed] [Google Scholar] · DOI
  133. [144]Bataller R, Schwabe RF, Choi YH, Yang L, Paik YH, Lindquist J, et al. NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis. J Clin Invest. 2003;112(9):1383–1394. doi: 10.1172/JCI18212. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  134. [145]Rosenkranz S, Flesch M, Amann K, Haeuseler C, Kilter H, Seeland U, et al. Alterations of β-adrenergic signalling and cardiac hypertrophy in transgenic mice overexpressing TGFβ1. Am J Physiol Heart Circ Physiol. 2002;283(3):H1253–1262. doi: 10.1152/ajpheart.00578.2001. [DOI] [PubMed] [Google Scholar] · DOI
  135. [146]Li RK, Li G, Mickle DA, Weisel RD, Merante F, Luss H, et al. Overexpression of transforming growth factor-β1 and insulin-like growth factor-I in patients with idiopathic hypertrophic cardiomyopathy. Circulation. 1997;96(3):874–881. doi: 10.1161/01.cir.96.3.874. [DOI] [PubMed] [Google Scholar] · DOI
  136. [147]Berk BC, Fujiwara K, Lehoux S. ECM remodelling in hypertensive heart disease. J Clin Invest. 2007;117(3):568–575. doi: 10.1172/JCI31044. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  137. [148]Iwano M, Neilson EG. Mechanisms of tubulointerstitial fibrosis. Curr Opin Nephrol Hypertens. 2004;13(3):279–284. doi: 10.1097/00041552-200405000-00003. [DOI] [PubMed] [Google Scholar] · DOI
  138. [150]Thompson K, Maltby J, Fallowfield J, McAulay M, Millward-Sadler H, Sheron N. Interleukin-10 expression and function in experimental murine liver inflammation and fibrosis. Hepatology. 1998;28(6):1597–1606. doi: 10.1002/hep.510280620. [DOI] [PubMed] [Google Scholar] · DOI
  139. [151]Louis H, Van Laethem JL, Wu W, Quertinmont E, Degraef C, Van den Berg K, et al. Interleukin-10 controls neutrophilic infiltration, hepatocyte proliferation, and liver fibrosis induced by carbon tetrachloride in mice. Hepatology. 1998;28(6):1607–1615. doi: 10.1002/hep.510280621. [DOI] [PubMed] [Google Scholar] · DOI
  140. [152]Arai T, Abe K, Matsuoka H, Yoshida M, Mori M, Goya S, et al. Introduction of the interleukin-10 gene into mice inhibited bleomycin-induced lung injury in vivo. Am J Physiol Lung Cell Mol Physiol. 2000;278(5):L914–922. doi: 10.1152/ajplung.2000.278.5.L914. [DOI] [PubMed] [Google Scholar] · DOI
  141. [153]Demols A, Van Laethem JL, Quertinmont E, Degraef C, Delhaye M, Geerts A, et al. Endogenous interleukin-10 modulates fibrosis and regeneration in experimental chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol. 2002;282(6):G1105–1112. doi: 10.1152/ajpgi.00431.2001. [DOI] [PubMed] [Google Scholar] · DOI
  142. [154]Wangoo A, Laban C, Cook HT, Glenville B, Shaw RJ. Interleukin-10- and corticosteroid-induced reduction in type I procollagen in a human ex vivo scar culture. Int J Exp Pathol. 1997;78(1):33–41. doi: 10.1046/j.1365-2613.1997.d01-241.x. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  143. [155]Wang SC, Ohata M, Schrum L, Rippe RA, Tsukamoto H. Expression of interleukin-10 by in vitro and in vivo activated hepatic stellate cells. J Biol Chem. 1998;273(1):302–308. doi: 10.1074/jbc.273.1.302. [DOI] [PubMed] [Google Scholar] · DOI
  144. [156]Nelson DR, Tu Z, Soldevila-Pico C, Abdelmalek M, Zhu H, Xu YL, et al. Long-term interleukin 10 therapy in chronic hepatitis C patients has a proviral and anti-inflammatory effect. Hepatology. 2003;38(4):859–868. doi: 10.1053/jhep.2003.50427. [DOI] [PubMed] [Google Scholar] · DOI
  145. [157]Wynn TA, Cheever AW, Williams ME, Hieny S, Caspar P, Kühn R, et al. IL-10 regulates liver pathology in acute murine schistosomiasis mansoni but is not required for immune down-modulation of chronic disease. J Immunol. 1998;160:5000–5008. [PubMed] [Google Scholar]
  146. [158]Hoffmann KF, Cheever AW, Wynn TA. 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. J Immunol. 2000;164(12):6406–6416. doi: 10.4049/jimmunol.164.12.6406. [DOI] [PubMed] [Google Scholar] · DOI
  147. [160]Taube C, Duez C, Cui ZH, Takeda K, Rha YH, Park JW, et al. The role of IL-13 in established allergic airway disease. J Immunol. 2002;169(11):6482–6489. doi: 10.4049/jimmunol.169.11.6482. [DOI] [PubMed] [Google Scholar] · DOI
  148. [161]Mattes J, Yang M, Siqueira A, Clark K, MacKenzie J, McKenzie AN, et al. IL-13 induces airways hyperreactivity independently of the IL-4R α chain in the allergic lung. J Immunol. 2001;167(3):1683–1692. doi: 10.4049/jimmunol.167.3.1683. [DOI] [PubMed] [Google Scholar] · DOI
  149. [162]Feng N, Lugli SM, Schnyder B, Gauchat JF, Graber P, Schlagenhauf E, et al. The interleukin-4/interleukin-13 receptor of human synovial fibroblasts: overexpression of the nonsignalling interleukin-13 receptor α2. Lab Invest. 1998;78(5):591–602. [PubMed] [Google Scholar]
  150. [163]Chiaramonte MG, Mentink-Kane M, Jacobson BA, Cheever AW, Whitters MJ, Goad ME, et al. Regulation and function of the interleukin 13 receptor α2 during a T helper cell type 2-dominant immune response. J Exp Med. 2003;197(6):687–701. doi: 10.1084/jem.20020903. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  151. [164]Mentink-Kane MM, Cheever AW, Thompson RW, Hari DM, Kabatereine NB, Vennervald BJ, et al. IL-13 receptor α2 down-modulates granulomatous inflammation and prolongs host survival in schistosomiasis. Proc Natl Acad Sci USA. 2004;101(2):90–586. doi: 10.1073/pnas.0305064101. Epub: 29 December 2003. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  152. [165]Issa R, Zhou X, Constandinou CM, Fallowfield J, Millward-Sadler H, Gaca MD, et al. Spontaneous recovery from micronodular cirrhosis: evidence for incomplete resolution associated with matrix cross-linking. Gastroenterology. 2004;126(7):808–1795. doi: 10.1053/j.gastro.2004.03.009. [DOI] [PubMed] [Google Scholar] · DOI
  153. [167]Fallowfield JA, Kendall TJ, Iredale JP. Reversal of fibrosis: no longer a pipe dream? Clin Liver Dis. 2006;10(3):481–497. doi: 10.1016/j.cld.2006.08.022. [DOI] [PubMed] [Google Scholar] · DOI
  154. [168]Vennervald BJ, Dunne DW. Morbidity in schistosomiasis: an update. Curr Opin Infect Dis. 2004;17(5):439–447. doi: 10.1097/00001432-200410000-00009. [DOI] [PubMed] [Google Scholar] · DOI
  155. [169]Lund RD, Wang S, Klimanskaya I, Holmes T, Ramos-Kelsey R, Lu B, et al. Human embryonic stem cell-derived cells rescue visual function in dystrophic RCS rats. Cloning Stem Cells. 2006;8(3):189–199. doi: 10.1089/clo.2006.8.189. [DOI] [PubMed] [Google Scholar] · DOI
  156. [170]Iredale JP, Benyon RC, Pickering J, McCullen M, Northrop M, Pawley S, et al. Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest. 1998;102(3):538–549. doi: 10.1172/JCI1018. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  157. [171]Thannickal VJ, Toews GB, White ES, Lynch JP, 3rd, Martinez FJ. Mechanisms of pulmonary fibrosis. Annu Rev Med. 2004;55:395–417. doi: 10.1146/annurev.med.55.091902.103810. [DOI] [PubMed] [Google Scholar] · DOI
  158. [172]Wright MC, Issa R, Smart DE, Trim N, Murray GI, Primrose JN, et al. Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cells and enhances the resolution of liver fibrosis in rats. Gastroenterology. 2001;121(3):685–698. doi: 10.1053/gast.2001.27188. [DOI] [PubMed] [Google Scholar] · DOI
  159. [173]Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006;98(5):1076–1084. doi: 10.1002/jcb.20886. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  160. [174]Huang H, Shiffman ML, Friedman S, Venkatesh R, Bzowej N, Abar OT, et al. A seven gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C. Hepatology. 2007;46(2):297–306. doi: 10.1002/hep.21695. [DOI] [PubMed] [Google Scholar] · DOI

Cited by

Sorted by citations

Authors
Wynn, T.
Venue
The Journal of Pathology
Publisher
Wiley
Published
2007-12-27
Volume
214
Issue
2
Pages
199-210
ISSN
  • 0022-3417 (ISSN-L)
  • 1096-9896
DOI
10.1002/path.2277
PMC
PMC2693329
OpenAlex
W1980325398
Cited by
4,495
References
14
Citations by year
2026: 226 · 2025: 255 · 2024: 321 · 2023: 312 · 2022: 300 · 2021: 361 · 2020: 285 · 2019: 257 · 2018: 238 · 2017: 224 · 2016: 220 · 2015: 245 · 2014: 210 · 2013: 216 · 2012: 236
FWCI
9.58
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • The Journal of Pathology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute of Allergy and Infectious Diseases (Z01AI001019, Z01AI000829)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
fibrosis, fibrogenesis, myofibroblasts, extracellular matrix deposition, collagen, epithelial-mesenchymal transition, endothelial-to-mesenchymal transition, fibrocytes, fibroblast activation, pattern recognition receptors, Toll-like receptors, pathogen-associated molecular patterns, cytokines, chemokines, renin-angiotensin-aldosterone system, antifibrotic agents, idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, renal fibrosis, cardiovascular fibrosis
MeSH terms
Angiotensin II, Chemotaxis, Fibroblasts, Fibrosis, Humans, Immunity, Innate, Interleukins, Cytokines, Transforming Growth Factor beta, Th1 Cells, Th2 Cells, Disease Progression, Chemokines

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review