Skip to main content
SpringerLink
Log in

Fibrotic Signaling in the Lung

  • Chapter
  • First Online:
Fibrosis in Disease

Part of the book series: Molecular and Translational Medicine ((MOLEMED))

  • 933 Accesses

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive scarring of the lung parenchyma, which ultimately leads to impaired gas exchange, respiratory failure, and death. Studies of patients, cells, and laboratory animals over the last 30 years have led to an ever-increasing corpus of knowledge, based on studies of ever-increasing degrees of sophistication and on the signaling events that occur during lung injury and fibrosis. This review summarizes many of the signaling mechanisms that occur in, arguably, the three principal cellular actors in the fibrotic lung: the epithelial cell, the macrophage, and the fibroblast. The growth of lung fibrosis research, coupled with an intense interest on the part of industry to devise therapies, suggests that new therapies are coming that are rationally designed to target these critical signaling events. This chapter will focus on both the cellular players and the signaling events that contribute to pulmonary fibrosis.

All authors (Justin A. Dutta, Harinath Bahudhanapati, Jiangning Tan, Alon Goldblum, and Daniel J. Kass) contributed to the design and composition of this manuscript. The authors do not present any new research, and therefore, this work did not require ethical oversight by the Institutional Review Board or the Institutional Animal Care and Use Committee. All authors have read and approved this submission.

This work was sponsored by NIH grant R01 HL 126990 to Daniel J. Kass.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Martinez FJ, Collard HR, Pardo A, Raghu G, Richeldi L, Selman M, et al. Idiopathic pulmonary fibrosis. Nat Rev Dis Prim. 2017;3:17074.

    Article  PubMed  Google Scholar 

  2. Bahudhanapati H, Kass DJ. Unwinding the collagen fibrils: elucidating the mechanism of pirfenidone and nintedanib in pulmonary fibrosis. Am J Respir Cell Mol Biol. 2017;57(1):10–1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. King TE Jr, Pardo A, Selman M. Idiopathic pulmonary fibrosis. Lancet. 2011;378(9807):1949–61.

    Article  PubMed  Google Scholar 

  4. Kass DJ, Kaminski N. Evolving genomic approaches to idiopathic pulmonary fibrosis: moving beyond genes. Clin Transl Sci. 2011;4(5):372–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Podolanczuk AJ, Oelsner EC, Barr RG, Bernstein EJ, Hoffman EA, Easthausen IJ, et al. High-attenuation areas on chest computed tomography and clinical respiratory outcomes in community-dwelling adults. Am J Respir Crit Care Med. 2017;196(11):1434–42.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Putman RK, Hatabu H, Araki T, Gudmundsson G, Gao W, Nishino M, et al. Association between interstitial lung abnormalities and all-cause mortality. JAMA. 2016;315(7):672–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Taskar VS, Coultas DB. Is idiopathic pulmonary fibrosis an environmental disease? Proc Am Thorac Soc. 2006;3(4):293–8.

    Article  PubMed  Google Scholar 

  8. Zoz DF, Lawson WE, Blackwell TS. Idiopathic pulmonary fibrosis: a disorder of epithelial cell dysfunction. Am J Med Sci. 2011;341(6):435–8.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Alder JK, Kass DJ. Another building in the IPF Manhattan plot skyline. Lancet Respir Med. 2017;5(11):837–9.

    Article  PubMed  Google Scholar 

  10. Alder JK, Chen JJ, Lancaster L, Danoff S, Su SC, Cogan JD, et al. Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc Natl Acad Sci U S A. 2008;105(35):13051–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med. 2007;356(13):1317–26.

    Article  CAS  PubMed  Google Scholar 

  12. Fehrenbach H. Alveolar epithelial type II cell: defender of the alveolus revisited. Respir Res. 2001;2(1):33–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Rock JR, Barkauskas CE, Cronce MJ, Xue Y, Harris JR, Liang J, et al. Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition. Proc Natl Acad Sci U S A. 2011;108(52):E1475–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Barkauskas CE, Cronce MJ, Rackley CR, Bowie EJ, Keene DR, Stripp BR, et al. Type 2 alveolar cells are stem cells in adult lung. J Clin Invest. 2013;123(7):3025–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Alder JK, Barkauskas CE, Limjunyawong N, Stanley SE, Kembou F, Tuder RM, et al. Telomere dysfunction causes alveolar stem cell failure. Proc Natl Acad Sci U S A. 2015;112(16):5099–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Stanley SE, Chen JJ, Podlevsky JD, Alder JK, Hansel NN, Mathias RA, et al. Telomerase mutations in smokers with severe emphysema. J Clin Invest. 2015;125(2):563–70.

    Article  PubMed  Google Scholar 

  17. Alder JK, Guo N, Kembou F, Parry EM, Anderson CJ, Gorgy AI, et al. Telomere length is a determinant of emphysema susceptibility. Am J Respir Crit Care Med. 2011;184(8):904–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Pollack A. F.D.A. approves first 2 drugs for treatment of a fatal lung disease. New York Times. 2014. 15 Oct 2014.

    Google Scholar 

  19. Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071–82.

    Article  PubMed  CAS  Google Scholar 

  20. Chaudhary NI, Roth GJ, Hilberg F, Muller-Quernheim J, Prasse A, Zissel G, et al. Inhibition of PDGF, VEGF and FGF signalling attenuates fibrosis. Eur Respir J. 2007;29(5):976–85.

    Article  CAS  PubMed  Google Scholar 

  21. Daniels CE, Lasky JA, Limper AH, Mieras K, Gabor E, Schroeder DR, et al. Imatinib treatment for idiopathic pulmonary fibrosis: randomized placebo-controlled trial results. Am J Respir Crit Care Med. 2010;181(6):604–10.

    Article  CAS  PubMed  Google Scholar 

  22. Conte E, Gili E, Fagone E, Fruciano M, Iemmolo M, Vancheri C. Effect of pirfenidone on proliferation, TGF-beta-induced myofibroblast differentiation and fibrogenic activity of primary human lung fibroblasts. Eur J Pharm Sci. 2014;58:13–9.

    Article  CAS  PubMed  Google Scholar 

  23. Didiasova M, Singh R, Wilhelm J, Kwapiszewska G, Wujak L, Zakrzewicz D, et al. Pirfenidone exerts antifibrotic effects through inhibition of GLI transcription factors. FASEB J. 2017;31:1916–28.

    Article  CAS  PubMed  Google Scholar 

  24. Nakazato H, Oku H, Yamane S, Tsuruta Y, Suzuki R. A novel anti-fibrotic agent pirfenidone suppresses tumor necrosis factor-alpha at the translational level. Eur J Pharmacol. 2002;446(1–3):177–85.

    Article  CAS  PubMed  Google Scholar 

  25. Sisson TH, Mendez M, Choi K, Subbotina N, Courey A, Cunningham A, et al. Targeted injury of type II alveolar epithelial cells induces pulmonary fibrosis. Am J Respir Crit Care Med. 2010;181(3):254–63.

    Article  CAS  PubMed  Google Scholar 

  26. Naikawadi RP, Disayabutr S, Mallavia B, Donne ML, Green G, La JL, et al. Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis. JCI Insight. 2016;1(14):e86704.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Qian YR, Zhang QR, Cheng T, Wan HY, Zhou M. RNA interference-mediated silencing of SOCS-1 via lentiviral vector promotes apoptosis of alveolar epithelial cells in vitro. Mol Med Rep. 2012;5(2):452–6.

    CAS  PubMed  Google Scholar 

  28. Tager AM, LaCamera P, Shea BS, Campanella GS, Selman M, Zhao Z, et al. The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak. Nat Med. 2008;14(1):45–54.

    Article  CAS  PubMed  Google Scholar 

  29. Funke M, Zhao Z, Xu Y, Chun J, Tager AM. The lysophosphatidic acid receptor LPA1 promotes epithelial cell apoptosis after lung injury. Am J Respir Cell Mol Biol. 2012;46(3):355–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lin ME, Herr DR, Chun J. Lysophosphatidic acid (LPA) receptors: signaling properties and disease relevance. Prostaglandins Other Lipid Mediat. 2010;91(3–4):130–8.

    Article  CAS  PubMed  Google Scholar 

  31. Knipe RS, Probst CK, Lagares D, Franklin A, Spinney JJ, Brazee PL, et al. The rho kinase isoforms ROCK1 and ROCK2 each contribute to the development of experimental pulmonary fibrosis. Am J Respir Cell Mol Biol. 2017;58:471–81.

    Article  Google Scholar 

  32. Huang LS, Fu P, Patel P, Harijith A, Sun T, Zhao Y, et al. Lysophosphatidic acid receptor-2 deficiency confers protection against bleomycin-induced lung injury and fibrosis in mice. Am J Respir Cell Mol Biol. 2013;49(6):912–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Mulugeta S, Nureki S, Beers MF. Lost after translation: insights from pulmonary surfactant for understanding the role of alveolar epithelial dysfunction and cellular quality control in fibrotic lung disease. Am J Physiol Lung Cell Mol Physiol. 2015;309(6):L507–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhang X, Zhang Y, Tao B, Teng L, Li Y, Cao R, et al. Loss of Shp2 in alveoli epithelia induces deregulated surfactant homeostasis, resulting in spontaneous pulmonary fibrosis. FASEB J. 2012;26(6):2338–50.

    Article  CAS  PubMed  Google Scholar 

  35. Upadhyay D, Bundesmann M, Panduri V, Correa-Meyer E, Kamp DW. Fibroblast growth factor-10 attenuates H2O2-induced alveolar epithelial cell DNA damage: role of MAPK activation and DNA repair. Am J Respir Cell Mol Biol. 2004;31(1):107–13.

    Article  CAS  PubMed  Google Scholar 

  36. Gupte VV, Ramasamy SK, Reddy R, Lee J, Weinreb PH, Violette SM, et al. Overexpression of fibroblast growth factor-10 during both inflammatory and fibrotic phases attenuates bleomycin-induced pulmonary fibrosis in mice. Am J Respir Crit Care Med. 2009;180(5):424–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yi ES, Williams ST, Lee H, Malicki DM, Chin EM, Yin S, et al. Keratinocyte growth factor ameliorates radiation- and bleomycin-induced lung injury and mortality. Am J Pathol. 1996;149(6):1963–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Bueno M, Lai YC, Romero Y, Brands J, St Croix CM, Kamga C, et al. PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis. J Clin Invest. 2015;125(2):521–38.

    Article  PubMed  Google Scholar 

  39. Yu G, Tzouvelekis A, Wang R, Herazo-Maya JD, Ibarra GH, Srivastava A, et al. Thyroid hormone inhibits lung fibrosis in mice by improving epithelial mitochondrial function. Nat Med. 2018;24(1):39–49.

    Article  CAS  PubMed  Google Scholar 

  40. Li M, Krishnaveni MS, Li C, Zhou B, Xing Y, Banfalvi A, et al. Epithelium-specific deletion of TGF-beta receptor type II protects mice from bleomycin-induced pulmonary fibrosis. J Clin Invest. 2011;121(1):277–87.

    Article  CAS  PubMed  Google Scholar 

  41. Degryse AL, Tanjore H, Xu XC, Polosukhin VV, Jones BR, Boomershine CS, et al. TGFbeta signaling in lung epithelium regulates bleomycin-induced alveolar injury and fibroblast recruitment. Am J Physiol Lung Cell Mol Physiol. 2011;300(6):L887–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Willis BC, Liebler JM, Luby-Phelps K, Nicholson AG, Crandall ED, du Bois RM, et al. Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis. Am J Pathol. 2005;166(5):1321–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Shukla MN, Rose JL, Ray R, Lathrop KL, Ray A, Ray P. Hepatocyte growth factor inhibits epithelial to myofibroblast transition in lung cells via Smad7. Am J Respir Cell Mol Biol. 2009;40(6):643–53.

    Article  CAS  PubMed  Google Scholar 

  44. Buckley ST, Medina C, Kasper M, Ehrhardt C. Interplay between RAGE, CD44, and focal adhesion molecules in epithelial-mesenchymal transition of alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2011;300(4):L548–59.

    Article  CAS  PubMed  Google Scholar 

  45. DeMaio L, Buckley ST, Krishnaveni MS, Flodby P, Dubourd M, Banfalvi A, et al. Ligand-independent transforming growth factor-beta type I receptor signalling mediates type I collagen-induced epithelial-mesenchymal transition. J Pathol. 2012;226(4):633–44.

    Article  CAS  PubMed  Google Scholar 

  46. Zhou B, Liu Y, Kahn M, Ann DK, Han A, Wang H, et al. Interactions between beta-catenin and transforming growth factor-beta signaling pathways mediate epithelial-mesenchymal transition and are dependent on the transcriptional co-activator cAMP-response element-binding protein (CREB)-binding protein (CBP). J Biol Chem. 2012;287(10):7026–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Song X, Liu W, Xie S, Wang M, Cao G, Mao C, et al. All-transretinoic acid ameliorates bleomycin-induced lung fibrosis by downregulating the TGF-beta1/Smad3 signaling pathway in rats. Lab Investig. 2013;93(11):1219–31.

    Article  CAS  PubMed  Google Scholar 

  48. Watanabe-Takano H, Takano K, Hatano M, Tokuhisa T, Endo T. DA-Raf-mediated suppression of the Ras – ERK pathway is essential for TGF-beta1-induced epithelial-mesenchymal transition in alveolar epithelial type 2 cells. PLoS One. 2015;10(5):e0127888.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Heise RL, Stober V, Cheluvaraju C, Hollingsworth JW, Garantziotis S. Mechanical stretch induces epithelial-mesenchymal transition in alveolar epithelia via hyaluronan activation of innate immunity. J Biol Chem. 2011;286(20):17435–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kim KK, Wei Y, Szekeres C, Kugler MC, Wolters PJ, Hill ML, et al. Epithelial cell alpha3beta1 integrin links beta-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis. J Clin Invest. 2009;119(1):213–24.

    CAS  PubMed  Google Scholar 

  51. Ulsamer A, Wei Y, Kim KK, Tan K, Wheeler S, Xi Y, et al. Axin pathway activity regulates in vivo pY654-beta-catenin accumulation and pulmonary fibrosis. J Biol Chem. 2012;287(7):5164–72.

    Article  CAS  PubMed  Google Scholar 

  52. van der Velden JL, Guala AS, Leggett SE, Sluimer J, Badura EC, Janssen-Heininger YM. Induction of a mesenchymal expression program in lung epithelial cells by wingless protein (Wnt)/beta-catenin requires the presence of c-Jun N-terminal kinase-1 (JNK1). Am J Respir Cell Mol Biol. 2012;47(3):306–14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Miyoshi K, Yanagi S, Kawahara K, Nishio M, Tsubouchi H, Imazu Y, et al. Epithelial Pten controls acute lung injury and fibrosis by regulating alveolar epithelial cell integrity. Am J Respir Crit Care Med. 2013;187(3):262–75.

    Article  CAS  PubMed  Google Scholar 

  54. Wang Y, Huang C, Reddy Chintagari N, Bhaskaran M, Weng T, Guo Y, et al. miR-375 regulates rat alveolar epithelial cell trans-differentiation by inhibiting Wnt/beta-catenin pathway. Nucleic Acids Res. 2013;41(6):3833–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Aoyagi-Ikeda K, Maeno T, Matsui H, Ueno M, Hara K, Aoki Y, et al. Notch induces myofibroblast differentiation of alveolar epithelial cells via transforming growth factor-{beta}-Smad3 pathway. Am J Respir Cell Mol Biol. 2011;45(1):136–44.

    CAS  PubMed  Google Scholar 

  56. Yang J, Velikoff M, Canalis E, Horowitz JC, Kim KK. Activated alveolar epithelial cells initiate fibrosis through autocrine and paracrine secretion of connective tissue growth factor. Am J Physiol Lung Cell Mol Physiol. 2014;306(8):L786–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Aumiller V, Balsara N, Wilhelm J, Gunther A, Konigshoff M. WNT/beta-catenin signaling induces IL-1beta expression by alveolar epithelial cells in pulmonary fibrosis. Am J Respir Cell Mol Biol. 2013;49(1):96–104.

    Article  CAS  PubMed  Google Scholar 

  58. Whittington HA, Armstrong L, Uppington KM, Millar AB. Interleukin-22: a potential immunomodulatory molecule in the lung. Am J Respir Cell Mol Biol. 2004;31(2):220–6.

    Article  CAS  PubMed  Google Scholar 

  59. Young LR, Gulleman PM, Short CW, Tanjore H, Sherrill T, Qi A, et al. Epithelial-macrophage interactions determine pulmonary fibrosis susceptibility in Hermansky-Pudlak syndrome. JCI Insight. 2016;1(17):e88947.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Kass DJ, Yu G, Loh KS, Savir A, Borczuk A, Kahloon R, et al. Cytokine-like factor 1 gene expression is enriched in idiopathic pulmonary fibrosis and drives the accumulation of CD4+ T cells in murine lungs: evidence for an antifibrotic role in bleomycin injury. Am J Pathol. 2012;180(5):1963–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. John AE, Wilson MR, Habgood A, Porte J, Tatler AL, Stavrou A, et al. Loss of epithelial Gq and G11 signaling inhibits TGFbeta production but promotes IL-33-mediated macrophage polarization and emphysema. Sci Signal. 2016;9(451):ra104.

    Article  PubMed  CAS  Google Scholar 

  62. Kato A, Okura T, Hamada C, Miyoshi S, Katayama H, Higaki J, et al. Cell stress induces upregulation of osteopontin via the ERK pathway in type II alveolar epithelial cells. PLoS One. 2014;9(6):e100106.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Pardo A, Gibson K, Cisneros J, Richards TJ, Yang Y, Becerril C, et al. Up-regulation and profibrotic role of osteopontin in human idiopathic pulmonary fibrosis. PLoS Med. 2005;2(9):e251.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Korfhagen TR, Swantz RJ, Wert SE, McCarty JM, Kerlakian CB, Glasser SW, et al. Respiratory epithelial cell expression of human transforming growth factor-alpha induces lung fibrosis in transgenic mice. J Clin Invest. 1994;93(4):1691–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wheaton AK, Agarwal M, Jia S, Kim KK. Lung epithelial cell focal adhesion kinase signaling inhibits lung injury and fibrosis. Am J Physiol Lung Cell Mol Physiol. 2017;312(5):L722–L30.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Kumar PA, Hu Y, Yamamoto Y, Hoe NB, Wei TS, Mu D, et al. Distal airway stem cells yield alveoli in vitro and during lung regeneration following H1N1 influenza infection. Cell. 2011;147(3):525–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Geddert H, Kiel S, Heep HJ, Gabbert HE, Sarbia M. The role of p63 and deltaNp63 (p40) protein expression and gene amplification in esophageal carcinogenesis. Hum Pathol. 2003;34(9):850–6.

    Article  CAS  PubMed  Google Scholar 

  68. Xi Y, Kim T, Brumwell AN, Driver IH, Wei Y, Tan V, et al. Local lung hypoxia determines epithelial fate decisions during alveolar regeneration. Nat Cell Biol. 2017;19(8):904–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Xu Y, Mizuno T, Sridharan A, Du Y, Guo M, Tang J, et al. Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis. JCI Insight. 2016;1(20):e90558.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Zepp JA, Zacharias WJ, Frank DB, Cavanaugh CA, Zhou S, Morley MP, et al. Distinct mesenchymal lineages and niches promote epithelial self-renewal and myofibrogenesis in the lung. Cell. 2017;170(6):1134–48. e10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Hokuto I, Ikegami M, Yoshida M, Takeda K, Akira S, Perl AK, et al. Stat-3 is required for pulmonary homeostasis during hyperoxia. J Clin Invest. 2004;113(1):28–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Quinton LJ, Jones MR, Robson BE, Simms BT, Whitsett JA, Mizgerd JP. Alveolar epithelial STAT3, IL-6 family cytokines, and host defense during Escherichia coli pneumonia. Am J Respir Cell Mol Biol. 2008;38(6):699–706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Kida H, Mucenski ML, Thitoff AR, Le Cras TD, Park KS, Ikegami M, et al. GP130-STAT3 regulates epithelial cell migration and is required for repair of the bronchiolar epithelium. Am J Pathol. 2008;172(6):1542–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Matsuzaki Y, Besnard V, Clark JC, Xu Y, Wert SE, Ikegami M, et al. STAT3 regulates ABCA3 expression and influences lamellar body formation in alveolar type II cells. Am J Respir Cell Mol Biol. 2008;38(5):551–8.

    Article  CAS  PubMed  Google Scholar 

  75. Zhang Y, Noth I, Garcia JG, Kaminski N. A variant in the promoter of MUC5B and idiopathic pulmonary fibrosis. N Engl J Med. 2011;364(16):1576–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Seibold MA, Wise AL, Speer MC, Steele MP, Brown KK, Loyd JE, et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med. 2011;364(16):1503–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Nakano Y, Yang IV, Walts AD, Watson AM, Helling BA, Fletcher AA, et al. MUC5B promoter variant rs35705950 affects MUC5B expression in the distal airways in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2016;193(4):464–6.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Murray LA, Chen Q, Kramer MS, Hesson DP, Argentieri RL, Peng X, et al. TGF-beta driven lung fibrosis is macrophage dependent and blocked by Serum amyloid P. Int J Biochem Cell Biol. 2011;43(1):154–62.

    Article  CAS  PubMed  Google Scholar 

  79. Borthwick LA, Barron L, Hart KM, Vannella KM, Thompson RW, Oland S, et al. Macrophages are critical to the maintenance of IL-13-dependent lung inflammation and fibrosis. Mucosal Immunol. 2016;9(1):38–55.

    Article  CAS  PubMed  Google Scholar 

  80. Misharin AV, Morales-Nebreda L, Reyfman PA, Cuda CM, Walter JM, McQuattie-Pimentel AC, et al. Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span. J Exp Med. 2017;214(8):2387–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41(1):14–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 2014;6:13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Wynn TA, Vannella KM. Macrophages in tissue repair, regeneration, and fibrosis. Immunity. 2016;44(3):450–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Wynn TA, Barron L, Thompson RW, Madala SK, Wilson MS, Cheever AW, et al. Quantitative assessment of macrophage functions in repair and fibrosis. Curr Protoc Immunol. 2011;Chapter 14:Unit14.22.

    Google Scholar 

  85. Schupp JC, Binder H, Jager B, Cillis G, Zissel G, Muller-Quernheim J, et al. Macrophage activation in acute exacerbation of idiopathic pulmonary fibrosis. PLoS One. 2015;10(1):e0116775.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Redente EF, Keith RC, Janssen W, Henson PM, Ortiz LA, Downey GP, et al. Tumor necrosis factor-alpha accelerates the resolution of established pulmonary fibrosis in mice by targeting profibrotic lung macrophages. Am J Respir Cell Mol Biol. 2014;50(4):825–37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Kannan Y, Perez-Lloret J, Li Y, Entwistle LJ, Khoury H, Papoutsopoulou S, et al. TPL-2 regulates macrophage lipid metabolism and M2 differentiation to control TH2-mediated immunopathology. PLoS Pathog. 2016;12(8):e1005783.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Larson-Casey JL, Deshane JS, Ryan AJ, Thannickal VJ, Carter AB. Macrophage Akt1 kinase-mediated mitophagy modulates apoptosis resistance and pulmonary fibrosis. Immunity. 2016;44(3):582–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Nie Y, Sun L, Wu Y, Yang Y, Wang J, He H, et al. AKT2 regulates pulmonary inflammation and fibrosis via modulating macrophage activation. J Immunol. 2017;198(11):4470–80.

    Article  CAS  PubMed  Google Scholar 

  90. Li D, Guabiraba R, Besnard AG, Komai-Koma M, Jabir MS, Zhang L, et al. IL-33 promotes ST2-dependent lung fibrosis by the induction of alternatively activated macrophages and innate lymphoid cells in mice. J Allergy Clin Immunol. 2014;134(6):1422–32. e11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Su S, Zhao Q, He C, Huang D, Liu J, Chen F, et al. miR-142-5p and miR-130a-3p are regulated by IL-4 and IL-13 and control profibrogenic macrophage program. Nat Commun. 2015;6:8523.

    Article  CAS  PubMed  Google Scholar 

  92. Murthy S, Ryan A, He C, Mallampalli RK, Carter AB. Rac1-mediated mitochondrial H2O2 generation regulates MMP-9 gene expression in macrophages via inhibition of SP-1 and AP-1. J Biol Chem. 2010;285(32):25062–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Gharib SA, Johnston LK, Huizar I, Birkland TP, Hanson J, Wang Y, et al. MMP28 promotes macrophage polarization toward M2 cells and augments pulmonary fibrosis. J Leukoc Biol. 2014;95(1):9–18.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Tao B, Jin W, Xu J, Liang Z, Yao J, Zhang Y, et al. Myeloid-specific disruption of tyrosine phosphatase Shp2 promotes alternative activation of macrophages and predisposes mice to pulmonary fibrosis. J Immunol. 2014;193(6):2801–11.

    Article  CAS  PubMed  Google Scholar 

  95. Ballinger MN, Newstead MW, Zeng X, Bhan U, Mo XM, Kunkel SL, et al. IRAK-M promotes alternative macrophage activation and fibroproliferation in bleomycin-induced lung injury. J Immunol. 2015;194(4):1894–904.

    Article  CAS  PubMed  Google Scholar 

  96. Trujillo G, O’Connor EC, Kunkel SL, Hogaboam CM. A novel mechanism for CCR4 in the regulation of macrophage activation in bleomycin-induced pulmonary fibrosis. Am J Pathol. 2008;172(5):1209–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Murthy S, Larson-Casey JL, Ryan AJ, He C, Kobzik L, Carter AB. Alternative activation of macrophages and pulmonary fibrosis are modulated by scavenger receptor, macrophage receptor with collagenous structure. FASEB J. 2015;29(8):3527–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Vermeulen Z, Hervent AS, Dugaucquier L, Vandekerckhove L, Rombouts M, Beyens M, et al. Inhibitory actions of the NRG-1/ErbB4 pathway in macrophages during tissue fibrosis in the heart, skin, and lung. Am J Physiol Heart Circ Physiol. 2017;313(5):H934–H45.

    Article  PubMed  CAS  Google Scholar 

  99. Sennello JA, Misharin AV, Flozak AS, Berdnikovs S, Cheresh P, Varga J, et al. Lrp5/beta-catenin signaling controls lung macrophage differentiation and inhibits resolution of fibrosis. Am J Respir Cell Mol Biol. 2017;56(2):191–201.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Wynes MW, Riches DW. Induction of macrophage insulin-like growth factor-I expression by the Th2 cytokines IL-4 and IL-13. J Immunol. 2003;171(7):3550–9.

    Article  CAS  PubMed  Google Scholar 

  101. McKee CM, Penno MB, Cowman M, Burdick MD, Strieter RM, Bao C, et al. Hyaluronan (HA) fragments induce chemokine gene expression in alveolar macrophages. The role of HA size and CD44. J Clin Invest. 1996;98(10):2403–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Antoniades HN, Bravo MA, Avila RE, Galanopoulos T, Neville-Golden J, Maxwell M, et al. Platelet-derived growth factor in idiopathic pulmonary fibrosis. J Clin Invest. 1990;86(4):1055–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Nagaoka I, Trapnell BC, Crystal RG. Upregulation of platelet-derived growth factor-A and -B gene expression in alveolar macrophages of individuals with idiopathic pulmonary fibrosis. J Clin Invest. 1990;85(6):2023–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Antoniades HN, Neville-Golden J, Galanopoulos T, Kradin RL, Valente AJ, Graves DT. Expression of monocyte chemoattractant protein 1 mRNA in human idiopathic pulmonary fibrosis. Proc Natl Acad Sci U S A. 1992;89(12):5371–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Rennard SI, Hunninghake GW, Bitterman PB, Crystal RG. Production of fibronectin by the human alveolar macrophage: mechanism for the recruitment of fibroblasts to sites of tissue injury in interstitial lung diseases. Proc Natl Acad Sci U S A. 1981;78(11):7147–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Xia H, Bodempudi V, Benyumov A, Hergert P, Tank D, Herrera J, et al. Identification of a cell-of-origin for fibroblasts comprising the fibrotic reticulum in idiopathic pulmonary fibrosis. Am J Pathol. 2014;184(5):1369–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Sun H, Zhu Y, Pan H, Chen X, Balestrini JL, Lam TT, et al. Netrin-1 regulates fibrocyte accumulation in the decellularized fibrotic sclerodermatous lung microenvironment and in bleomycin-induced pulmonary fibrosis. Arthritis Rheumatol. 2016;68(5):1251–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Munger JS, Huang X, Kawakatsu H, Griffiths MJ, Dalton SL, Wu J, et al. The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell. 1999;96(3):319–28.

    Article  CAS  PubMed  Google Scholar 

  110. Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev. 2000;14(2):163–76.

    PubMed  PubMed Central  Google Scholar 

  111. Massague J. TGFbeta signalling in context. Nat Rev Mol Cell Biol. 2012;13(10):616–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Kottmann RM, Kulkarni AA, Smolnycki KA, Lyda E, Dahanayake T, Salibi R, et al. Lactic acid is elevated in idiopathic pulmonary fibrosis and induces myofibroblast differentiation via pH-dependent activation of transforming growth factor-beta. Am J Respir Crit Care Med. 2012;186(8):740–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Hoyles RK, Derrett-Smith EC, Khan K, Shiwen X, Howat SL, Wells AU, et al. An essential role for resident fibroblasts in experimental lung fibrosis is defined by lineage-specific deletion of high-affinity type II transforming growth factor beta receptor. Am J Respir Crit Care Med. 2011;183(2):249–61.

    Article  CAS  PubMed  Google Scholar 

  114. Cogan JG, Subramanian SV, Polikandriotis JA, Kelm RJ Jr, Strauch AR. Vascular smooth muscle alpha-actin gene transcription during myofibroblast differentiation requires Sp1/3 protein binding proximal to the MCAT enhancer. J Biol Chem. 2002;277(39):36433–42.

    Article  CAS  PubMed  Google Scholar 

  115. Hu B, Wu Z, Phan SH. Smad3 mediates transforming growth factor-beta-induced alpha-smooth muscle actin expression. Am J Respir Cell Mol Biol. 2003;29(3 Pt 1):397–404.

    Article  CAS  PubMed  Google Scholar 

  116. Gu L, Zhu YJ, Yang X, Guo ZJ, Xu WB, Tian XL. Effect of TGF-beta/Smad signaling pathway on lung myofibroblast differentiation. Acta Pharmacol Sin. 2007;28(3):382–91.

    Article  CAS  PubMed  Google Scholar 

  117. Kang JH, Jung MY, Yin X, Andrianifahanana M, Hernandez DM, Leof EB. Cell-penetrating peptides selectively targeting SMAD3 inhibit profibrotic TGF-beta signaling. J Clin Invest. 2017;127(7):2541–54.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Liu G, Friggeri A, Yang Y, Milosevic J, Ding Q, Thannickal VJ, et al. miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis. J Exp Med. 2010;207(8):1589–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Cui H, Banerjee S, Xie N, Ge J, Liu RM, Matalon S, et al. MicroRNA-27a-3p is a negative regulator of lung fibrosis by targeting myofibroblast differentiation. Am J Respir Cell Mol Biol. 2016;54(6):843–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Huang C, Xiao X, Yang Y, Mishra A, Liang Y, Zeng X, et al. MicroRNA-101 attenuates pulmonary fibrosis by inhibiting fibroblast proliferation and activation. J Biol Chem. 2017;292(40):16420–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Huang X, Gai Y, Yang N, Lu B, Samuel CS, Thannickal VJ, et al. Relaxin regulates myofibroblast contractility and protects against lung fibrosis. Am J Pathol. 2011;179(6):2751–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Heeg MH, Koziolek MJ, Vasko R, Schaefer L, Sharma K, Muller GA, et al. The antifibrotic effects of relaxin in human renal fibroblasts are mediated in part by inhibition of the Smad2 pathway. Kidney Int. 2005;68(1):96–109.

    Article  CAS  PubMed  Google Scholar 

  123. Tan J, Tedrow JR, Dutta JA, Juan-Guardela B, Nouraie M, Chu Y, et al. Expression of RXFP1 is decreased in idiopathic pulmonary fibrosis. Implications for relaxin-based therapies. Am J Respir Crit Care Med. 2016;194(11):1392–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Lagares D, Kapoor M. Targeting focal adhesion kinase in fibrotic diseases. BioDrugs. 2013;27(1):15–23.

    Article  CAS  PubMed  Google Scholar 

  125. Thannickal VJ, Lee DY, White ES, Cui Z, Larios JM, Chacon R, et al. Myofibroblast differentiation by transforming growth factor-beta1 is dependent on cell adhesion and integrin signaling via focal adhesion kinase. J Biol Chem. 2003;278(14):12384–9.

    Article  CAS  PubMed  Google Scholar 

  126. Thomas PE, Peters-Golden M, White ES, Thannickal VJ, Moore BB. 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.

    Article  CAS  PubMed  Google Scholar 

  127. Lagares D, Busnadiego O, Garcia-Fernandez RA, Kapoor M, Liu S, Carter DE, et al. Inhibition of focal adhesion kinase prevents experimental lung fibrosis and myofibroblast formation. Arthritis Rheum. 2012;64(5):1653–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Conte E, Fruciano M, Fagone E, Gili E, Caraci F, Iemmolo M, et al. Inhibition of PI3K prevents the proliferation and differentiation of human lung fibroblasts into myofibroblasts: the role of class I P110 isoforms. PLoS One. 2011;6(10):e24663.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Kulkarni AA, Thatcher TH, Olsen KC, Maggirwar SB, Phipps RP, Sime PJ. PPAR-gamma ligands repress TGFbeta-induced myofibroblast differentiation by targeting the PI3K/Akt pathway: implications for therapy of fibrosis. PLoS One. 2011;6(1):e15909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Ding Q, Cai GQ, Hu M, Yang Y, Zheng A, Tang Q, et al. FAK-related nonkinase is a multifunctional negative regulator of pulmonary fibrosis. Am J Pathol. 2013;182(5):1572–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Liu X, Kelm RJ Jr, Strauch AR. Transforming growth factor beta1-mediated activation of the smooth muscle alpha-actin gene in human pulmonary myofibroblasts is inhibited by tumor necrosis factor-alpha via mitogen-activated protein kinase kinase 1-dependent induction of the Egr-1 transcriptional repressor. Mol Biol Cell. 2009;20(8):2174–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Wang XM, Zhang Y, Kim HP, Zhou Z, Feghali-Bostwick CA, Liu F, et al. Caveolin-1: a critical regulator of lung fibrosis in idiopathic pulmonary fibrosis. J Exp Med. 2006;203(13):2895–906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Hecker L, Vittal R, Jones T, Jagirdar R, Luckhardt TR, Horowitz JC, et al. NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury. Nat Med. 2009;15(9):1077–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Sandbo N, Ngam C, Torr E, Kregel S, Kach J, Dulin N. Control of myofibroblast differentiation by microtubule dynamics through a regulated localization of mDia2. J Biol Chem. 2013;288(22):15466–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Hoffmann-Vold AM, Tennoe AH, Garen T, Midtvedt O, Abraityte A, Aalokken TM, et al. High level of chemokine CCL18 is associated with pulmonary function deterioration, lung fibrosis progression, and reduced survival in systemic sclerosis. Chest. 2016;150(2):299–306.

    Article  PubMed  Google Scholar 

  136. Sandbo N, Kregel S, Taurin S, Bhorade S, Dulin NO. Critical role of serum response factor in pulmonary myofibroblast differentiation induced by TGF-beta. Am J Respir Cell Mol Biol. 2009;41(3):332–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Lagares D, Ghassemi-Kakroodi P, Tremblay C, Santos A, Probst CK, Franklin A, et al. ADAM10-mediated ephrin-B2 shedding promotes myofibroblast activation and organ fibrosis. Nat Med. 2017;23(12):1405–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Sava P, Ramanathan A, Dobronyi A, Peng X, Sun H, Ledesma-Mendoza A, et al. Human pericytes adopt myofibroblast properties in the microenvironment of the IPF lung. JCI Insight. 2017;2(24):96352.

    Article  PubMed  Google Scholar 

  139. Shi-Wen X, Chen Y, Denton CP, Eastwood M, Renzoni EA, Bou-Gharios G, et al. Endothelin-1 promotes myofibroblast induction through the ETA receptor via a rac/phosphoinositide 3-kinase/Akt-dependent pathway and is essential for the enhanced contractile phenotype of fibrotic fibroblasts. Mol Biol Cell. 2004;15(6):2707–19.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Kulasekaran P, Scavone CA, Rogers DS, Arenberg DA, Thannickal VJ, Horowitz JC. Endothelin-1 and transforming growth factor-beta1 independently induce fibroblast resistance to apoptosis via AKT activation. Am J Respir Cell Mol Biol. 2009;41(4):484–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Horowitz JC, Ajayi IO, Kulasekaran P, Rogers DS, White JB, Townsend SK, et al. Survivin expression induced by endothelin-1 promotes myofibroblast resistance to apoptosis. Int J Biochem Cell Biol. 2012;44(1):158–69.

    Article  CAS  PubMed  Google Scholar 

  142. Hashimoto S, Gon Y, Takeshita I, Matsumoto K, Maruoka S, Horie T. Transforming growth Factor-beta1 induces phenotypic modulation of human lung fibroblasts to myofibroblast through a c-Jun-NH2-terminal kinase-dependent pathway. Am J Respir Crit Care Med. 2001;163(1):152–7.

    Article  CAS  PubMed  Google Scholar 

  143. Finlay GA, Thannickal VJ, Fanburg BL, Paulson KE. Transforming growth factor-beta 1-induced activation of the ERK pathway/activator protein-1 in human lung fibroblasts requires the autocrine induction of basic fibroblast growth factor. J Biol Chem. 2000;275(36):27650–6.

    CAS  PubMed  Google Scholar 

  144. Booth AJ, Hadley R, Cornett AM, Dreffs AA, Matthes SA, Tsui JL, et al. Acellular normal and fibrotic human lung matrices as a culture system for in vitro investigation. Am J Respir Crit Care Med. 2012;186(9):866–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Jenkins RG, Simpson JK, Saini G, Bentley JH, Russell AM, Braybrooke R, et al. Longitudinal change in collagen degradation biomarkers in idiopathic pulmonary fibrosis: an analysis from the prospective, multicentre PROFILE study. Lancet Respir Med. 2015;3(6):462–72.

    Article  CAS  PubMed  Google Scholar 

  146. Rahaman SO, Grove LM, Paruchuri S, Southern BD, Abraham S, Niese KA, et al. TRPV4 mediates myofibroblast differentiation and pulmonary fibrosis in mice. J Clin Invest. 2014;124(12):5225–38.

    Article  PubMed  PubMed Central  Google Scholar 

  147. Schwartze JT, Becker S, Sakkas E, Wujak LA, Niess G, Usemann J, et al. Glucocorticoids recruit Tgfbr3 and Smad1 to shift transforming growth factor-beta signaling from the Tgfbr1/Smad2/3 axis to the Acvrl1/Smad1 axis in lung fibroblasts. J Biol Chem. 2014;289(6):3262–75.

    Article  CAS  PubMed  Google Scholar 

  148. Idiopathic Pulmonary Fibrosis Clinical Research N, Raghu G, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012;366(21):1968–77.

    Article  Google Scholar 

  149. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Jiang D, Liang J, Noble PW. Hyaluronan as an immune regulator in human diseases. Physiol Rev. 2011;91(1):221–64.

    Article  CAS  PubMed  Google Scholar 

  151. Jiang D, Liang J, Fan J, Yu S, Chen S, Luo Y, et al. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat Med. 2005;11(11):1173–9.

    Article  CAS  PubMed  Google Scholar 

  152. Liu F, Lagares D, Choi KM, Stopfer L, Marinkovic A, Vrbanac V, et al. Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis. Am J Physiol Lung Cell Mol Physiol. 2015;308(4):L344–57.

    Article  CAS  PubMed  Google Scholar 

  153. Mitani A, Nagase T, Fukuchi K, Aburatani H, Makita R, Kurihara H. Transcriptional coactivator with PDZ-binding motif is essential for normal alveolarization in mice. Am J Respir Crit Care Med. 2009;180(4):326–38.

    Article  CAS  PubMed  Google Scholar 

  154. Knipe RS, Tager AM, Liao JK. The Rho kinases: critical mediators of multiple profibrotic processes and rational targets for new therapies for pulmonary fibrosis. Pharmacol Rev. 2015;67(1):103–17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. Zhou Y, Huang X, Hecker L, Kurundkar D, Kurundkar A, Liu H, et al. Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrosis. J Clin Invest. 2013;123(3):1096–108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Kimani PW, Holmes AJ, Grossmann RE, McGowan SE. PDGF-R alpha gene expression predicts proliferation, but PDGF-A suppresses transdifferentiation of neonatal mouse lung myofibroblasts. Respir Res. 2009;10:119.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Rice AB, Ingram JL, Bonner JC. p38 mitogen-activated protein kinase regulates growth factor-induced mitogenesis of rat pulmonary myofibroblasts. Am J Respir Cell Mol Biol. 2002;27(6):759–65.

    Article  CAS  PubMed  Google Scholar 

  158. Wang YZ, Zhang P, Rice AB, Bonner JC. Regulation of interleukin-1beta -induced platelet-derived growth factor receptor-alpha expression in rat pulmonary myofibroblasts by p38 mitogen-activated protein kinase. J Biol Chem. 2000;275(29):22550–7.

    Article  CAS  PubMed  Google Scholar 

  159. Rice AB, Moomaw CR, Morgan DL, Bonner JC. Specific inhibitors of platelet-derived growth factor or epidermal growth factor receptor tyrosine kinase reduce pulmonary fibrosis in rats. Am J Pathol. 1999;155(1):213–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Lindroos PM, Rice AB, Wang YZ, Bonner JC. Role of nuclear factor-kappa B and mitogen-activated protein kinase signaling pathways in IL-1 beta-mediated induction of alpha-PDGF receptor expression in rat pulmonary myofibroblasts. J Immunol. 1998;161(7):3464–8.

    PubMed  Google Scholar 

  161. Bonner JC, Lindroos PM, Rice AB, Moomaw CR, Morgan DL. Induction of PDGF receptor-alpha in rat myofibroblasts during pulmonary fibrogenesis in vivo. Am J Phys. 1998;274(1 Pt 1):L72–80.

    CAS  Google Scholar 

  162. Noskovicova N, Petrek M, Eickelberg O, Heinzelmann K. Platelet-derived growth factor signaling in the lung. From lung development and disease to clinical studies. Am J Respir Cell Mol Biol. 2015;52(3):263–84.

    Article  CAS  PubMed  Google Scholar 

  163. Hung CF, Rohani MG, Lee SS, Chen P, Schnapp LM. Role of IGF-1 pathway in lung fibroblast activation. Respir Res. 2013;14:102.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  164. Guzy RD, Stoilov I, Elton TJ, Mecham RP, Ornitz DM. Fibroblast growth factor 2 is required for epithelial recovery, but not for pulmonary fibrosis, in response to bleomycin. Am J Respir Cell Mol Biol. 2015;52(1):116–28.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Khalil N, Xu YD, O’Connor R, Duronio V. Proliferation of pulmonary interstitial fibroblasts is mediated by transforming growth factor-beta1-induced release of extracellular fibroblast growth factor-2 and phosphorylation of p38 MAPK and JNK. J Biol Chem. 2005;280(52):43000–9.

    Article  CAS  PubMed  Google Scholar 

  166. Marchand-Adam S, Plantier L, Bernuau D, Legrand A, Cohen M, Marchal J, et al. Keratinocyte growth factor expression by fibroblasts in pulmonary fibrosis: poor response to interleukin-1beta. Am J Respir Cell Mol Biol. 2005;32(5):470–7.

    Article  CAS  PubMed  Google Scholar 

  167. 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):438–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Hashimoto N, Jin H, Liu T, Chensue SW, Phan SH. Bone marrow-derived progenitor cells in pulmonary fibrosis. J Clin Invest. 2004;113(2):243–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Cool CD, Groshong SD, Rai PR, Henson PM, Stewart JS, Brown KK. Fibroblast foci are not discrete sites of lung injury or repair: the fibroblast reticulum. Am J Respir Crit Care Med. 2006;174(6):654–8.

    Article  PubMed  PubMed Central  Google Scholar 

  170. Thannickal VJ, Horowitz JC. Evolving concepts of apoptosis in idiopathic pulmonary fibrosis. Proc Am Thorac Soc. 2006;3(4):350–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Lawson WE, Crossno PF, Polosukhin VV, Roldan J, Cheng DS, Lane KB, et al. Endoplasmic reticulum stress in alveolar epithelial cells is prominent in IPF: association with altered surfactant protein processing and herpesvirus infection. Am J Physiol Lung Cell Mol Physiol. 2008;294(6):L1119–26.

    Article  CAS  PubMed  Google Scholar 

  172. Bridges RS, Kass D, Loh K, Glackin C, Borczuk AC, Greenberg S. Gene expression profiling of pulmonary fibrosis identifies Twist1 as an antiapoptotic molecular ‘rectifier’ of growth factor signaling. Am J Pathol. 2009;175(6):2351–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Ajayi IO, Sisson TH, Higgins PD, Booth AJ, Sagana RL, Huang SK, et al. X-linked inhibitor of apoptosis regulates lung fibroblast resistance to Fas-mediated apoptosis. Am J Respir Cell Mol Biol. 2013;49(1):86–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Gao Z, Sasaoka T, Fujimori T, Oya T, Ishii Y, Sabit H, et al. Deletion of the PDGFR-beta gene affects key fibroblast functions important for wound healing. J Biol Chem. 2005;280(10):9375–89.

    Article  CAS  PubMed  Google Scholar 

  175. Xia H, Khalil W, Kahm J, Jessurun J, Kleidon J, Henke CA. Pathologic caveolin-1 regulation of PTEN in idiopathic pulmonary fibrosis. Am J Pathol. 176(6):2626–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Xia H, Diebold D, Nho R, Perlman D, Kleidon J, Kahm J, et al. Pathological integrin signaling enhances proliferation of primary lung fibroblasts from patients with idiopathic pulmonary fibrosis. J Exp Med. 2008;205(7):1659–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Le Cras TD, Korfhagen TR, Davidson C, Schmidt S, Fenchel M, Ikegami M, et al. Inhibition of PI3K by PX-866 prevents transforming growth factor-alpha-induced pulmonary fibrosis. Am J Pathol. 2010;176(2):679–86.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  178. Nagahama KY, Togo S, Holz O, Magnussen H, Liu X, Seyama K, et al. Oncostatin M modulates fibroblast function via signal transducers and activators of transcription proteins-3. Am J Respir Cell Mol Biol. 2013;49(4):582–91.

    Article  CAS  PubMed  Google Scholar 

  179. Moodley YP, Scaffidi AK, Misso NL, Keerthisingam C, McAnulty RJ, Laurent GJ, et al. Fibroblasts isolated from normal lungs and those with idiopathic pulmonary fibrosis differ in interleukin-6/gp130-mediated cell signaling and proliferation. Am J Pathol. 2003;163(1):345–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Moodley YP, Misso NL, Scaffidi AK, Fogel-Petrovic M, McAnulty RJ, Laurent GJ, et al. Inverse effects of interleukin-6 on apoptosis of fibroblasts from pulmonary fibrosis and normal lungs. Am J Respir Cell Mol Biol. 2003;29(4):490–8.

    Article  CAS  PubMed  Google Scholar 

  181. Pechkovsky DV, Prele CM, Wong J, Hogaboam CM, McAnulty RJ, Laurent GJ, et al. STAT3-mediated signaling dysregulates lung fibroblast-myofibroblast activation and differentiation in UIP/IPF. Am J Pathol. 2012;180(4):1398–412.

    Article  CAS  PubMed  Google Scholar 

  182. Selman M, King TE, Pardo A, American Thoracic S, European Respiratory S, American College of Chest P. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med. 2001;134(2):136–51.

    Article  CAS  PubMed  Google Scholar 

  183. Reilkoff RA, Peng H, Murray LA, Peng X, Russell T, Montgomery R, et al. Semaphorin 7a+ regulatory T cells are associated with progressive idiopathic pulmonary fibrosis and are implicated in transforming growth factor-beta1-induced pulmonary fibrosis. Am J Respir Crit Care Med. 2013;187(2):180–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Xue J, Kass DJ, Bon J, Vuga L, Tan J, Csizmadia E, et al. Plasma B lymphocyte stimulator and B cell differentiation in idiopathic pulmonary fibrosis patients. J Immunol. 2013;191(5):2089–95.

    Article  CAS  PubMed  Google Scholar 

  185. Prasse A, Probst C, Bargagli E, Zissel G, Toews GB, Flaherty KR, et al. Serum CC-chemokine ligand 18 concentration predicts outcome in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2009;179(8):717–23.

    Article  CAS  PubMed  Google Scholar 

  186. Luzina IG, Kopach P, Lockatell V, Kang PH, Nagarsekar A, Burke AP, et al. Interleukin-33 potentiates bleomycin-induced lung injury. Am J Respir Cell Mol Biol. 2013;49(6):999–1008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Donahoe M, Valentine VG, Chien N, Gibson KF, Raval JS, Saul M, et al. Autoantibody-targeted treatments for acute exacerbations of idiopathic pulmonary fibrosis. PLoS One. 2015;10(6):e0127771.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  188. Herazo-Maya JD, Noth I, Duncan SR, Kim S, Ma SF, Tseng GC, et al. Peripheral blood mononuclear cell gene expression profiles predict poor outcome in idiopathic pulmonary fibrosis. Sci Transl Med. 2013;5(205):205ra136.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  189. Song JS, Kang CM, Kang HH, Yoon HK, Kim YK, Kim KH, et al. Inhibitory effect of CXC chemokine receptor 4 antagonist AMD3100 on bleomycin induced murine pulmonary fibrosis. Exp Mol Med. 2010;42(6):465–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Frid MG, Li M, Gnanasekharan M, Burke DL, Fragoso M, Strassheim D, et al. Sustained hypoxia leads to the emergence of cells with enhanced growth, migratory, and promitogenic potentials within the distal pulmonary artery wall. Am J Physiol Lung Cell Mol Physiol. 2009;297(6):L1059–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Li M, Riddle SR, Frid MG, El Kasmi KC, McKinsey TA, Sokol RJ, et al. Emergence of fibroblasts with a proinflammatory epigenetically altered phenotype in severe hypoxic pulmonary hypertension. J Immunol. 2011;187(5):2711–22.

    Article  CAS  PubMed  Google Scholar 

  192. Tan J, Tedrow JR, Nouraie M, Dutta JA, Miller DT, Li X, et al. Loss of Twist1 in the mesenchymal compartment promotes increased fibrosis in experimental lung injury by enhanced expression of CXCL12. J Immunol. 2017;198(6):2269–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Bleul CC, Fuhlbrigge RC, Casasnovas JM, Aiuti A, Springer TA. A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). J Exp Med. 1996;184(3):1101–9.

    Article  CAS  PubMed  Google Scholar 

  194. Balabanian K, Lagane B, Infantino S, Chow KY, Harriague J, Moepps B, et al. The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. J Biol Chem. 2005;280(42):35760–6.

    Article  CAS  PubMed  Google Scholar 

  195. Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, 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.

    Article  CAS  PubMed  Google Scholar 

  196. Xu J, Mora A, Shim H, Stecenko A, Brigham KL, Rojas M. Role of the SDF-1/CXCR4 axis in the pathogenesis of lung injury and fibrosis. Am J Respir Cell Mol Biol. 2007;37(3):291–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Madge LA, May MJ. Classical NF-kappaB activation negatively regulates noncanonical NF-kappaB-dependent CXCL12 expression. J Biol Chem. 2010;285(49):38069–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Sun X, Chen E, Dong R, Chen W, Hu Y. Nuclear factor (NF)-kappaB p65 regulates differentiation of human and mouse lung fibroblasts mediated by TGF-beta. Life Sci. 2015;122:8–14.

    Article  CAS  PubMed  Google Scholar 

  199. Lin CH, Shih CH, Tseng CC, Yu CC, Tsai YJ, Bien MY, et al. CXCL12 induces connective tissue growth factor expression in human lung fibroblasts through the Rac1/ERK, JNK, and AP-1 pathways. PLoS One. 2014;9(8):e104746.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  200. Pierer M, Rethage J, Seibl R, Lauener R, Brentano F, Wagner U, et al. Chemokine secretion of rheumatoid arthritis synovial fibroblasts stimulated by Toll-like receptor 2 ligands. J Immunol. 2004;172(2):1256–65.

    Article  CAS  PubMed  Google Scholar 

  201. Rudisch A, Dewhurst MR, Horga LG, Kramer N, Harrer N, Dong M, et al. High EMT signature score of invasive non-small cell lung cancer (NSCLC) cells correlates with NFkappaB driven colony-stimulating factor 2 (CSF2/GM-CSF) secretion by neighboring stromal fibroblasts. PLoS One. 2015;10(4):e0124283.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  202. Taniguchi T, Asano Y, Nakamura K, Yamashita T, Saigusa R, Ichimura Y, et al. Fli1 deficiency induces CXCL6 expression in dermal fibroblasts and endothelial cells, contributing to the development of fibrosis and vasculopathy in systemic sclerosis. J Rheumatol. 2017;44(8):1198–205.

    Article  PubMed  Google Scholar 

  203. Seher A, Nickel J, Mueller TD, Kneitz S, Gebhardt S, ter Vehn TM, et al. Gene expression profiling of connective tissue growth factor (CTGF) stimulated primary human tenon fibroblasts reveals an inflammatory and wound healing response in vitro. Mol Vis. 2011;17:53–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Vistejnova L, Safrankova B, Nesporova K, Slavkovsky R, Hermannova M, Hosek P, et al. Low molecular weight hyaluronan mediated CD44 dependent induction of IL-6 and chemokines in human dermal fibroblasts potentiates innate immune response. Cytokine. 2014;70(2):97–103.

    Article  CAS  PubMed  Google Scholar 

  205. Acosta JC, O’Loghlen A, Banito A, Guijarro MV, Augert A, Raguz S, et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell. 2008;133(6):1006–18.

    Article  CAS  PubMed  Google Scholar 

  206. Yanaba K, Komura K, Kodera M, Matsushita T, Hasegawa M, Takehara K, et al. Serum levels of monocyte chemotactic protein-3/CCL7 are raised in patients with systemic sclerosis: association with extent of skin sclerosis and severity of pulmonary fibrosis. Ann Rheum Dis. 2006;65(1):124–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Choi ES, Jakubzick C, Carpenter KJ, Kunkel SL, Evanoff H, Martinez FJ, et al. Enhanced monocyte chemoattractant protein-3/CC chemokine ligand-7 in usual interstitial pneumonia. Am J Respir Crit Care Med. 2004;170(5):508–15.

    Article  PubMed  Google Scholar 

  208. Ong VH, Evans LA, Shiwen X, Fisher IB, Rajkumar V, Abraham DJ, et al. Monocyte chemoattractant protein 3 as a mediator of fibrosis: overexpression in systemic sclerosis and the type 1 tight-skin mouse. Arthritis Rheum. 2003;48(7):1979–91.

    Article  CAS  PubMed  Google Scholar 

  209. Jung DW, Che ZM, Kim J, Kim K, Kim KY, Williams D, et al. Tumor-stromal crosstalk in invasion of oral squamous cell carcinoma: a pivotal role of CCL7. Int J Cancer. 2010;127(2):332–44.

    CAS  PubMed  Google Scholar 

  210. Virakul S, Phetsuksiri T, van Holten-Neelen C, Schrijver B, van Steensel L, Dalm VA, et al. Histamine induces NF-kappaB controlled cytokine secretion by orbital fibroblasts via histamine receptor type-1. Exp Eye Res. 2016;147:85–93.

    Article  CAS  PubMed  Google Scholar 

  211. Moore BB, Murray L, Das A, Wilke CA, Herrygers AB, Toews GB. The role of CCL12 in the recruitment of fibrocytes and lung fibrosis. Am J Respir Cell Mol Biol. 2006;35(2):175–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Ong VH, Carulli MT, Xu S, Khan K, Lindahl G, Abraham DJ, et al. Cross-talk between MCP-3 and TGFbeta promotes fibroblast collagen biosynthesis. Exp Cell Res. 2009;315(2):151–61.

    Article  CAS  PubMed  Google Scholar 

  213. Chilosi M, Poletti V, Zamo A, Lestani M, Montagna L, Piccoli P, et al. Aberrant Wnt/beta-catenin pathway activation in idiopathic pulmonary fibrosis. Am J Pathol. 2003;162(5):1495–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Konigshoff M, Eickelberg O. WNT signaling in lung disease: a failure or a regeneration signal? Am J Respir Cell Mol Biol. 2010;42(1):21–31.

    Article  PubMed  CAS  Google Scholar 

  215. Vuga LJ, Ben-Yehudah A, Kovkarova-Naumovski E, Oriss T, Gibson KF, Feghali-Bostwick C, et al. WNT5A is a regulator of fibroblast proliferation and resistance to apoptosis. Am J Respir Cell Mol Biol. 2009;41(5):583–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Lam AP, Flozak AS, Russell S, Wei J, Jain M, Mutlu GM, et al. Nuclear beta-catenin is increased in systemic sclerosis pulmonary fibrosis and promotes lung fibroblast migration and proliferation. Am J Respir Cell Mol Biol. 2011;45(5):915–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Sun Z, Gong X, Zhu H, Wang C, Xu X, Cui D, et al. Inhibition of Wnt/beta-catenin signaling promotes engraftment of mesenchymal stem cells to repair lung injury. J Cell Physiol. 2014;229(2):213–24.

    Article  CAS  PubMed  Google Scholar 

  218. Hung C, Linn G, Chow YH, Kobayashi A, Mittelsteadt K, Altemeier WA, et al. Role of lung pericytes and resident fibroblasts in the pathogenesis of pulmonary fibrosis. Am J Respir Crit Care Med. 2013;188(7):820–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Xia H, Seeman J, Hong J, Hergert P, Bodem V, Jessurun J, et al. Low alpha(2)beta(1) integrin function enhances the proliferation of fibroblasts from patients with idiopathic pulmonary fibrosis by activation of the beta-catenin pathway. Am J Pathol. 2012;181(1):222–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Baarsma HA, Engelbertink LH, van Hees LJ, Menzen MH, Meurs H, Timens W, et al. Glycogen synthase kinase-3 (GSK-3) regulates TGF-beta(1)-induced differentiation of pulmonary fibroblasts. Br J Pharmacol. 2013;169(3):590–603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Cao Z, Lis R, Ginsberg M, Chavez D, Shido K, Rabbany SY, et al. Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis. Nat Med. 2016;22(2):154–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Suzuki T, Tada Y, Gladson S, Nishimura R, Shimomura I, Karasawa S, et al. Vildagliptin ameliorates pulmonary fibrosis in lipopolysaccharide-induced lung injury by inhibiting endothelial-to-mesenchymal transition. Respir Res. 2017;18(1):177.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  223. Yin Q, Wang W, Cui G, Yan L, Zhang S. Potential role of the Jagged1/Notch1 signaling pathway in the endothelial-myofibroblast transition during BLM-induced pulmonary fibrosis. J Cell Physiol. 2018;233(3):2451–63.

    Article  CAS  PubMed  Google Scholar 

  224. Singh KK, Lovren F, Pan Y, Quan A, Ramadan A, Matkar PN, et al. The essential autophagy gene ATG7 modulates organ fibrosis via regulation of endothelial-to-mesenchymal transition. J Biol Chem. 2015;290(5):2547–59.

    Article  CAS  PubMed  Google Scholar 

  225. Xie T, Liang J, Liu N, Huan C, Zhang Y, Liu W, et al. Transcription factor TBX4 regulates myofibroblast accumulation and lung fibrosis. J Clin Invest. 2016;126(8):3063–79.

    Article  PubMed  PubMed Central  Google Scholar 

  226. Meinecke AK, Nagy N, Lago GD, Kirmse S, Klose R, Schrodter K, et al. Aberrant mural cell recruitment to lymphatic vessels and impaired lymphatic drainage in a murine model of pulmonary fibrosis. Blood. 2012;119(24):5931–42.

    Article  CAS  PubMed  Google Scholar 

  227. Selman M, Pardo A, King TE Jr. Hypersensitivity pneumonitis: insights in diagnosis and pathobiology. Am J Respir Crit Care Med. 2012;186(4):314–24.

    Article  CAS  PubMed  Google Scholar 

  228. Kass DJ, Kaminski N. Time to share: lessons from post hoc analyses of IPF trials. Thorax. 2017;72(2):101–2.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease and the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Justin A. Dutta, Harinath Bahudhanapati, Jiangning Tan, Alon Goldblum & Daniel J. Kass

Authors
  1. Justin A. Dutta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Harinath Bahudhanapati
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiangning Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alon Goldblum
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daniel J. Kass
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniel J. Kass .

Editor information

Editors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Krannert Institute of Cardiology, Indiana University School of Medicine, Indiana Center for Musculoskeletal Health, Indianapolis, IN, USA

    Monte S. Willis

  2. Department of Health Promotion and Development, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Nursing, Pittsburgh, PA, USA

    Cecelia C. Yates

  3. Department of Pharmacology and Department of Pathology and Lab Medicine, McAllister Heart Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Jonathan C. Schisler

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Dutta, J.A., Bahudhanapati, H., Tan, J., Goldblum, A., Kass, D.J. (2019). Fibrotic Signaling in the Lung. In: Willis, M., Yates, C., Schisler, J. (eds) Fibrosis in Disease . Molecular and Translational Medicine. Humana Press, Cham. https://doi.org/10.1007/978-3-319-98143-7_4

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-98143-7_4

  • Published:

  • Publisher Name: Humana Press, Cham

  • Print ISBN: 978-3-319-98142-0

  • Online ISBN: 978-3-319-98143-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation