The Pathogenesis of Intraabdominal Adhesions: Similarities and Differences to Luminal Fibrosis

  • Edward MacarakEmail author
  • Joel Rosenbloom


Essentially every organ in the human body, including the intestine, can be affected by fibrotic reactions. Under normal homeostatic conditions these reactions are self-limited and constitute an important reparative process aimed at the restoration of the functional integrity of injured tissues. However, under pathologic circumstances the homeostatic regulatory mechanisms evolve into an uncontrolled fibrotic process characterized by the accumulation of large amounts of fibrotic tissue, which disrupts normal organ architecture and ultimately leads to organ failure. Even though their etiology varies greatly, all fibrotic reactions share common features. It is universally accepted that myofibroblasts are the cells ultimately responsible for the pathologic fibrotic process. Myofibroblasts, expressing α-smooth muscle actin (α-SMA), comprise a distinctive population of mesenchymal cells. When activated, they markedly increase the production of fibrillar collagens (types I, III, V, and VI) and other extracellular matrix (ECM) macromolecules coupled with an increased inhibition of ECM-degradative enzymes which may result in the production of injurious scar tissue in the intestine. While abdominal adhesions may be caused by infection, inflammation or ischemia, surgical procedures are the primary cause. Unfortunately, adequate therapeutic solutions have proven elusive. The peritoneal surfaces, both visceral and parietal, are covered by a monolayer of mesothelial cells bound to a basement membrane. Because the mesothelial cells are weakly connected, the peritoneal surface is delicate and easily injured, resulting in a series of events, which can be broken down into coagulation cascade and inflammatory stages leading to a fibrous adhesion stage. TGF-β, IL-6 and likely other cytokines and growth factors play critical roles in adhesion formation by mediating the formation of myofibroblasts and stimulating the production of ECM. In the pathogenesis of fibrosis in inflammatory bowel disease (IBD), many factors need to be considered, including a much more sustained inflammatory response, a clear if still poorly understood genetic predisposition, the potential involvement of multiple mesenchymal cells, exposure of the mucosa to intestinal bacteria and the involvement of the immune system. In IBD, the normal wound healing process triggered by injury and inflammation fails and, instead of resolution, there is continued ECM production by myofibroblasts. Because of a protracted inflammatory response, one could imagine that anti-inflammatory therapy might be an effective approach. Unfortunately, this has not been the case, and it appears that once the damaging fibrotic reaction has been initiated in fibrosis-prone individuals, it is self-propagating. Thus, as in other fibrotic situations, the aberrant myofibroblast becomes the ultimate target. However, unlike adhesions in which the potential instigators can be anticipated and candidate drugs given over a fairly short time, in IBD the pathogenesis is much more protracted. There are a number of FDA—approved drugs capable of intercepting pathways potentially critical in the fibrotic reaction. TGF-β signaling is, of course, the primary target. However, because of the manifold activities of TGF-β, one or more downstream events in the signaling pathways must be judiciously selected so as not to elicit toxic responses. The same caution must be applied when dealing with other potential targets. Because of the inherent redundancy in signaling from multiple cytokines/growth factors involved in fibrotic reactions, it is likely that more than one drug must be administered simultaneously to obtain effective beneficial inhibition.


Fibrosis Myofibroblasts TGF-β Abdominal adhesions Inflammatory bowel disease Crohn’s disease Ulcerative colitis 


  1. 1.
    Rosenbloom J, Castro SV, Jimenez SA. Narrative review: fibrotic diseases: cellular and molecular mechanisms and novel therapies. Ann Intern Med. 2010;152(3):159–66.PubMedCrossRefGoogle Scholar
  2. 2.
    Rockey DC, Bell PD, Hill JA. Fibrosis--a common pathway to organ injury and failure. N Engl J Med. 2015;372(12):1138–49.PubMedCrossRefGoogle Scholar
  3. 3.
    Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214(2):199–210.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest. 2007;117(3):557–67.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Ho YY, Lagares D, Tager AM, Kapoor M. Fibrosis--a lethal component of systemic sclerosis. Nat Rev Rheumatol. 2014;10(7):390–402.PubMedCrossRefGoogle Scholar
  6. 6.
    Rosenbloom J, Mendoza FA, Jimenez SA. Strategies for anti-fibrotic therapies. Biochim Biophys Acta. 2013;1832(7):1088–103.PubMedCrossRefGoogle Scholar
  7. 7.
    Denton CP. Systemic sclerosis: from pathogenesis to targeted therapy. Clin Exp Rheumatol. 2015;33(4 Suppl 92):S3–7.PubMedGoogle Scholar
  8. 8.
    Karsdal MA, Manon-Jensen T, Genovese F, Kristensen JH, Nielsen MJ, Sand JM, et al. Novel insights into the function and dynamics of extracellular matrix in liver fibrosis. Am J Physiol Gastrointest Liver Physiol. 2015;308(10):G807–30.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Thannickal VJ, Henke CA, Horowitz JC, Noble PW, Roman J, Sime PJ, et al. Matrix biology of idiopathic pulmonary fibrosis: a workshop report of the national heart, lung, and blood institute. Am J Pathol. 2014;184(6):1643–51.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Gabbiani G. The myofibroblast: a key cell for wound healing and fibrocontractive diseases. Prog Clin Biol Res. 1981;54:183–94.PubMedGoogle Scholar
  11. 11.
    Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G. The myofibroblast: one function, multiple origins. Am J Pathol. 2007;170(6):1807–16.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Hinz B, Phan SH, Thannickal VJ, Prunotto M, Desmouliere A, Varga J, et al. Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am J Pathol. 2012;180(4):1340–55.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    McAnulty RJ. Fibroblasts and myofibroblasts: their source, function and role in disease. Int J Biochem Cell Biol. 2007;39(4):666–71.PubMedCrossRefGoogle Scholar
  14. 14.
    Kirk TZ, Mark ME, Chua CC, Chua BH, Mayes MD. Myofibroblasts from scleroderma skin synthesize elevated levels of collagen and tissue inhibitor of metalloproteinase (TIMP-1) with two forms of TIMP-1. J Biol Chem. 1995;270(7):3423–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Kendall RT, Feghali-Bostwick CA. Fibroblasts in fibrosis: novel roles and mediators. Front Pharmacol. 2014;5:123.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Gilbane AJ, Denton CP, Holmes AM. Scleroderma pathogenesis: a pivotal role for fibroblasts as effector cells. Arthritis Res Ther. 2013;15(3):215.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Laurent GJ, Chambers RC, Hill MR, McAnulty RJ. Regulation of matrix turnover: fibroblasts, forces, factors and fibrosis. Biochem Soc Trans. 2007;35(Pt 4):647–51.PubMedCrossRefGoogle Scholar
  18. 18.
    Wells RG, Discher DE. Matrix elasticity, cytoskeletal tension, and TGF-beta: the insoluble and soluble meet. Sci Signal. 2008;1(10):pe13.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Hinz B. Tissue stiffness, latent TGF-beta1 activation, and mechanical signal transduction: implications for the pathogenesis and treatment of fibrosis. Curr Rheumatol Rep. 2009;11(2):120–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Parker MW, Rossi D, Peterson M, Smith K, Sikstrom K, White ES, et al. Fibrotic extracellular matrix activates a profibrotic positive feedback loop. J Clin Invest. 2014;124(4):1622–35.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Postlethwaite AE, Shigemitsu H, Kanangat S. Cellular origins of fibroblasts: possible implications for organ fibrosis in systemic sclerosis. Curr Opin Rheumatol. 2004;16(6):733–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Humphreys BD, Lin SL, Kobayashi A, Hudson TE, Nowlin BT, Bonventre JV, et al. Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am J Pathol. 2010;176(1):85–97.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Piera-Velazquez S, Mendoza FA, Jimenez SA. Endothelial to Mesenchymal Transition (EndoMT) in the pathogenesis of human fibrotic diseases. J Clin Med. 2016;5(4):E45.PubMedCrossRefGoogle Scholar
  24. 24.
    Iozzo RV, Schaefer L. Proteoglycan form and function: a comprehensive nomenclature of proteoglycans. Matrix Biol. 2015;42:11–55.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Murphy-Ullrich JE, Sage EH. Revisiting the matricellular concept. Matrix Biol. 2014;37:1–14.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Resovi A, Pinessi D, Chiorino G, Taraboletti G. Current understanding of the thrombospondin-1 interactome. Matrix Biol. 2014;37:83–91.PubMedCrossRefGoogle Scholar
  27. 27.
    Kramann R, DiRocco DP, Humphreys BD. Understanding the origin, activation and regulation of matrix-producing myofibroblasts for treatment of fibrotic disease. J Pathol. 2013;231(3):273–89.PubMedCrossRefGoogle Scholar
  28. 28.
    Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield LM, et al. Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci U S A. 1986;83(12):4167–71.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Sporn MB, Roberts AB. Transforming growth factor-beta. Multiple actions and potential clinical applications. JAMA. 1989;262(7):938–41.PubMedCrossRefGoogle Scholar
  30. 30.
    Moses HL, Roberts AB, Derynck R. The discovery and early days of TGF-beta: a historical perspective. Cold Spring Harb Perspect Biol. 2016;8(7):a021865.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Fujio K, Komai T, Inoue M, Morita K, Okamura T, Yamamoto K. Revisiting the regulatory roles of the TGF-beta family of cytokines. Autoimmun Rev. 2016;15(9):917–22.PubMedCrossRefGoogle Scholar
  32. 32.
    Goumans MJ, Liu Z, ten Dijke P. TGF-beta signaling in vascular biology and dysfunction. Cell Res. 2009;19(1):116–27.PubMedCrossRefGoogle Scholar
  33. 33.
    Medici D, Potenta S, Kalluri R. Transforming growth factor-beta2 promotes Snail-mediated endothelial-mesenchymal transition through convergence of Smad-dependent and Smad-independent signalling. Biochem J. 2011;437(3):515–20.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    van Meeteren LA, ten Dijke P. Regulation of endothelial cell plasticity by TGF-beta. Cell Tissue Res. 2012;347(1):177–86.PubMedCrossRefGoogle Scholar
  35. 35.
    Jimenez SA, Castro SV, Piera-Velazquez S. Role of growth factors in the pathogenesis of tissue fibrosis in systemic sclerosis. Curr Rheumatol Rev. 2010;6(4):283–94.PubMedCrossRefGoogle Scholar
  36. 36.
    Lafyatis R. Transforming growth factor beta--at the Centre of systemic sclerosis. Nat Rev Rheumatol. 2014;10(12):706–19.PubMedCrossRefGoogle Scholar
  37. 37.
    Pohlers D, Brenmoehl J, Loffler I, Muller CK, Leipner C, Schultze-Mosgau S, et al. TGF-beta and fibrosis in different organs – molecular pathway imprints. Biochim Biophys Acta. 2009;1792(8):746–56.PubMedCrossRefGoogle Scholar
  38. 38.
    Biernacka A, Dobaczewski M, Frangogiannis NG. TGF-beta signaling in fibrosis. Growth Factors. 2011;29(5):196–202.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Meng XM, Nikolic-Paterson DJ, Lan HY. TGF-beta: the master regulator of fibrosis. Nat Rev Nephrol. 2016;12(6):325–38.PubMedCrossRefGoogle Scholar
  40. 40.
    ten Dijke P, Hill CS. New insights into TGF-beta-Smad signalling. Trends Biochem Sci. 2004;29(5):265–73.PubMedCrossRefGoogle Scholar
  41. 41.
    Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature. 2003;425(6958):577–84.PubMedCrossRefGoogle Scholar
  42. 42.
    Moustakas A, Heldin CH. Non-Smad TGF-beta signals. J Cell Sci. 2005;118(Pt 16):3573–84.PubMedCrossRefGoogle Scholar
  43. 43.
    Wilkes MC, Leof EB. Transforming growth factor beta activation of c-Abl is independent of receptor internalization and regulated by phosphatidylinositol 3-kinase and PAK2 in mesenchymal cultures. J Biol Chem. 2006;281(38):27846–54.PubMedCrossRefGoogle Scholar
  44. 44.
    Jimenez SA, Gaidarova S, Saitta B, Sandorfi N, Herrich DJ, Rosenbloom JC, et al. Role of protein kinase C-delta in the regulation of collagen gene expression in scleroderma fibroblasts. J Clin Invest. 2001;108(9):1395–403.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Bujor AM, Asano Y, Haines P, Lafyatis R, Trojanowska M. The c-Abl tyrosine kinase controls protein kinase Cdelta-induced Fli-1 phosphorylation in human dermal fibroblasts. Arthritis Rheum. 2011;63(6):1729–37.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Lawler S, Feng XH, Chen RH, Maruoka EM, Turck CW, Griswold-Prenner I, et al. The type II transforming growth factor-beta receptor autophosphorylates not only on serine and threonine but also on tyrosine residues. J Biol Chem. 1997;272(23):14850–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Galliher AJ, Schiemann WP. Src phosphorylates Tyr284 in TGF-beta type II receptor and regulates TGF-beta stimulation of p38 MAPK during breast cancer cell proliferation and invasion. Cancer Res. 2007;67(8):3752–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Caraci F, Gili E, Calafiore M, Failla M, La Rosa C, Crimi N, et al. TGF-beta1 targets the GSK-3beta/beta-catenin pathway via ERK activation in the transition of human lung fibroblasts into myofibroblasts. Pharmacol Res. 2008;57(4):274–82.PubMedCrossRefGoogle Scholar
  49. 49.
    Pannu J, Asano Y, Nakerakanti S, Smith E, Jablonska S, Blaszczyk M, et al. Smad1 pathway is activated in systemic sclerosis fibroblasts and is targeted by imatinib mesylate. Arthritis Rheum. 2008;58(8):2528–37.PubMedCrossRefGoogle Scholar
  50. 50.
    Andrianifahanana M, Wilkes MC, Gupta SK, Rahimi RA, Repellin CE, Edens M, et al. Profibrotic TGFbeta responses require the cooperative action of PDGF and ErbB receptor tyrosine kinases. FASEB J. 2013;27(11):4444–54.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Kawanabe Y, Nauli SM. Endothelin. Cell Mol Life Sci. 2011;68(2):195–203.PubMedCrossRefGoogle Scholar
  52. 52.
    Thorin E, Clozel M. The cardiovascular physiology and pharmacology of endothelin-1. Adv Pharmacol. 2010;60:1–26.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Shi-Wen X, Denton CP, Dashwood MR, Holmes AM, Bou-Gharios G, Pearson JD, et al. Fibroblast matrix gene expression and connective tissue remodeling: role of endothelin-1. J Invest Dermatol. 2001;116(3):417–25.PubMedCrossRefGoogle Scholar
  54. 54.
    Jing J, Dou TT, Yang JQ, Chen XB, Cao HL, Min M, et al. Role of endothelin-1 in the skin fibrosis of systemic sclerosis. Eur Cytokine Netw. 2015;26(1):10–4.PubMedGoogle Scholar
  55. 55.
    Xu SW, Howat SL, Renzoni EA, Holmes A, Pearson JD, Dashwood MR, et al. Endothelin-1 induces expression of matrix-associated genes in lung fibroblasts through MEK/ERK. J Biol Chem. 2004;279(22):23098–103.PubMedCrossRefGoogle Scholar
  56. 56.
    Park SH, Saleh D, Giaid A, Michel RP. Increased endothelin-1 in bleomycin-induced pulmonary fibrosis and the effect of an endothelin receptor antagonist. Am J Respir Crit Care Med. 1997;156(2 Pt 1):600–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Ross B, D’Orleans-Juste P, Giaid A. Potential role of endothelin-1 in pulmonary fibrosis: from the bench to the clinic. Am J Respir Cell Mol Biol. 2010;42(1):16–20.PubMedCrossRefGoogle Scholar
  58. 58.
    Widyantoro B, Emoto N, Nakayama K, Anggrahini DW, Adiarto S, Iwasa N, et al. Endothelial cell-derived endothelin-1 promotes cardiac fibrosis in diabetic hearts through stimulation of endothelial-to-mesenchymal transition. Circulation. 2010;121(22):2407–18.PubMedCrossRefGoogle Scholar
  59. 59.
    Kim KK, Chapman HA. Endothelin-1 as initiator of epithelial-mesenchymal transition: potential new role for endothelin-1 during pulmonary fibrosis. Am J Respir Cell Mol Biol. 2007;37(1):1–2.PubMedCrossRefGoogle Scholar
  60. 60.
    Cipriani P, Di Benedetto P, Ruscitti P, Capece D, Zazzeroni F, Liakouli V, et al. The endothelial-mesenchymal transition in systemic sclerosis is induced by endothelin-1 and transforming growth factor-beta and may be blocked by macitentan, a dual endothelin-1 receptor antagonist. J Rheumatol. 2015;42(10):1808–16.PubMedCrossRefGoogle Scholar
  61. 61.
    Grotendorst GR. Connective tissue growth factor: a mediator of TGF-beta action on fibroblasts. Cytokine Growth Factor Rev. 1997;8(3):171–9.PubMedCrossRefGoogle Scholar
  62. 62.
    Leask A, Abraham DJ. The role of connective tissue growth factor, a multifunctional matricellular protein, in fibroblast biology. Biochem Cell Biol. 2003;81(6):355–63.PubMedCrossRefGoogle Scholar
  63. 63.
    Igarashi A, Nashiro K, Kikuchi K, Sato S, Ihn H, Grotendorst GR, et al. Significant correlation between connective tissue growth factor gene expression and skin sclerosis in tissue sections from patients with systemic sclerosis. J Invest Dermatol. 1995;105(2):280–4.PubMedCrossRefGoogle Scholar
  64. 64.
    Shi-Wen X, Leask A, Abraham D. Regulation and function of connective tissue growth factor/CCN2 in tissue repair, scarring and fibrosis. Cytokine Growth Factor Rev. 2008;19(2):133–44.PubMedCrossRefGoogle Scholar
  65. 65.
    Ponticos M, Holmes AM, Shi-wen X, Leoni P, Khan K, Rajkumar VS, et al. Pivotal role of connective tissue growth factor in lung fibrosis: MAPK-dependent transcriptional activation of type I collagen. Arthritis Rheum. 2009;60(7):2142–55.PubMedCrossRefGoogle Scholar
  66. 66.
    Ruperez M, Rodrigues-Diez R, Blanco-Colio LM, Sanchez-Lopez E, Rodriguez-Vita J, Esteban V, et al. HMG-CoA reductase inhibitors decrease angiotensin II-induced vascular fibrosis: role of RhoA/ROCK and MAPK pathways. Hypertension. 2007;50(2):377–83.PubMedCrossRefGoogle Scholar
  67. 67.
    Betsholtz C. Biology of platelet-derived growth factors in development. Birth Defects Res C Embryo Today. 2003;69(4):272–85.PubMedCrossRefGoogle Scholar
  68. 68.
    Farooqi AA, Waseem S, Riaz AM, Dilawar BA, Mukhtar S, Minhaj S, et al. PDGF: the nuts and bolts of signalling toolbox. Tumour Biol. 2011;32(6):1057–70.PubMedCrossRefGoogle Scholar
  69. 69.
    Alvarez RH, Kantarjian HM, Cortes JE. Biology of platelet-derived growth factor and its involvement in disease. Mayo Clin Proc. 2006;81(9):1241–57.PubMedCrossRefGoogle Scholar
  70. 70.
    Bonner JC. Regulation of PDGF and its receptors in fibrotic diseases. Cytokine Growth Factor Rev. 2004;15(4):255–73.PubMedCrossRefGoogle Scholar
  71. 71.
    Tallquist M, Kazlauskas A. PDGF signaling in cells and mice. Cytokine Growth Factor Rev. 2004;15(4):205–13.PubMedCrossRefGoogle Scholar
  72. 72.
    Yamakage A, Kikuchi K, Smith EA, LeRoy EC, Trojanowska M. Selective upregulation of platelet-derived growth factor alpha receptors by transforming growth factor beta in scleroderma fibroblasts. J Exp Med. 1992;175(5):1227–34.PubMedCrossRefGoogle Scholar
  73. 73.
    Olson LE, Soriano P. Increased PDGFRalpha activation disrupts connective tissue development and drives systemic fibrosis. Dev Cell. 2009;16(2):303–13.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Czochra P, Klopcic B, Meyer E, Herkel J, Garcia-Lazaro JF, Thieringer F, et al. Liver fibrosis induced by hepatic overexpression of PDGF-B in transgenic mice. J Hepatol. 2006;45(3):419–28.PubMedCrossRefGoogle Scholar
  75. 75.
    Ogawa S, Ochi T, Shimada H, Inagaki K, Fujita I, Nii A, et al. Anti-PDGF-B monoclonal antibody reduces liver fibrosis development. Hepatol Res. 2010;40(11):1128–41.PubMedCrossRefGoogle Scholar
  76. 76.
    Heldin CH, Westermark B. Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev. 1999;79(4):1283–316.PubMedCrossRefGoogle Scholar
  77. 77.
    Clevers H, Nusse R. Wnt/beta-catenin signaling and disease. Cell. 2012;149(6):1192–205.PubMedCrossRefGoogle Scholar
  78. 78.
    Niehrs C. The complex world of WNT receptor signalling. Nat Rev Mol Cell Biol. 2012;13(12):767–79.PubMedCrossRefGoogle Scholar
  79. 79.
    Bergmann C, Distler JH. Canonical Wnt signaling in systemic sclerosis. Lab Invest. 2016;96(2):151–5.PubMedCrossRefGoogle Scholar
  80. 80.
    Wei J, Fang F, Lam AP, Sargent JL, Hamburg E, Hinchcliff ME, et al. Wnt/beta-catenin signaling is hyperactivated in systemic sclerosis and induces Smad-dependent fibrotic responses in mesenchymal cells. Arthritis Rheum. 2012;64(8):2734–45.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Beyer C, Schramm A, Akhmetshina A, Dees C, Kireva T, Gelse K, et al. Beta-catenin is a central mediator of pro-fibrotic Wnt signaling in systemic sclerosis. Ann Rheum Dis. 2012;71(5):761–7.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Huang H, He X. Wnt/beta-catenin signaling: new (and old) players and new insights. Curr Opin Cell Biol. 2008;20(2):119–25.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Nusse R. Wnt signaling in disease and in development. Cell Res. 2005;15(1):28–32.PubMedCrossRefGoogle Scholar
  84. 84.
    He W, Dai C, Li Y, Zeng G, Monga SP, Liu Y. Wnt/beta-catenin signaling promotes renal interstitial fibrosis. J Am Soc Nephrol. 2009;20(4):765–76.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Konigshoff M, Balsara N, Pfaff EM, Kramer M, Chrobak I, Seeger W, et al. Functional Wnt signaling is increased in idiopathic pulmonary fibrosis. PLoS One. 2008;3(5):e2142.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Trensz F, Haroun S, Cloutier A, Richter MV, Grenier G. A muscle resident cell population promotes fibrosis in hindlimb skeletal muscles of mdx mice through the Wnt canonical pathway. Am J Physiol Cell Physiol. 2010;299(5):C939–47.PubMedCrossRefGoogle Scholar
  87. 87.
    Pinzone JJ, Hall BM, Thudi NK, Vonau M, Qiang YW, Rosol TJ, et al. The role of Dickkopf-1 in bone development, homeostasis, and disease. Blood. 2009;113(3):517–25.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Bafico A, Liu G, Yaniv A, Gazit A, Aaronson SA. Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/arrow. Nat Cell Biol. 2001;3(7):683–6.PubMedCrossRefGoogle Scholar
  89. 89.
    Echelard Y, Epstein DJ, St-Jacques B, Shen L, Mohler J, McMahon JA, et al. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell. 1993;75(7):1417–30.PubMedCrossRefGoogle Scholar
  90. 90.
    Rohatgi R, Milenkovic L, Corcoran RB, Scott MP. Hedgehog signal transduction by smoothened: pharmacologic evidence for a 2-step activation process. Proc Natl Acad Sci U S A. 2009;106(9):3196–201.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Rohatgi R, Scott MP. Patching the gaps in hedgehog signalling. Nat Cell Biol. 2007;9(9):1005–9.PubMedCrossRefGoogle Scholar
  92. 92.
    Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, et al. Activating smoothened mutations in sporadic basal-cell carcinoma. Nature. 1998;391(6662):90–2.PubMedCrossRefGoogle Scholar
  93. 93.
    Thayer SP, di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY, et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature. 2003;425(6960):851–6.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Horn A, Palumbo K, Cordazzo C, Dees C, Akhmetshina A, Tomcik M, et al. Hedgehog signaling controls fibroblast activation and tissue fibrosis in systemic sclerosis. Arthritis Rheum. 2012;64(8):2724–33.PubMedCrossRefGoogle Scholar
  95. 95.
    Fortini ME. Notch signaling: the core pathway and its posttranslational regulation. Dev Cell. 2009;16(5):633–47.PubMedCrossRefGoogle Scholar
  96. 96.
    D’Souza B, Miyamoto A, Weinmaster G. The many facets of Notch ligands. Oncogene. 2008;27(38):5148–67.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Borggrefe T, Liefke R. Fine-tuning of the intracellular canonical Notch signaling pathway. Cell Cycle. 2012;11(2):264–76.PubMedCrossRefGoogle Scholar
  98. 98.
    Louvi A, Artavanis-Tsakonas S. Notch and disease: a growing field. Semin Cell Dev Biol. 2012;23(4):473–80.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Dees C, Tomcik M, Zerr P, Akhmetshina A, Horn A, Palumbo K, et al. Notch signalling regulates fibroblast activation and collagen release in systemic sclerosis. Ann Rheum Dis. 2011;70(7):1304–10.PubMedCrossRefGoogle Scholar
  100. 100.
    Kavian N, Servettaz A, Weill B, Batteux F. New insights into the mechanism of notch signalling in fibrosis. Open Rheumatol J. 2012;6:96–102.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Huang X, Yang N, Fiore VF, Barker TH, Sun Y, Morris SW, et al. Matrix stiffness-induced myofibroblast differentiation is mediated by intrinsic mechanotransduction. Am J Respir Cell Mol Biol. 2012;47(3):340–8.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Kessler D, Dethlefsen S, Haase I, Plomann M, Hirche F, Krieg T, et al. Fibroblasts in mechanically stressed collagen lattices assume a “synthetic” phenotype. J Biol Chem. 2001;276(39):36575–85.PubMedCrossRefGoogle Scholar
  103. 103.
    Hayashida T, Decaestecker M, Schnaper HW. Cross-talk between ERK MAP kinase and Smad signaling pathways enhances TGF-beta-dependent responses in human mesangial cells. FASEB J. 2003;17(11):1576–8.PubMedCrossRefGoogle Scholar
  104. 104.
    Al-Jaroudi D, Tulandi T. Adhesion prevention in gynecologic surgery. Obstet Gynecol Surv. 2004;59(5):360–7.PubMedCrossRefGoogle Scholar
  105. 105.
    Boland GM, Weigel RJ. Formation and prevention of postoperative abdominal adhesions. J Surg Res. 2006;132(1):3–12.PubMedCrossRefGoogle Scholar
  106. 106.
    Ellis H. The clinical significance of adhesions: focus on intestinal obstruction. Eur J Surg Suppl. 1997;577:5–9.Google Scholar
  107. 107.
    Ozel H, Avsar FM, Topaloglu S, Sahin M. Induction and assessment methods used in experimental adhesion studies. Wound Repair Regen. 2005;13(4):358–64.PubMedCrossRefGoogle Scholar
  108. 108.
    Beyene RT, Kavalukas SL, Barbul A. Intra-abdominal adhesions: anatomy, physiology, pathophysiology, and treatment. Curr Probl Surg. 2015;52(7):271–319.PubMedCrossRefGoogle Scholar
  109. 109.
    Arung W, Meurisse M, Detry O. Pathophysiology and prevention of postoperative peritoneal adhesions. World J Gastroenterol. 2011;17(41):4545–53.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Moris D, Chakedis J, Rahnemai-Azar AA, Wilson A, Hennessy MM, Athanasiou A, et al. Postoperative abdominal adhesions: clinical significance and advances in prevention and management. J Gastrointest Surg. 2017;21(10):1713–22.PubMedCrossRefGoogle Scholar
  111. 111.
    Pados G, Venetis CA, Almaloglou K, Tarlatzis BC. Prevention of intra-peritoneal adhesions in gynaecological surgery: theory and evidence. Reprod Biomed Online. 2010;21(3):290–303.PubMedCrossRefGoogle Scholar
  112. 112.
    Gabbiani G. The myofibroblast in wound healing and fibrocontractive diseases. J Pathol. 2003;200(4):500–3.PubMedCrossRefGoogle Scholar
  113. 113.
    Strippoli R, Moreno-Vicente R, Battistelli C, Cicchini C, Noce V, Amicone L, et al. Molecular mechanisms underlying peritoneal EMT and fibrosis. Stem Cells Int. 2016;2016:3543678.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Jin X, Ren S, Macarak E, Rosenbloom J. Pathobiological mechanisms of peritoneal adhesions: the mesenchymal transition of rat peritoneal mesothelial cells induced by TGF-beta1 and IL-6 requires activation of Erk1/2 and Smad2 linker region phosphorylation. Matrix Biol. 2016;51:55–64.PubMedCrossRefGoogle Scholar
  115. 115.
    Haensel D, Dai X. Epithelial-to-mesenchymal transition in cutaneous wound healing: where we are and where we are heading. Dev Dyn. 2017;247(3):473–80.PubMedCrossRefGoogle Scholar
  116. 116.
    Sanchez-Duffhues G, Garcia de Vinuesa A, Ten Dijke P. Endothelial to mesenchymal transition in cardiovascular diseases: developmental signalling pathways gone awry. Dev Dyn. 2017;247(3):492–508.PubMedCrossRefGoogle Scholar
  117. 117.
    Voon DC, Huang RY, Jackson RA, Thiery JP. The EMT spectrum and therapeutic opportunities. Mol Oncol. 2017;11(7):878–91.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Gonzalez DM, Medici D. Signaling mechanisms of the epithelial-mesenchymal transition. Sci Signal. 2014;7(344):re8.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Flier SN, Tanjore H, Kokkotou EG, Sugimoto H, Zeisberg M, Kalluri R. Identification of epithelial to mesenchymal transition as a novel source of fibroblasts in intestinal fibrosis. J Biol Chem. 2010;285(26):20202–12.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Lee JM, Dedhar S, Kalluri R, Thompson EW. The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol. 2006;172(7):973–81.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Gabbiani G, Ryan GB, Majne G. Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction. Experientia. 1971;27(5):549–50.PubMedCrossRefGoogle Scholar
  122. 122.
    Singer II, Kawka DW, Kazazis DM, Clark RA. In vivo co-distribution of fibronectin and actin fibers in granulation tissue: immunofluorescence and electron microscope studies of the fibronexus at the myofibroblast surface. J Cell Biol. 1984;98(6):2091–106.PubMedCrossRefGoogle Scholar
  123. 123.
    Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol. 2002;3(5):349–63.PubMedCrossRefGoogle Scholar
  124. 124.
    Brown LF, Dubin D, Lavigne L, Logan B, Dvorak HF, Van de Water L. Macrophages and fibroblasts express embryonic fibronectins during cutaneous wound healing. Am J Pathol. 1993;142(3):793–801.PubMedPubMedCentralGoogle Scholar
  125. 125.
    Serini G, Bochaton-Piallat ML, Ropraz P, Geinoz A, Borsi L, Zardi L, et al. The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-beta1. J Cell Biol. 1998;142(3):873–81.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Vaughan MB, Howard EW, Tomasek JJ. Transforming growth factor-beta1 promotes the morphological and functional differentiation of the myofibroblast. Exp Cell Res. 2000;257(1):180–9.PubMedCrossRefGoogle Scholar
  127. 127.
    Colak S, Ten Dijke P. Targeting TGF-beta signaling in cancer. Trends Cancer. 2017;3(1):56–71.PubMedCrossRefGoogle Scholar
  128. 128.
    Tolcher AW, Berlin JD, Cosaert J, Kauh J, Chan E, Piha-Paul SA, et al. A phase 1 study of anti-TGFbeta receptor type-II monoclonal antibody LY3022859 in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2017;79(4):673–80.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Castellone MD, Laukkanen MO. TGF-beta1, WNT, and SHH signaling in tumor progression and in fibrotic diseases. Front Biosci (Schol Ed). 2017;9:31–45.CrossRefGoogle Scholar
  130. 130.
    Costa-Pereira AP. Regulation of IL-6-type cytokine responses by MAPKs. Biochem Soc Trans. 2014;42(1):59–62.PubMedCrossRefGoogle Scholar
  131. 131.
    Fielding CA, Jones GW, McLoughlin RM, McLeod L, Hammond VJ, Uceda J, et al. Interleukin-6 signaling drives fibrosis in unresolved inflammation. Immunity. 2014;40(1):40–50.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Rokavec M, Oner MG, Li H, Jackstadt R, Jiang L, Lodygin D, et al. IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. J Clin Invest. 2014;124(4):1853–67.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Ward BC, Panitch A. Abdominal adhesions: current and novel therapies. J Surg Res. 2011;165(1):91–111.PubMedCrossRefGoogle Scholar
  134. 134.
    Falk P, Bergstrom M, Palmgren I, Holmdahl L, Breimer ME, Ivarsson ML. Studies of TGF-beta(1-3) in serosal fluid during abdominal surgery and their effect on in vitro human mesothelial cell proliferation. J Surg Res. 2009;154(2):312–6.PubMedCrossRefGoogle Scholar
  135. 135.
    Cheong YC, Shelton JB, Laird SM, Richmond M, Kudesia G, Li TC, et al. IL-1, IL-6 and TNF-alpha concentrations in the peritoneal fluid of women with pelvic adhesions. Hum Reprod. 2002;17(1):69–75.PubMedCrossRefGoogle Scholar
  136. 136.
    Akinleye A, Furqan M, Mukhi N, Ravella P, Liu D. MEK and the inhibitors: from bench to bedside. J Hematol Oncol. 2013;6:27.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet. 2008;40(8):955–62.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Brant SR. Promises, delivery, and challenges of inflammatory bowel disease risk gene discovery. Clin Gastroenterol Hepatol. 2013;11(1):22–6.PubMedCrossRefGoogle Scholar
  139. 139.
    Cho JH, Brant SR. Recent insights into the genetics of inflammatory bowel disease. Gastroenterology. 2011;140(6):1704–12.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491(7422):119–24.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Burke JP, Mulsow JJ, O’Keane C, Docherty NG, Watson RW, O’Connell PR. Fibrogenesis in Crohn’s disease. Am J Gastroenterol. 2007;102(2):439–48.PubMedCrossRefGoogle Scholar
  142. 142.
    Hugot JP. Genetic origin of IBD. Inflamm Bowel Dis. 2004;10(Suppl 1):S11–5.PubMedCrossRefGoogle Scholar
  143. 143.
    Meijer MJ, Mieremet-Ooms MA, Sier CF, van Hogezand RA, Lamers CB, Hommes DW, et al. Matrix metalloproteinases and their tissue inhibitors as prognostic indicators for diagnostic and surgical recurrence in Crohn’s disease. Inflamm Bowel Dis. 2009;15(1):84–92.PubMedCrossRefGoogle Scholar
  144. 144.
    Mostafa RM, Moustafa YM, Hamdy H. Interstitial cells of Cajal, the Maestro in health and disease. World J Gastroenterol. 2010;16(26):3239–48.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Powell DW, Mifflin RC, Valentich JD, Crowe SE, Saada JI, West AB. Myofibroblasts. II. Intestinal subepithelial myofibroblasts. Am J Phys. 1999;277(2 Pt 1):C183–201.CrossRefGoogle Scholar
  146. 146.
    Drygiannakis I, Valatas V, Sfakianaki O, Bourikas L, Manousou P, Kambas K, et al. Proinflammatory cytokines induce crosstalk between colonic epithelial cells and subepithelial myofibroblasts: implication in intestinal fibrosis. J Crohns Colitis. 2013;7(4):286–300.PubMedCrossRefGoogle Scholar
  147. 147.
    Okuno T, Andoh A, Bamba S, Araki Y, Fujiyama Y, Fujiyama M, et al. Interleukin-1beta and tumor necrosis factor-alpha induce chemokine and matrix metalloproteinase gene expression in human colonic subepithelial myofibroblasts. Scand J Gastroenterol. 2002;37(3):317–24.PubMedCrossRefGoogle Scholar
  148. 148.
    Rogler G, Gelbmann CM, Vogl D, Brunner M, Scholmerich J, Falk W, et al. Differential activation of cytokine secretion in primary human colonic fibroblast/myofibroblast cultures. Scand J Gastroenterol. 2001;36(4):389–98.PubMedCrossRefGoogle Scholar
  149. 149.
    Otte JM, Rosenberg IM, Podolsky DK. Intestinal myofibroblasts in innate immune responses of the intestine. Gastroenterology. 2003;124(7):1866–78.PubMedCrossRefGoogle Scholar
  150. 150.
    Zawahir S, Li G, Banerjee A, Shiu J, Blanchard TG, Okogbule-Wonodi AC. Inflammatory and immune activation in intestinal myofibroblasts is developmentally regulated. J Interf Cytokine Res. 2015;35(8):634–40.CrossRefGoogle Scholar
  151. 151.
    Saada JI, Pinchuk IV, Barrera CA, Adegboyega PA, Suarez G, Mifflin RC, et al. Subepithelial myofibroblasts are novel nonprofessional APCs in the human colonic mucosa. J Immunol. 2006;177(9):5968–79.PubMedCrossRefGoogle Scholar
  152. 152.
    Rieder F, Fiocchi C. Intestinal fibrosis in IBD--a dynamic, multifactorial process. Nat Rev Gastroenterol Hepatol. 2009;6(4):228–35.PubMedCrossRefGoogle Scholar
  153. 153.
    Speca S, Giusti I, Rieder F, Latella G. Cellular and molecular mechanisms of intestinal fibrosis. World J Gastroenterol. 2012;18(28):3635–61.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Pinchuk IV, Mifflin RC, Saada JI, Powell DW. Intestinal mesenchymal cells. Curr Gastroenterol Rep. 2010;12(5):310–8.PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Flynn RS, Murthy KS, Grider JR, Kellum JM, Kuemmerle JF. Endogenous IGF-I and alphaVbeta3 integrin ligands regulate increased smooth muscle hyperplasia in stricturing Crohn’s disease. Gastroenterology. 2010;138(1):285–93.PubMedCrossRefGoogle Scholar
  156. 156.
    Rieder F, de Bruyn JR, Pham BT, Katsanos K, Annese V, Higgins PD, et al. Results of the 4th scientific workshop of the ECCO (Group II): markers of intestinal fibrosis in inflammatory bowel disease. J Crohns Colitis. 2014;8(10):1166–78.PubMedCrossRefGoogle Scholar
  157. 157.
    Makitalo L, Sipponen T, Karkkainen P, Kolho KL, Saarialho-Kere U. Changes in matrix metalloproteinase (MMP) and tissue inhibitors of metalloproteinases (TIMP) expression profile in Crohn’s disease after immunosuppressive treatment correlate with histological score and calprotectin values. Int J Color Dis. 2009;24(10):1157–67.CrossRefGoogle Scholar
  158. 158.
    McKaig BC, McWilliams D, Watson SA, Mahida YR. Expression and regulation of tissue inhibitor of metalloproteinase-1 and matrix metalloproteinases by intestinal myofibroblasts in inflammatory bowel disease. Am J Pathol. 2003;162(4):1355–60.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Di Sabatino A, Jackson CL, Pickard KM, Buckley M, Rovedatti L, Leakey NA, et al. Transforming growth factor beta signalling and matrix metalloproteinases in the mucosa overlying Crohn’s disease strictures. Gut. 2009;58(6):777–89.PubMedCrossRefGoogle Scholar
  160. 160.
    Murphy G, Nagase H. Progress in matrix metalloproteinase research. Mol Asp Med. 2008;29(5):290–308.CrossRefGoogle Scholar
  161. 161.
    Monteleone G, Caruso R, Fina D, Peluso I, Gioia V, Stolfi C, et al. Control of matrix metalloproteinase production in human intestinal fibroblasts by interleukin 21. Gut. 2006;55(12):1774–80.PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Warnaar N, Hofker HS, Maathuis MH, Niesing J, Bruggink AH, Dijkstra G, et al. Matrix metalloproteinases as profibrotic factors in terminal ileum in Crohn’s disease. Inflamm Bowel Dis. 2006;12(9):863–9.PubMedCrossRefGoogle Scholar
  163. 163.
    Lech M, Anders HJ. Macrophages and fibrosis: how resident and infiltrating mononuclear phagocytes orchestrate all phases of tissue injury and repair. Biochim Biophys Acta. 2013;1832(7):989–97.PubMedCrossRefGoogle Scholar
  164. 164.
    Fiocchi C, Lund PK. Themes in fibrosis and gastrointestinal inflammation. Am J Physiol Gastrointest Liver Physiol. 2011;300(5):G677–83.PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Bailey JR, Bland PW, Tarlton JF, Peters I, Moorghen M, Sylvester PA, et al. IL-13 promotes collagen accumulation in Crohn’s disease fibrosis by down-regulation of fibroblast MMP synthesis: a role for innate lymphoid cells? PLoS One. 2012;7(12):e52332.PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Brand S. Crohn’s disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn’s disease. Gut. 2009;58(8):1152–67.PubMedCrossRefGoogle Scholar
  167. 167.
    Higashi K, Inagaki Y, Fujimori K, Nakao A, Kaneko H, Nakatsuka I. Interferon-gamma interferes with transforming growth factor-beta signaling through direct interaction of YB-1 with Smad3. J Biol Chem. 2003;278(44):43470–9.PubMedCrossRefGoogle Scholar
  168. 168.
    Raghu G, Brown KK, Bradford WZ, Starko K, Noble PW, Schwartz DA, et al. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2004;350(2):125–33.PubMedCrossRefGoogle Scholar
  169. 169.
    Biancheri P, Pender SL, Ammoscato F, Giuffrida P, Sampietro G, Ardizzone S, et al. The role of interleukin 17 in Crohn’s disease-associated intestinal fibrosis. Fibrogenesis Tissue Repair. 2013;6(1):13.PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Meng F, Wang K, Aoyama T, Grivennikov SI, Paik Y, Scholten D, et al. Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology. 2012;143(3):765–76 e3.PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Speca S, Dubuquoy L, Desreumaux P. Peroxisome proliferator-activated receptor gamma in the colon: inflammation and innate antimicrobial immunity. J Clin Gastroenterol. 2014;48(Suppl 1):S23–7.PubMedCrossRefGoogle Scholar
  172. 172.
    Lu D, Carson DA. Repression of beta-catenin signaling by PPAR gamma ligands. Eur J Pharmacol. 2010;636(1–3):198–202.PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Zhao C, Chen W, Yang L, Chen L, Stimpson SA, Diehl AM. PPARgamma agonists prevent TGFbeta1/Smad3-signaling in human hepatic stellate cells. Biochem Biophys Res Commun. 2006;350(2):385–91.PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Ghosh AK, Bhattacharyya S, Lakos G, Chen SJ, Mori Y, Varga J. Disruption of transforming growth factor beta signaling and profibrotic responses in normal skin fibroblasts by peroxisome proliferator-activated receptor gamma. Arthritis Rheum. 2004;50(4):1305–18.PubMedCrossRefGoogle Scholar
  175. 175.
    Tan X, Dagher H, Hutton CA, Bourke JE. Effects of PPAR gamma ligands on TGF-beta1-induced epithelial-mesenchymal transition in alveolar epithelial cells. Respir Res. 2010;11:21.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    de Bruyn M, Vandooren J, Ugarte-Berzal E, Arijs I, Vermeire S, Opdenakker G. The molecular biology of matrix metalloproteinases and tissue inhibitors of metalloproteinases in inflammatory bowel diseases. Crit Rev Biochem Mol Biol. 2016;51(5):295–358.PubMedCrossRefGoogle Scholar
  177. 177.
    Macarak Edward J, Lotto Christine E, Deepika K, Xiaoling J, Wermuth Peter J, Anna-Karin O, Matthew M, Joel R. Trametinib prevents mesothelial-mesenchymal transition and ameliorates abdominal adhesion.formation. J Surg Res. 2018;227:198–210. Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.The Joan and Joel Rosenbloom Center for Fibrotic DiseasesPhiladelphiaUSA
  2. 2.Department of Dermatology and Cutaneous BiologySydney Kimmel Medical College, Thomas Jefferson UniversityPhiladelphiaUSA

Personalised recommendations