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Inflammation Research

, Volume 66, Issue 6, pp 451–465 | Cite as

Myofibroblast repair mechanisms post-inflammatory response: a fibrotic perspective

  • Casimiro Gerarduzzi
  • John A. Di Battista
Review

Abstract

Introduction

Fibrosis is a complex chronic disease characterized by a persistent repair response. Its pathogenesis is poorly understood but it is typically the result of chronic inflammation and maintained with the required activity of transforming growth factor-β (TGFβ) and extracellular matrix (ECM) tension, both of which drive fibroblasts to transition into a myofibroblast phenotype.

Findings

As the effector cells of repair, myofibroblasts migrate to the site of injury to deposit excessive amounts of matrix proteins and stimulate high levels of contraction. Myofibroblast activity is a decisive factor in whether a tissue is properly repaired by controlled wound healing or rendered fibrotic by deregulated repair. Extensive studies have documented the various contributing factors to an abrogated repair response. Though these fibrotic factors are known, very little is understood about the opposing antifibrotic molecules that assist in a successful repair, such as prostaglandin E2 (PGE2) and ECM retraction. The following review will discuss the general development of fibrosis through the transformation of myofibroblasts, focusing primarily on the prominent profibrotic pathways of TGFβ and ECM tension and antifibrotic pathways of PGE2 and ECM retraction.

Conclusions

The idea is to understand the ways in which the cell, after an injury and inflammatory response, normally controls its repair mechanisms through its homeostatic regulators so as to mimic them therapeutically to control abnormal pathways.

Keywords

Prostaglandin E2 Fibroblasts Myofibroblasts Fibrosis TGFβ 

Notes

Acknowledgements

This work was supported in part by the Canadian Institutes for Health Research (JDB) Grant Numbers M11557 and IMH-112312 (JDB).

References

  1. 1.
    Desmouliere A, Darby IA, Gabbiani G. Normal and pathologic soft tissue remodeling: role of the myofibroblast, with special emphasis on liver and kidney fibrosis. Lab Investig. 2003;83(12):1689–707.PubMedCrossRefGoogle Scholar
  2. 2.
    Moreira RK. Hepatic stellate cells and liver fibrosis. Arch Pathol Lab Med. 2007;131(11):1728–34.PubMedGoogle Scholar
  3. 3.
    Hinz B. The myofibroblast: paradigm for a mechanically active cell. J Biomech. 2010;43(1):146–55.PubMedCrossRefGoogle Scholar
  4. 4.
    Gabbiani G. The myofibroblast in wound healing and fibrocontractive diseases. J Pathol. 2003;200(4):500–3.PubMedCrossRefGoogle Scholar
  5. 5.
    Wilson MS, Wynn TA. Pulmonary fibrosis: pathogenesis, etiology and regulation. Mucosal Immunol. 2009;2(2):103–21.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Liu Y. Renal fibrosis: new insights into the pathogenesis and therapeutics. Kidney Int. 2006;69(2):213–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Maher TM, Wells AU, Laurent GJ. Idiopathic pulmonary fibrosis: multiple causes and multiple mechanisms? Eur Respir J. 2007;30(5):835–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Denton CP, Black CM, Abraham DJ. Mechanisms and consequences of fibrosis in systemic sclerosis. Nat Clin Pract Rheumatol. 2006;2(3):134–44.PubMedCrossRefGoogle Scholar
  9. 9.
    Trojanowska M, Varga J. Molecular pathways as novel therapeutic targets in systemic sclerosis. Curr Opin Rheumatol. 2007;19(6):568–73.PubMedCrossRefGoogle Scholar
  10. 10.
    Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214(2):199–210.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Investig. 2007;117(3):557–67.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Tyagi SC. Homocyst(e)ine and heart disease: pathophysiology of extracellular matrix. Clin Exp Hypertens. 1999;21(3):181–98.PubMedCrossRefGoogle Scholar
  13. 13.
    Bataller R, Brenner DA. Liver fibrosis. J Clin Investig. 2005;115(2):209–18.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Zisman DA, et al. Pulmonary fibrosis. Methods Mol Med. 2005;117:3–44.PubMedGoogle Scholar
  15. 15.
    Zeisberg M, Strutz F, Muller GA. Role of fibroblast activation in inducing interstitial fibrosis. J Nephrol. 2000;13(Suppl 3):S111–20.PubMedGoogle Scholar
  16. 16.
    Darby IA, Hewitson TD. Fibroblast differentiation in wound healing and fibrosis. Int Rev Cytol. 2007;257:143–79.PubMedCrossRefGoogle Scholar
  17. 17.
    Hinz B, et al. Alpha-smooth muscle actin is crucial for focal adhesion maturation in myofibroblasts. Mol Biol Cell. 2003;14(6):2508–19.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Kojima Y, et al. Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts. Proc Natl Acad Sci USA. 2010;107(46):20009–14.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Dabiri G, et al. A TGF-beta1-dependent autocrine loop regulates the structure of focal adhesions in hypertrophic scar fibroblasts. J Invest Dermatol. 2006;126(5):963–70.PubMedCrossRefGoogle Scholar
  20. 20.
    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
  21. 21.
    Ohji M, SundarRaj N, Thoft RA. Transforming growth factor-beta stimulates collagen and fibronectin synthesis by human corneal stromal fibroblasts in vitro. Curr Eye Res. 1993;12(8):703–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Roberts AB, 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 USA. 1986;83(12):4167–71.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Borsi L, et al. Transforming growth factor-beta regulates the splicing pattern of fibronectin messenger RNA precursor. FEBS Lett. 1990;261(1):175–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Duffield JS, et al. Host responses in tissue repair and fibrosis. Annu Rev Pathol. 2013;8:241–76.PubMedCrossRefGoogle Scholar
  25. 25.
    Pardo A, Selman M. Matrix metalloproteases in aberrant fibrotic tissue remodeling. Proc Am Thorac Soc. 2006;3(4):383–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Giannandrea M, Parks WC. Diverse functions of matrix metalloproteinases during fibrosis. Dis Model Mech. 2014;7(2):193–203.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Carlson MA, Longaker MT, Thompson JS. Wound splinting regulates granulation tissue survival. J Surg Res. 2003;110(1):304–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Moulin V, et al. Normal skin wound and hypertrophic scar myofibroblasts have differential responses to apoptotic inductors. J Cell Physiol. 2004;198(3):350–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Driesen RB, et al. Reversible and irreversible differentiation of cardiac fibroblasts. Cardiovasc Res. 2014;101(3):411–22.PubMedCrossRefGoogle Scholar
  30. 30.
    Hecker L, et al. Reversible differentiation of myofibroblasts by MyoD. Exp Cell Res. 2011;317(13):1914–21.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Thannickal VJ, et al. Mechanisms of pulmonary fibrosis. Annu Rev Med. 2004;55:395–417.PubMedCrossRefGoogle Scholar
  32. 32.
    Pohlers D, et al. TGF-beta and fibrosis in different organs—molecular pathway imprints. Biochim Biophys Acta. 2009;1792(8):746–56.PubMedCrossRefGoogle Scholar
  33. 33.
    Orimo A, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005;121(3):335–48.PubMedCrossRefGoogle Scholar
  34. 34.
    Muller GA, Rodemann HP. Characterization of human renal fibroblasts in health and disease: I. Immunophenotyping of cultured tubular epithelial cells and fibroblasts derived from kidneys with histologically proven interstitial fibrosis. Am J Kidney Dis. 1991;17(6):680–3.PubMedCrossRefGoogle Scholar
  35. 35.
    Bucala R, et al. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol Med. 1994;1(1):71–81.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Quan TE, et al. Circulating fibrocytes: collagen-secreting cells of the peripheral blood. Int J Biochem Cell Biol. 2004;36(4):598–606.PubMedCrossRefGoogle Scholar
  37. 37.
    Quan TE, Cowper SE, Bucala R. The role of circulating fibrocytes in fibrosis. Curr Rheumatol Rep. 2006;8(2):145–50.PubMedCrossRefGoogle Scholar
  38. 38.
    Wada T, et al. Fibrocytes: a new insight into kidney fibrosis. Kidney Int. 2007;72(3):269–73.PubMedCrossRefGoogle Scholar
  39. 39.
    Abe R, et al. Peripheral blood fibrocytes: differentiation pathway and migration to wound sites. J Immunol. 2001;166(12):7556–62.PubMedCrossRefGoogle Scholar
  40. 40.
    Schmidt M, et al. Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma. J Immunol. 2003;171(1):380–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Haudek SB, et al. Bone marrow-derived fibroblast precursors mediate ischemic cardiomyopathy in mice. Proc Natl Acad Sci USA. 2006;103(48):18284–9.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Iwano M, et al. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Investig. 2002;110(3):341–50.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Rygiel KA, et al. Epithelial-mesenchymal transition contributes to portal tract fibrogenesis during human chronic liver disease. Lab Investig. 2008;88(2):112–23.PubMedCrossRefGoogle Scholar
  44. 44.
    Strutz F. Pathogenesis of tubulointerstitial fibrosis in chronic allograft dysfunction. Clin Transplant. 2009;23(Suppl 21):26–32.PubMedCrossRefGoogle Scholar
  45. 45.
    Strutz F, Neilson EG. New insights into mechanisms of fibrosis in immune renal injury. Springer Semin Immunopathol. 2003;24(4):459–76.PubMedCrossRefGoogle Scholar
  46. 46.
    Greenhalgh SN, Iredale JP, Henderson NC. Origins of fibrosis: pericytes take centre stage. F1000Prime Rep. 2013;5:37.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Ferenbach DA, Bonventre JV. Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD. Nat Rev Nephrol. 2015;11(5):264–76.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Falke LL, et al. Diverse origins of the myofibroblast—implications for kidney fibrosis. Nat Rev Nephrol. 2015;11(4):233–44.PubMedCrossRefGoogle Scholar
  49. 49.
    Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev. 2008;88(1):125–72.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Lee YA, Wallace MC, Friedman SL. Pathobiology of liver fibrosis: a translational success story. Gut. 2015;64(5):830–41.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Barrientos S, et al. Growth factors and cytokines in wound healing. Wound Repair Regen. 2008;16(5):585–601.PubMedCrossRefGoogle Scholar
  52. 52.
    Horowitz JC, Thannickal VJ. Epithelial–mesenchymal interactions in pulmonary fibrosis. Sem Respir Crit Care Med. 2006;27(6):600–12.CrossRefGoogle Scholar
  53. 53.
    Morrisey EE. Wnt signaling and pulmonary fibrosis. Am J Pathol. 2003;162(5):1393–7.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Chetty A, Cao GJ, Nielsen HC. Insulin-like growth factor-I signaling mechanisms, type I collagen and alpha smooth muscle actin in human fetal lung fibroblasts. Pediatr Res. 2006;60(4):389–94.PubMedCrossRefGoogle Scholar
  55. 55.
    Wynn TA, Barron L. Macrophages: master regulators of inflammation and fibrosis. Semin Liver Dis. 2010;30(3):245–57.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Zhang HY, et al. Lung fibroblast alpha-smooth muscle actin expression and contractile phenotype in bleomycin-induced pulmonary fibrosis. Am J Pathol. 1996;148(2):527–37.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Desmouliere A, et al. Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol. 1993;122(1):103–11.PubMedCrossRefGoogle Scholar
  58. 58.
    Desmouliere A. Factors influencing myofibroblast differentiation during wound healing and fibrosis. Cell Biol Int. 1995;19(5):471–6.PubMedCrossRefGoogle Scholar
  59. 59.
    Horowitz JC, et al. Activation of the pro-survival phosphatidylinositol 3-kinase/AKT pathway by transforming growth factor-beta1 in mesenchymal cells is mediated by p38 MAPK-dependent induction of an autocrine growth factor. J Biol Chem. 2004;279(2):1359–67.PubMedCrossRefGoogle Scholar
  60. 60.
    Lasky JA, Brody AR. Interstitial fibrosis and growth factors. Environ Health Perspect. 2000;108(Suppl 4):751–62.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Yoshida M, et al. Transforming growth factor-beta stimulates the expression of desmosomal proteins in bronchial epithelial cells. Am J Respir Cell Mol Biol. 1992;6(4):439–45.PubMedCrossRefGoogle Scholar
  62. 62.
    Postlethwaite AE, et al. Stimulation of the chemotactic migration of human fibroblasts by transforming growth factor beta. J Exp Med. 1987;165(1):251–6.PubMedCrossRefGoogle Scholar
  63. 63.
    Montesano R, Orci L. Transforming growth factor beta stimulates collagen-matrix contraction by fibroblasts: implications for wound healing. Proc Natl Acad Sci USA. 1988;85(13):4894–7.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Tomasek JJ, et al. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol. 2002;3(5):349–63.PubMedCrossRefGoogle Scholar
  65. 65.
    Youssef J, et al. Mechanotransduction is enhanced by the synergistic action of heterotypic cell interactions and TGF-beta1. FASEB J. 2012;26(6):2522–30.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Meyer-ter-Vehn T, et al. Contractility as a prerequisite for TGF-beta-induced myofibroblast transdifferentiation in human tenon fibroblasts. Invest Ophthalmol Vis Sci. 2006;47(11):4895–904.PubMedCrossRefGoogle Scholar
  67. 67.
    Schmid P, et al. Enhanced expression of transforming growth factor-beta type I and type II receptors in wound granulation tissue and hypertrophic scar. Am J Pathol. 1998;152(2):485–93.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Kim SJ, et al. Autoinduction of transforming growth factor beta 1 is mediated by the AP-1 complex. Mol Cell Biol. 1990;10(4):1492–7.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Khalil N, et al. Increased production and immunohistochemical localization of transforming growth factor-beta in idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol. 1991;5(2):155–62.PubMedCrossRefGoogle Scholar
  70. 70.
    Broekelmann TJ, et al. Transforming growth factor beta 1 is present at sites of extracellular matrix gene expression in human pulmonary fibrosis. Proc Natl Acad Sci USA. 1991;88(15):6642–6.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Salez F, et al. Transforming growth factor-beta1 in sarcoidosis. Eur Respir J. 1998;12(4):913–9.PubMedCrossRefGoogle Scholar
  72. 72.
    Wojnarowski C, et al. Cytokine expression in bronchial biopsies of cystic fibrosis patients with and without acute exacerbation. Eur Respir J. 1999;14(5):1136–44.PubMedCrossRefGoogle Scholar
  73. 73.
    He S, et al. Mechanisms of transforming growth factor beta(1)/Smad signalling mediated by mitogen-activated protein kinase pathways in keloid fibroblasts. Br J Dermatol. 2010;162(3):538–46.PubMedCrossRefGoogle Scholar
  74. 74.
    Gauldie J, Kolb M, Sime PJ. A new direction in the pathogenesis of idiopathic pulmonary fibrosis? Respir Res. 2002;3:1.PubMedCrossRefGoogle Scholar
  75. 75.
    Grande MT, et al. Deletion of H-Ras decreases renal fibrosis and myofibroblast activation following ureteral obstruction in mice. Kidney Int. 2010;77(6):509–18.PubMedCrossRefGoogle Scholar
  76. 76.
    Lopez JI, Mouw JK, Weaver VM. Biomechanical regulation of cell orientation and fate. Oncogene. 2008;27(55):6981–93.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Tamariz E, Grinnell F. Modulation of fibroblast morphology and adhesion during collagen matrix remodeling. Mol Biol Cell. 2002;13(11):3915–29.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Marenzana M, et al. The origins and regulation of tissue tension: identification of collagen tension-fixation process in vitro. Exp Cell Res. 2006;312(4):423–33.PubMedCrossRefGoogle Scholar
  79. 79.
    Butcher DT, Alliston T, Weaver VM. A tense situation: forcing tumour progression. Nat Rev Cancer. 2009;9(2):108–22.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Liu F, et al. Feedback amplification of fibrosis through matrix stiffening and COX-2 suppression. J Cell Biol. 2010;190(4):693–706.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Hinz B, et al. Mechanical tension controls granulation tissue contractile activity and myofibroblast differentiation. Am J Pathol. 2001;159(3):1009–20.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Hinz B, et al. The myofibroblast: one function, multiple origins. Am J Pathol. 2007;170(6):1807–16.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Hinz B, et al. Alpha-smooth muscle actin expression upregulates fibroblast contractile activity. Mol Biol Cell. 2001;12(9):2730–41.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Pasapera AM, et al. Myosin II activity regulates vinculin recruitment to focal adhesions through FAK-mediated paxillin phosphorylation. J Cell Biol. 2010;188(6):877–90.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Vicente-Manzanares M, et al. Non-muscle myosin II takes centre stage in cell adhesion and migration. Nat Rev Mol Cell Biol. 2009;10(11):778–90.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Deakin NO, Turner CE. Paxillin comes of age. J Cell Sci. 2008;121(Pt 15):2435–44.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Hiroi T. Regulation of epithelial junctions by proteins of the ADP-ribosylation factor family. Front Biosci. 2009;14:717–30.CrossRefGoogle Scholar
  88. 88.
    Besser A, Schwarz US. Coupling biochemistry and mechanics in cell adhesion: a model for inhomogeneous stress fiber contraction. New J. Phys. 2007;9(11):425.CrossRefGoogle Scholar
  89. 89.
    Chen CS. Mechanotransduction—a field pulling together? J Cell Sci. 2008;121(Pt 20):3285–92.PubMedCrossRefGoogle Scholar
  90. 90.
    Maltseva O, et al. Fibroblast growth factor reversal of the corneal myofibroblast phenotype. Invest Ophthalmol Vis Sci. 2001;42(11):2490–5.PubMedGoogle Scholar
  91. 91.
    Grinnell F, et al. Release of mechanical tension triggers apoptosis of human fibroblasts in a model of regressing granulation tissue. Exp Cell Res. 1999;248(2):608–19.PubMedCrossRefGoogle Scholar
  92. 92.
    Niland S, et al. Contraction-dependent apoptosis of normal dermal fibroblasts. J Invest Dermatol. 2001;116(5):686–92.PubMedCrossRefGoogle Scholar
  93. 93.
    Narumiya S, Sugimoto Y, Ushikubi F. Prostanoid receptors: structures, properties, and functions. Physiol Rev. 1999;79(4):1193–226.PubMedGoogle Scholar
  94. 94.
    Funk CD. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science. 2001;294(5548):1871–5.PubMedCrossRefGoogle Scholar
  95. 95.
    Ham EA, et al. Inhibition by prostaglandins of leukotriene B4 release from activated neutrophils. Proc Natl Acad Sci USA. 1983;80(14):4349–53.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Standiford TJ, et al. Regulation of human alveolar macrophage- and blood monocyte-derived interleukin-8 by prostaglandin E2 and dexamethasone. Am J Respir Cell Mol Biol. 1992;6(1):75–81.PubMedCrossRefGoogle Scholar
  97. 97.
    Prins BA, et al. Prostaglandin E2 and prostacyclin inhibit the production and secretion of endothelin from cultured endothelial cells. J Biol Chem. 1994;269(16):11938–44.PubMedGoogle Scholar
  98. 98.
    Kunkel SL, et al. Prostaglandin E2 regulates macrophage-derived tumor necrosis factor gene expression. J Biol Chem. 1988;263(11):5380–4.PubMedGoogle Scholar
  99. 99.
    Huang S, et al. Prostaglandin E(2) inhibits collagen expression and proliferation in patient-derived normal lung fibroblasts via E prostanoid 2 receptor and cAMP signaling. Am J Physiol Lung Cell Mol Physiol. 2007;292(2):L405–13.PubMedCrossRefGoogle Scholar
  100. 100.
    Huang SK, et al. Prostaglandin E2 inhibits specific lung fibroblast functions via selective actions of PKA and Epac-1. Am J Respir Cell Mol Biol. 2008;39(4):482–9.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Baud L, et al. Modulation of fibroblast proliferation by sulfidopeptide leukotrienes: effect of indomethacin. J Immunol. 1987;138(4):1190–5.PubMedGoogle Scholar
  102. 102.
    White ES, et al. Prostaglandin E(2) inhibits fibroblast migration by E-prostanoid 2 receptor-mediated increase in PTEN activity. Am J Respir Cell Mol Biol. 2005;32(2):135–41.PubMedCrossRefGoogle Scholar
  103. 103.
    Kohyama T, et al. Prostaglandin E(2) inhibits fibroblast chemotaxis. Am J Physiol Lung Cell Mol Physiol. 2001;281(5):L1257–63.PubMedGoogle Scholar
  104. 104.
    Gerarduzzi C, et al. Prostaglandin E2-dependent phosphorylation of RAS inhibition 1 (RIN1) at ser 291 and 292 inhibits transforming growth factor-beta-induced RAS activation pathway in human synovial fibroblasts: role in cell migration. J Cell Physiol. 2017;232(1):202–15.PubMedCrossRefGoogle Scholar
  105. 105.
    Baum BJ, et al. Effect of cyclic AMP on the intracellular degradation of newly synthesized collagen. J Biol Chem. 1980;255(7):2843–7.PubMedGoogle Scholar
  106. 106.
    Kolodsick JE, et al. Prostaglandin E2 inhibits fibroblast to myofibroblast transition via E. prostanoid receptor 2 signaling and cyclic adenosine monophosphate elevation. Am J Respir Cell Mol Biol. 2003;29(5):537–44.PubMedCrossRefGoogle Scholar
  107. 107.
    Thomas PE, et al. PGE(2) inhibition of TGF-beta1-induced myofibroblast differentiation is Smad-independent but involves cell shape and adhesion-dependent signaling. Am J Physiol Lung Cell Mol Physiol. 2007;293(2):L417–28.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Gerarduzzi C, et al. Prostaglandin E(2)-dependent blockade of actomyosin and stress fibre formation is mediated through S1379 phosphorylation of ROCK2. J Cell Biochem. 2014;115(9):1516–27.PubMedCrossRefGoogle Scholar
  109. 109.
    Moore BB, et al. Bleomycin-induced E prostanoid receptor changes alter fibroblast responses to prostaglandin E2. J Immunol. 2005;174(9):5644–9.PubMedCrossRefGoogle Scholar
  110. 110.
    Gerarduzzi C, et al. Quantitative phosphoproteomic analysis of signaling downstream of the prostaglandin e2/g-protein coupled receptor in human synovial fibroblasts: potential antifibrotic networks. J Proteome Res. 2014;13(11):5262–80.PubMedCrossRefGoogle Scholar
  111. 111.
    Borok Z, et al. Augmentation of functional prostaglandin E levels on the respiratory epithelial surface by aerosol administration of prostaglandin E. Am Rev Respir Dis. 1991;144(5):1080–4.PubMedCrossRefGoogle Scholar
  112. 112.
    Ozaki T, et al. Regulatory effect of prostaglandin E2 on fibronectin release from human alveolar macrophages. Am Rev Respir Dis. 1990;141(4 Pt 1):965–9.PubMedCrossRefGoogle Scholar
  113. 113.
    Wilborn J, et al. Cultured lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis have a diminished capacity to synthesize prostaglandin E2 and to express cyclooxygenase-2. J Clin Investig. 1995;95(4):1861–8.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Vancheri C, et al. Different expression of TNF-alpha receptors and prostaglandin E(2)Production in normal and fibrotic lung fibroblasts: potential implications for the evolution of the inflammatory process. Am J Respir Cell Mol Biol. 2000;22(5):628–34.PubMedCrossRefGoogle Scholar
  115. 115.
    Maher TM, et al. Diminished prostaglandin E2 contributes to the apoptosis paradox in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2010;182(1):73–82.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Coward WR, et al. Defective histone acetylation is responsible for the diminished expression of cyclooxygenase 2 in idiopathic pulmonary fibrosis. Mol Cell Biol. 2009;29(15):4325–39.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Petkova DK, et al. Reduced expression of cyclooxygenase (COX) in idiopathic pulmonary fibrosis and sarcoidosis. Histopathology. 2003;43(4):381–6.PubMedCrossRefGoogle Scholar
  118. 118.
    Ogushi F, et al. Decreased prostaglandin E2 synthesis by lung fibroblasts isolated from rats with bleomycin-induced lung fibrosis. Int J Exp Pathol. 1999;80(1):41–9.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Moore BB, et al. GM-CSF regulates bleomycin-induced pulmonary fibrosis via a prostaglandin-dependent mechanism. J Immunol. 2000;165(7):4032–9.PubMedCrossRefGoogle Scholar
  120. 120.
    Keerthisingam CB, et al. Cyclooxygenase-2 deficiency results in a loss of the anti-proliferative response to transforming growth factor-beta in human fibrotic lung fibroblasts and promotes bleomycin-induced pulmonary fibrosis in mice. Am J Pathol. 2001;158(4):1411–22.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Huang SK, et al. Variable prostaglandin E2 resistance in fibroblasts from patients with usual interstitial pneumonia. Am J Respir Crit Care Med. 2008;177(1):66–74.PubMedCrossRefGoogle Scholar
  122. 122.
    Huang SK, et al. Hypermethylation of PTGER2 confers prostaglandin E2 resistance in fibrotic fibroblasts from humans and mice. Am J Pathol. 2010;177(5):2245–55.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Gharaee-Kermani M, et al. Recent advances in molecular targets and treatment of idiopathic pulmonary fibrosis: focus on TGFbeta signaling and the myofibroblast. Curr Med Chem. 2009;16(11):1400–17.PubMedCrossRefGoogle Scholar
  124. 124.
    Lynch JP 3rd, White E, Flaherty K. Corticosteroids in idiopathic pulmonary fibrosis. Curr Opin Pulm Med. 2001;7(5):298–308.PubMedCrossRefGoogle Scholar
  125. 125.
    Kehrer JP, et al. Enhanced acute lung damage following corticosteroid treatment. Am Rev Respir Dis. 1984;130(2):256–61.PubMedGoogle Scholar
  126. 126.
    Entzian P, et al. Comparative study on effects of pentoxifylline, prednisolone and colchicine in experimental alveolitis. Int J Immunopharmacol. 1998;20(12):723–35.PubMedCrossRefGoogle Scholar
  127. 127.
    Blanquaert F, Pereira RC, Canalis E. Cortisol inhibits hepatocyte growth factor/scatter factor expression and induces c-met transcripts in osteoblasts. Am J Physiol Endocrinol Metab. 2000;278(3):E509–15.PubMedGoogle Scholar
  128. 128.
    Kujubu DA, Herschman HR. Dexamethasone inhibits mitogen induction of the TIS10 prostaglandin synthase/cyclooxygenase gene. J Biol Chem. 1992;267(12):7991–4.PubMedGoogle Scholar
  129. 129.
    Stichtenoth DO, et al. Microsomal prostaglandin E synthase is regulated by proinflammatory cytokines and glucocorticoids in primary rheumatoid synovial cells. J Immunol. 2001;167(1):469–74.PubMedCrossRefGoogle Scholar
  130. 130.
    Homo-Delarche F, Bach JF, Dardenne M. In vitro inhibition of prostaglandin production by azathioprine and 6-mercaptopurine. Prostaglandins. 1988;35(4):479–91.PubMedCrossRefGoogle Scholar
  131. 131.
    Williams AS, et al. Prostaglandin and tumor necrosis factor secretion by peritoneal macrophages isolated from normal and arthritic rats treated with liposomal methotrexate. J Pharmacol Toxicol Methods. 1994;32(1):53–8.PubMedCrossRefGoogle Scholar
  132. 132.
    Vergne P, et al. Methotrexate and cyclooxygenase metabolism in cultured human rheumatoid synoviocytes. J Rheumatol. 1998;25(3):433–40.PubMedGoogle Scholar
  133. 133.
    Sanghi S., et al. Cyclooxygenase-2 inhibitors: a painful lesson. Cardiovasc Hematol Disord Drug Targets. 2006;6(2):85–100.PubMedCrossRefGoogle Scholar
  134. 134.
    Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med. 1999;340(24):1888–99.PubMedCrossRefGoogle Scholar
  135. 135.
    Selman M, King TE, Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med. 2001;134(2):136–51.PubMedCrossRefGoogle Scholar
  136. 136.
    Varga J, Pasche B. Antitransforming growth factor-beta therapy in fibrosis: recent progress and implications for systemic sclerosis. Curr Opin Rheumatol. 2008;20(6):720–8.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Varga J, Pasche B. Antitransforming growth factor-beta therapy in fibrosis: recent progress and implications for systemic sclerosis. Curr Opin Rheumatol. 2008;20(6):720–8.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Denton CP, et al. Recombinant human anti-transforming growth factor beta1 antibody therapy in systemic sclerosis: a multicenter, randomized, placebo-controlled phase I/II trial of CAT-192. Arthr Rheum. 2007;56(1):323–33.CrossRefGoogle Scholar
  139. 139.
    Bond JE, et al. Wound contraction is attenuated by fasudil inhibition of Rho-associated kinase. Plast Reconstr Surg. 2011;128(5):438e–50e.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Satoh S, et al. Fasudil attenuates interstitial fibrosis in rat kidneys with unilateral ureteral obstruction. Eur J Pharmacol. 2002;455(2–3):169–74.PubMedCrossRefGoogle Scholar
  141. 141.
    Tada S, et al. A selective ROCK inhibitor, Y27632, prevents dimethylnitrosamine-induced hepatic fibrosis in rats. J Hepatol. 2001;34(4):529–36.PubMedCrossRefGoogle Scholar
  142. 142.
    Ikeda H, et al. Rho-kinase inhibitor prevents hepatocyte damage in acute liver injury induced by carbon tetrachloride in rats. Am J Physiol Gastrointest Liver Physiol. 2007;293(4):G911–7.PubMedCrossRefGoogle Scholar
  143. 143.
    Nagatoya K, et al. Y-27632 prevents tubulointerstitial fibrosis in mouse kidneys with unilateral ureteral obstruction. Kidney Int. 2002;61(5):1684–95.PubMedCrossRefGoogle Scholar
  144. 144.
    Takeda Y, et al. Beneficial effects of a combination of Rho-kinase inhibitor and ACE inhibitor on tubulointerstitial fibrosis induced by unilateral ureteral obstruction. Hypertens Res. 2010;33(9):965–73.PubMedCrossRefGoogle Scholar
  145. 145.
    Mochitate K, Pawelek P, Grinnell F. Stress relaxation of contracted collagen gels: disruption of actin filament bundles, release of cell surface fibronectin, and down-regulation of DNA and protein synthesis. Exp Cell Res. 1991;193(1):198–207.PubMedCrossRefGoogle Scholar
  146. 146.
    Lagares D, et al. Inhibition of focal adhesion kinase prevents experimental lung fibrosis and myofibroblast formation. Arthr Rheum. 2012;64(5):1653–64.CrossRefGoogle Scholar
  147. 147.
    Garneau-Tsodikova S, Thannickal VJ. Protein kinase inhibitors in the treatment of pulmonary fibrosis. Curr Med Chem. 2008;15(25):2632–40.PubMedCrossRefGoogle Scholar
  148. 148.
    Huang S, et al. Prostaglandin E(2) inhibits collagen expression and proliferation in patient-derived normal lung fibroblasts via E prostanoid 2 receptor and cAMP signaling. Am J Physiol Lung Cell Mol Physiol. 2007;292(2):L405–13.PubMedCrossRefGoogle Scholar
  149. 149.
    Kach J, et al. Antifibrotic effects of noscapine through activation of prostaglandin E2 receptors and protein kinase A. J Biol Chem. 2014;289(11):7505–13.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Dunkern TR, et al. Inhibition of TGF-beta induced lung fibroblast to myofibroblast conversion by phosphodiesterase inhibiting drugs and activators of soluble guanylyl cyclase. Eur J Pharmacol. 2007;572(1):12–22.PubMedCrossRefGoogle Scholar
  151. 151.
    Togo S, et al. PDE4 inhibitors roflumilast and rolipram augment PGE2 inhibition of TGF-{beta}1-stimulated fibroblasts. Am J Physiol Lung Cell Mol Physiol. 2009;296(6):L959–69.PubMedCrossRefGoogle Scholar
  152. 152.
    Kohyama T, et al. PDE4 inhibitors attenuate fibroblast chemotaxis and contraction of native collagen gels. Am J Respir Cell Mol Biol. 2002;26(6):694–701.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing 2016

Authors and Affiliations

  1. 1.Renal Division, Department of Medicine, Brigham and Women’s HospitalHarvard Institutes of MedicineBostonUSA
  2. 2.Department of Medicine and Experimental Medicine, McGill University and the Division of Rheumatology, Royal Victoria HospitalMcGill University Health Centre Research InstituteMontréalCanada

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