Skip to main content
SpringerLink
Log in

Latest progress on the molecular mechanisms of idiopathic pulmonary fibrosis

  • Review
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Idiopathic pulmonary fibrosis (IPF) is a serious life-threatening lung disease, and the median survival period of PF patients after diagnosis is only 2.5–3.5 years. At present, there are no effective drugs or therapeutics to reverse or even inhibit IPF. The main pathological characteristics of pulmonary fibrosis (PF) include damage to alveolar epithelial cells, fibroblast activation and extracellular matrix accumulation, which gradually lead to damage to the lung structure and decreased lung function. It is important to understand the cellular and molecular mechanisms of PF comprehensively and clearly. In this paper, critical signaling pathways related to PF were reviewed to present updates on the molecular mechanisms of PF.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Cottin V, Hirani NA, Hotchkin DL, Nambiar AM, Ogura T, Otaola M, Skowasch D, Park JS, Poonyagariyagorn HK, Wuyts W, Wells AU (2018) Presentation, diagnosis and clinical course of the spectrum of progressive-fibrosing interstitial lung diseases. Eur Respir Rev. https://doi.org/10.1183/16000617.0076-2018

    Article  PubMed  Google Scholar 

  2. Karkkainen M, Nurmi H, Kettunen HP, Selander T, Purokivi M, Kaarteenaho R (2018) Underlying and immediate causes of death in patients with idiopathic pulmonary fibrosis. BMC Pulm Med 18:69. https://doi.org/10.1186/s12890-018-0642-4

    Article  PubMed  PubMed Central  Google Scholar 

  3. Kropski JA, Blackwell TS (2019) Progress in understanding and treating idiopathic pulmonary fibrosis. Annu Rev Med 70:211–224. https://doi.org/10.1146/annurev-med-041317-102715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Heukels P, Moor CC, von der Thusen JH, Wijsenbeek MS, Kool M (2019) Inflammation and immunity in IPF pathogenesis and treatment. Respir Med 147:79–91. https://doi.org/10.1016/j.rmed.2018.12.015

    Article  CAS  PubMed  Google Scholar 

  5. Morikawa M, Derynck R, Miyazono K (2016) TGF-beta and the TGF-beta family: context-dependent roles in cell and tissue physiology. Cold Spring Harb Perspect Biol. https://doi.org/10.1101/cshperspect.a021873

    Article  PubMed  PubMed Central  Google Scholar 

  6. Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield LM, Heine UI, Liotta LA, Falanga V, Kehrl JH, Et A (1986) Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci U S A 83:4167–4171. https://doi.org/10.1073/pnas.83.12.4167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kolahian S, Fernandez IE, Eickelberg O, Hartl D (2016) Immune mechanisms in pulmonary fibrosis. Am J Respir Cell Mol Biol 55:309–322. https://doi.org/10.1165/rcmb.2016-0121TR

    Article  CAS  PubMed  Google Scholar 

  8. Massague J (1996) TGFbeta signaling: receptors, transducers, and Mad proteins. Cell 85:947–950. https://doi.org/10.1016/s0092-8674(00)81296-9

    Article  CAS  PubMed  Google Scholar 

  9. Blobe GC, Schiemann WP, Lodish HF (2000) Role of transforming growth factor beta in human disease. N Engl J Med 342:1350–1358. https://doi.org/10.1056/NEJM200005043421807

    Article  CAS  PubMed  Google Scholar 

  10. Shou J, Cao J, Zhang S, Sun R, Zhao M, Chen K, Su SB, Yang J, Yang T (2018) SIS3, a specific inhibitor of smad3, attenuates bleomycin-induced pulmonary fibrosis in mice. Biochem Biophys Res Commun 503:757–762. https://doi.org/10.1016/j.bbrc.2018.06.072

    Article  CAS  PubMed  Google Scholar 

  11. Ryan RM, Mineo-Kuhn MM, Kramer CM, Finkelstein JN (1994) Growth factors alter neonatal type II alveolar epithelial cell proliferation. Am J Physiol 266:L17–L22. https://doi.org/10.1152/ajplung.1994.266.1.L17

    Article  CAS  PubMed  Google Scholar 

  12. Mishra R, Cool BL, Laderoute KR, Foretz M, Viollet B, Simonson MS (2008) AMP-activated protein kinase inhibits transforming growth factor-beta-induced Smad3-dependent transcription and myofibroblast transdifferentiation. J Biol Chem 283:10461–10469. https://doi.org/10.1074/jbc.M800902200

    Article  CAS  PubMed  Google Scholar 

  13. Rangarajan S, Bone NB, Zmijewska AA, Jiang S, Park DW, Bernard K, Locy ML, Ravi S, Deshane J, Mannon RB, Abraham E, Darley-Usmar V, Thannickal VJ, Zmijewski JW (2018) Metformin reverses established lung fibrosis in a bleomycin model. Nat Med 24:1121–1127. https://doi.org/10.1038/s41591-018-0087-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mackinnon AC, Gibbons MA, Farnworth SL, Leffler H, Nilsson UJ, Delaine T, Simpson AJ, Forbes SJ, Hirani N, Gauldie J, Sethi T (2012) Regulation of transforming growth factor-beta1-driven lung fibrosis by galectin-3. Am J Respir Crit Care Med 185:537–546. https://doi.org/10.1164/rccm.201106-0965OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hsu YA, Chang CY, Lan JL, Li JP, Lin HJ, Chen CS, Wan L, Liu FT (2020) Amelioration of bleomycin-induced pulmonary fibrosis via TGF-beta-induced Smad and non-Smad signaling pathways in galectin-9-deficient mice and fibroblast cells. J Biomed Sci 27:24. https://doi.org/10.1186/s12929-020-0616-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bennett D, Bargagli E, Bianchi N, Landi C, Fossi A, Fui A, Sestini P, Refini RM, Rottoli P (2020) Elevated level of Galectin-1 in bronchoalveolar lavage of patients with idiopathic pulmonary fibrosis. Respir Physiol Neurobiol 273:103323. https://doi.org/10.1016/j.resp.2019.103323

    Article  CAS  PubMed  Google Scholar 

  17. Liu YL, Chen BY, Nie J, Zhao GH, Zhuo JY, Yuan J, Li YC, Wang LL, Chen ZW (2020) Polydatin prevents bleomycin-induced pulmonary fibrosis by inhibiting the TGF-beta/Smad/ERK signaling pathway. Exp Ther Med 20:62. https://doi.org/10.3892/etm.2020.9190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kwon OS, Kim KT, Lee E, Kim M, Choi SH, Li H, Fornace AJ, Cho JH, Lee YS, Lee JS, Lee YJ, Cha HJ (2016) Induction of MiR-21 by stereotactic body radiotherapy contributes to the pulmonary fibrotic response. PLoS ONE 11:e154942. https://doi.org/10.1371/journal.pone.0154942

    Article  CAS  Google Scholar 

  19. Xiao X, Huang C, Zhao C, Gou X, Senavirathna LK, Hinsdale M, Lloyd P, Liu L (2015) Regulation of myofibroblast differentiation by miR-424 during epithelial-to-mesenchymal transition. Arch Biochem Biophys 566:49–57. https://doi.org/10.1016/j.abb.2014.12.007

    Article  CAS  PubMed  Google Scholar 

  20. Huang C, Xiao X, Yang Y, Mishra A, Liang Y, Zeng X, Yang X, Xu D, Blackburn MR, Henke CA, Liu L (2019) Correction: microRNA-101 attenuates pulmonary fibrosis by inhibiting fibroblast proliferation and activation. J Biol Chem 294:6694. https://doi.org/10.1074/jbc.AAC119.008714

    Article  PubMed  PubMed Central  Google Scholar 

  21. Zhang Y, Yao XH, Wu Y, Cao GK, Han D (2020) LncRNA NEAT1 regulates pulmonary fibrosis through miR-9-5p and TGF-beta signaling pathway. Eur Rev Med Pharmacol Sci 24:8483–8492. https://doi.org/10.26355/eurrev_202008_22661

    Article  CAS  PubMed  Google Scholar 

  22. Liang C, Li X, Zhang L, Cui D, Quan X, Yang W (2015) The anti-fibrotic effects of microRNA-153 by targeting TGFBR-2 in pulmonary fibrosis. Exp Mol Pathol 99:279–285. https://doi.org/10.1016/j.yexmp.2015.07.011

    Article  CAS  PubMed  Google Scholar 

  23. Zhang Q, Ye H, Xiang F, Song LJ, Zhou LL, Cai PC, Zhang JC, Yu F, Shi HZ, Su Y, Xin JB, Ma WL (2017) miR-18a-5p inhibits sub-pleural pulmonary fibrosis by targeting TGF-beta receptor II. Mol Ther 25:728–738. https://doi.org/10.1016/j.ymthe.2016.12.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Das S, Kumar M, Negi V, Pattnaik B, Prakash YS, Agrawal A, Ghosh B (2014) MicroRNA-326 regulates profibrotic functions of transforming growth factor-beta in pulmonary fibrosis. Am J Respir Cell Mol Biol 50:882–892. https://doi.org/10.1165/rcmb.2013-0195OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Graham JR, Williams CM, Yang Z (2014) MicroRNA-27b targets gremlin 1 to modulate fibrotic responses in pulmonary cells. J Cell Biochem 115:1539–1548. https://doi.org/10.1002/jcb.24809

    Article  CAS  PubMed  Google Scholar 

  26. Zhang A, Wang H, Wang B, Yuan Y, Klein JD, Wang XH (2019) Exogenous miR-26a suppresses muscle wasting and renal fibrosis in obstructive kidney disease. FASEB J 33:13590–13601. https://doi.org/10.1096/fj.201900884R

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Jin SX, Wu QY, Yan WW, Ni CH (2017) Therapeutic effect of miR-489 in a mouse model of silica-induced matured pulmonary fibrosis. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi 35:337–341. https://doi.org/10.3760/cma.j.issn.1001-9391.2017.05.004

    Article  CAS  PubMed  Google Scholar 

  28. Lawrence J, Nho R (2018) The role of the mammalian target of rapamycin (mTOR) in pulmonary fibrosis. Int J Mol Sci. https://doi.org/10.3390/ijms19030778

    Article  PubMed  PubMed Central  Google Scholar 

  29. Patel AS, Lin L, Geyer A, Haspel JA, An CH, Cao J, Rosas IO, Morse D (2012) Autophagy in idiopathic pulmonary fibrosis. PLoS ONE 7:e41394. https://doi.org/10.1371/journal.pone.0041394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mi S, Li Z, Yang HZ, Liu H, Wang JP, Ma YG, Wang XX, Liu HZ, Sun W, Hu ZW (2011) Blocking IL-17A promotes the resolution of pulmonary inflammation and fibrosis via TGF-beta1-dependent and -independent mechanisms. J Immunol 187:3003–3014. https://doi.org/10.4049/jimmunol.1004081

    Article  CAS  PubMed  Google Scholar 

  31. Xie T, Xu Q, Wan H, Xing S, Shang C, Gao Y, He Z (2019) Lipopolysaccharide promotes lung fibroblast proliferation through autophagy inhibition via activation of the PI3K-Akt-mTOR pathway. Lab Investig 99:625–633. https://doi.org/10.1038/s41374-018-0160-2

    Article  CAS  PubMed  Google Scholar 

  32. Lu Y, Azad N, Wang L, Iyer AK, Castranova V, Jiang BH, Rojanasakul Y (2010) Phosphatidylinositol-3-kinase/akt regulates bleomycin-induced fibroblast proliferation and collagen production. Am J Respir Cell Mol Biol 42:432–441. https://doi.org/10.1165/rcmb.2009-0002OC

    Article  CAS  PubMed  Google Scholar 

  33. Gui YS, Wang L, Tian X, Li X, Ma A, Zhou W, Zeng N, Zhang J, Cai B, Zhang H, Chen JY, Xu KF (2015) mTOR overactivation and compromised autophagy in the pathogenesis of pulmonary fibrosis. PLoS ONE 10:e138625. https://doi.org/10.1371/journal.pone.0138625

    Article  CAS  Google Scholar 

  34. Gui X, Chen H, Cai H, Sun L, Gu L (2018) Leptin promotes pulmonary fibrosis development by inhibiting autophagy via PI3K/Akt/mTOR pathway. Biochem Biophys Res Commun 498:660–666. https://doi.org/10.1016/j.bbrc.2018.03.039

    Article  CAS  PubMed  Google Scholar 

  35. Saxton RA, Sabatini DM (2017) mTOR signaling in growth, metabolism, and disease. Cell 168:960–976. https://doi.org/10.1016/j.cell.2017.02.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Huang J, Manning BD (2008) The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J 412:179–190. https://doi.org/10.1042/BJ20080281

    Article  CAS  PubMed  Google Scholar 

  37. Zinzalla V, Stracka D, Oppliger W, Hall MN (2011) Activation of mTORC2 by association with the ribosome. Cell 144:757–768. https://doi.org/10.1016/j.cell.2011.02.014

    Article  CAS  PubMed  Google Scholar 

  38. Huang J, Manning BD (2009) A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans 37:217–222. https://doi.org/10.1042/BST0370217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Yin W, Han J, Zhang Z, Han Z, Wang S (2018) Aloperine protects mice against bleomycin-induced pulmonary fibrosis by attenuating fibroblast proliferation and differentiation. Sci Rep 8:6265. https://doi.org/10.1038/s41598-018-24565-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Stracke ML, Krutzsch HC, Unsworth EJ, Arestad A, Cioce V, Schiffmann E, Liotta LA (1992) Identification, purification, and partial sequence analysis of autotaxin, a novel motility-stimulating protein. J Biol Chem 267:2524–2529

    CAS  PubMed  Google Scholar 

  41. Ninou I, Magkrioti C, Aidinis V (2018) Autotaxin in pathophysiology and pulmonary fibrosis. Front Med (Lausanne) 5:180. https://doi.org/10.3389/fmed.2018.00180

    Article  Google Scholar 

  42. Barbayianni E, Kaffe E, Aidinis V, Kokotos G (2015) Autotaxin, a secreted lysophospholipase D, as a promising therapeutic target in chronic inflammation and cancer. Prog Lipid Res 58:76–96. https://doi.org/10.1016/j.plipres.2015.02.001

    Article  CAS  PubMed  Google Scholar 

  43. Oikonomou N, Mouratis MA, Tzouvelekis A, Kaffe E, Valavanis C, Vilaras G, Karameris A, Prestwich GD, Bouros D, Aidinis V (2012) Pulmonary autotaxin expression contributes to the pathogenesis of pulmonary fibrosis. Am J Respir Cell Mol Biol 47:566–574. https://doi.org/10.1165/rcmb.2012-0004OC

    Article  CAS  PubMed  Google Scholar 

  44. Pradere JP, Klein J, Gres S, Guigne C, Neau E, Valet P, Calise D, Chun J, Bascands JL, Saulnier-Blache JS, Schanstra JP (2007) LPA1 receptor activation promotes renal interstitial fibrosis. J Am Soc Nephrol 18:3110–3118. https://doi.org/10.1681/ASN.2007020196

    Article  CAS  PubMed  Google Scholar 

  45. Kaffe E, Katsifa A, Xylourgidis N, Ninou I, Zannikou M, Harokopos V, Foka P, Dimitriadis A, Evangelou K, Moulas AN, Georgopoulou U, Gorgoulis VG, Dalekos GN, Aidinis V (2017) Hepatocyte autotaxin expression promotes liver fibrosis and cancer. Hepatology 65:1369–1383. https://doi.org/10.1002/hep.28973

    Article  CAS  PubMed  Google Scholar 

  46. Benesch MG, Ko YM, McMullen TP, Brindley DN (2014) Autotaxin in the crosshairs: taking aim at cancer and other inflammatory conditions. FEBS Lett 588:2712–2727. https://doi.org/10.1016/j.febslet.2014.02.009

    Article  CAS  PubMed  Google Scholar 

  47. Badri L, Lama VN (2012) Lysophosphatidic acid induces migration of human lung-resident mesenchymal stem cells through the beta-catenin pathway. Stem Cells 30:2010–2019. https://doi.org/10.1002/stem.1171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Cao P, Aoki Y, Badri L, Walker NM, Manning CM, Lagstein A, Fearon ER, Lama VN (2017) Autocrine lysophosphatidic acid signaling activates beta-catenin and promotes lung allograft fibrosis. J Clin Investig 127:1517–1530. https://doi.org/10.1172/JCI88896

    Article  PubMed  PubMed Central  Google Scholar 

  49. Huang LS, Fu P, Patel P, Harijith A, Sun T, Zhao Y, Garcia JG, Chun J, Natarajan V (2013) Lysophosphatidic acid receptor-2 deficiency confers protection against bleomycin-induced lung injury and fibrosis in mice. Am J Respir Cell Mol Biol 49:912–922. https://doi.org/10.1165/rcmb.2013-0070OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Gierse J, Thorarensen A, Beltey K, Bradshaw-Pierce E, Cortes-Burgos L, Hall T, Johnston A, Murphy M, Nemirovskiy O, Ogawa S, Pegg L, Pelc M, Prinsen M, Schnute M, Wendling J, Wene S, Weinberg R, Wittwer A, Zweifel B, Masferrer J (2010) A novel autotaxin inhibitor reduces lysophosphatidic acid levels in plasma and the site of inflammation. J Pharmacol Exp Ther 334:310–317. https://doi.org/10.1124/jpet.110.165845

    Article  CAS  PubMed  Google Scholar 

  51. Cortinovis M, Aiello S, Mister M, Conde-Knape K, Noris M, Novelli R, Solini S, Rodriguez OP, Benigni A, Remuzzi G (2020) Autotaxin inhibitor protects from chronic allograft injury in rat kidney allotransplantation. Nephron 144:38–48. https://doi.org/10.1159/000502908

    Article  CAS  PubMed  Google Scholar 

  52. Nikolaou A, Ninou I, Kokotou MG, Kaffe E, Afantitis A, Aidinis V, Kokotos G (2018) Hydroxamic acids constitute a novel class of autotaxin inhibitors that exhibit in vivo efficacy in a pulmonary fibrosis model. J Med Chem 61:3697–3711. https://doi.org/10.1021/acs.jmedchem.8b00232

    Article  CAS  PubMed  Google Scholar 

  53. Desroy N, Housseman C, Bock X, Joncour A, Bienvenu N, Cherel L, Labeguere V, Rondet E, Peixoto C, Grassot JM, Picolet O, Annoot D, Triballeau N, Monjardet A, Wakselman E, Roncoroni V, Le Tallec S, Blanque R, Cottereaux C, Vandervoort N, Christophe T, Mollat P, Lamers M, Auberval M, Hrvacic B, Ralic J, Oste L, van der Aar E, Brys R, Heckmann B (2017) Discovery of 2-[[2-ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methyli midazo[1,2-a]pyridin-3-yl]methylamino]-4-(4-fluorophenyl)thiazole-5-carbonitrile (GLPG1690), a first-in-class autotaxin inhibitor undergoing clinical evaluation for the treatment of idiopathic pulmonary fibrosis. J Med Chem 60:3580–3590. https://doi.org/10.1021/acs.jmedchem.7b00032

    Article  CAS  PubMed  Google Scholar 

  54. van der Aar E, Desrivot J, Dupont S, Heckmann B, Fieuw A, Stutvoet S, Fagard L, Van de Wal K, Helmer E (2019) Safety, pharmacokinetics, and pharmacodynamics of the autotaxin inhibitor GLPG1690 in healthy subjects: Phase 1 randomized trials. J Clin Pharmacol 59:1366–1378. https://doi.org/10.1002/jcph.1424

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Konigshoff M, Balsara N, Pfaff EM, Kramer M, Chrobak I, Seeger W, Eickelberg O (2008) Functional Wnt signaling is increased in idiopathic pulmonary fibrosis. PLoS ONE 3:e2142. https://doi.org/10.1371/journal.pone.0002142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Skronska-Wasek W, Gosens R, Konigshoff M, Baarsma HA (2018) WNT receptor signalling in lung physiology and pathology. Pharmacol Ther 187:150–166. https://doi.org/10.1016/j.pharmthera.2018.02.009

    Article  CAS  PubMed  Google Scholar 

  57. Vuga LJ, Ben-Yehudah A, Kovkarova-Naumovski E, Oriss T, Gibson KF, Feghali-Bostwick C, Kaminski N (2009) WNT5A is a regulator of fibroblast proliferation and resistance to apoptosis. Am J Respir Cell Mol Biol 41:583–589. https://doi.org/10.1165/rcmb.2008-0201OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Cao H, Wang C, Chen X, Hou J, Xiang Z, Shen Y, Han X (2018) Inhibition of Wnt/beta-catenin signaling suppresses myofibroblast differentiation of lung resident mesenchymal stem cells and pulmonary fibrosis. Sci Rep 8:13644. https://doi.org/10.1038/s41598-018-28968-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Xu L, Cui WH, Zhou WC, Li DL, Li LC, Zhao P, Mo XT, Zhang Z, Gao J (2017) Activation of Wnt/beta-catenin signalling is required for TGF-beta/Smad2/3 signalling during myofibroblast proliferation. J Cell Mol Med 21:1545–1554. https://doi.org/10.1111/jcmm.13085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Sennello JA, Misharin AV, Flozak AS, Berdnikovs S, Cheresh P, Varga J, Kamp DW, Budinger GR, Gottardi CJ, Lam AP (2017) Lrp5/beta-catenin signaling controls lung macrophage differentiation and inhibits resolution of fibrosis. Am J Respir Cell Mol Biol 56:191–201. https://doi.org/10.1165/rcmb.2016-0147OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Acebron SP, Karaulanov E, Berger BS, Huang YL, Niehrs C (2014) Mitotic wnt signaling promotes protein stabilization and regulates cell size. Mol Cell 54:663–674. https://doi.org/10.1016/j.molcel.2014.04.014

    Article  CAS  PubMed  Google Scholar 

  62. Chen X, Shi C, Cao H, Chen L, Hou J, Xiang Z, Hu K, Han X (2018) The hedgehog and Wnt/beta-catenin system machinery mediate myofibroblast differentiation of LR-MSCs in pulmonary fibrogenesis. Cell Death Dis 9:639. https://doi.org/10.1038/s41419-018-0692-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Aumiller V, Balsara N, Wilhelm J, Gunther A, Konigshoff M (2013) WNT/beta-catenin signaling induces IL-1beta expression by alveolar epithelial cells in pulmonary fibrosis. Am J Respir Cell Mol Biol 49:96–104. https://doi.org/10.1165/rcmb.2012-0524OC

    Article  CAS  PubMed  Google Scholar 

  64. Tanjore H, Degryse AL, Crossno PF, Xu XC, McConaha ME, Jones BR, Polosukhin VV, Bryant AJ, Cheng DS, Newcomb DC, McMahon FB, Gleaves LA, Blackwell TS, Lawson WE (2013) Beta-catenin in the alveolar epithelium protects from lung fibrosis after intratracheal bleomycin. Am J Respir Crit Care Med 187:630–639. https://doi.org/10.1164/rccm.201205-0972OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Konigshoff M, Kramer M, Balsara N, Wilhelm J, Amarie OV, Jahn A, Rose F, Fink L, Seeger W, Schaefer L, Gunther A, Eickelberg O (2009) WNT1-inducible signaling protein-1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis. J Clin Investig 119:772–787. https://doi.org/10.1172/JCI33950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Henderson WJ, Chi EY, Ye X, Nguyen C, Tien YT, Zhou B, Borok Z, Knight DA, Kahn M (2010) Inhibition of Wnt/beta-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis. Proc Natl Acad Sci U S A 107:14309–14314. https://doi.org/10.1073/pnas.1001520107

    Article  PubMed  PubMed Central  Google Scholar 

  67. Boyapally R, Pulivendala G, Bale S, Godugu C (2019) Niclosamide alleviates pulmonary fibrosis in vitro and in vivo by attenuation of epithelial-to-mesenchymal transition, matrix proteins and Wnt/beta-catenin signaling: a drug repurposing study. Life Sci 220:8–20. https://doi.org/10.1016/j.lfs.2018.12.061

    Article  CAS  PubMed  Google Scholar 

  68. Hosseinzadeh A, Javad-Moosavi SA, Reiter RJ, Hemati K, Ghaznavi H, Mehrzadi S (2018) Idiopathic pulmonary fibrosis (IPF) signaling pathways and protective roles of melatonin. Life Sci 201:17–29. https://doi.org/10.1016/j.lfs.2018.03.032

    Article  CAS  PubMed  Google Scholar 

  69. Kiyokawa H, Morimoto M (2020) Notch signaling in the mammalian respiratory system, specifically the trachea and lungs, in development, homeostasis, regeneration, and disease. Dev Growth Differ 62:67–79. https://doi.org/10.1111/dgd.12628

    Article  PubMed  Google Scholar 

  70. Vaughan AE, Brumwell AN, Xi Y, Gotts JE, Brownfield DG, Treutlein B, Tan K, Tan V, Liu FC, Looney MR, Matthay MA, Rock JR, Chapman HA (2015) Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury. Nature 517:621–625. https://doi.org/10.1038/nature14112

    Article  CAS  PubMed  Google Scholar 

  71. Li X, Zhang X, Leathers R, Makino A, Huang C, Parsa P, Macias J, Yuan JX, Jamieson SW, Thistlethwaite PA (2009) Notch3 signaling promotes the development of pulmonary arterial hypertension. Nat Med 15:1289–1297. https://doi.org/10.1038/nm.2021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Xing Y, Li A, Borok Z, Li C, Minoo P (2012) NOTCH1 is required for regeneration of Clara cells during repair of airway injury. Stem Cells 30:946–955. https://doi.org/10.1002/stem.1059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Ono Y, Sensui H, Okutsu S, Nagatomi R (2007) Notch2 negatively regulates myofibroblastic differentiation of myoblasts. J Cell Physiol 210:358–369. https://doi.org/10.1002/jcp.20838

    Article  CAS  PubMed  Google Scholar 

  74. Xu K, Nieuwenhuis E, Cohen BL, Wang W, Canty AJ, Danska JS, Coultas L, Rossant J, Wu MY, Piscione TD, Nagy A, Gossler A, Hicks GG, Hui CC, Henkelman RM, Yu LX, Sled JG, Gridley T, Egan SE (2010) Lunatic Fringe-mediated Notch signaling is required for lung alveogenesis. Am J Physiol Lung Cell Mol Physiol 298:L45–L56. https://doi.org/10.1152/ajplung.90550.2008

    Article  CAS  PubMed  Google Scholar 

  75. Aoyagi-Ikeda K, Maeno T, Matsui H, Ueno M, Hara K, Aoki Y, Aoki F, Shimizu T, Doi H, Kawai-Kowase K, Iso T, Suga T, Arai M, Kurabayashi M (2011) Notch induces myofibroblast differentiation of alveolar epithelial cells via transforming growth factor-{beta}-Smad3 pathway. Am J Respir Cell Mol Biol 45:136–144. https://doi.org/10.1165/rcmb.2010-0140oc

    Article  CAS  PubMed  Google Scholar 

  76. Eliasz S, Liang S, Chen Y, De Marco MA, Machek O, Skucha S, Miele L, Bocchetta M (2010) Notch-1 stimulates survival of lung adenocarcinoma cells during hypoxia by activating the IGF-1R pathway. Oncogene 29:2488–2498. https://doi.org/10.1038/onc.2010.7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Cao Z, Lis R, Ginsberg M, Chavez D, Shido K, Rabbany SY, Fong GH, Sakmar TP, Rafii S, Ding BS (2016) Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis. Nat Med 22:154–162. https://doi.org/10.1038/nm.4035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Chu H, Shi Y, Jiang S, Zhong Q, Zhao Y, Liu Q, Ma Y, Shi X, Ding W, Zhou X, Cui J, Jin L, Guo G, Wang J (2017) Treatment effects of the traditional Chinese medicine Shenks in bleomycin-induced lung fibrosis through regulation of TGF-beta/Smad3 signaling and oxidative stress. Sci Rep 7:2252. https://doi.org/10.1038/s41598-017-02293-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Grosche J, Meissner J, Eble JA (2018) More than a syllable in fib-ROS-is: the role of ROS on the fibrotic extracellular matrix and on cellular contacts. Mol Asp Med 63:30–46. https://doi.org/10.1016/j.mam.2018.03.005

    Article  CAS  Google Scholar 

  80. Bernard K, Logsdon NJ, Miguel V, Benavides GA, Zhang J, Carter AB, Darley-Usmar VM, Thannickal VJ (2017) NADPH oxidase 4 (Nox4) suppresses mitochondrial biogenesis and bioenergetics in lung fibroblasts via a nuclear factor erythroid-derived 2-like 2 (Nrf2)-dependent pathway. J Biol Chem 292:3029–3038. https://doi.org/10.1074/jbc.M116.752261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Anathy V, Lahue KG, Chapman DG, Chia SB, Casey DT, Aboushousha R, van der Velden J, Elko E, Hoffman SM, McMillan DH, Jones JT, Nolin JD, Abdalla S, Schneider R, Seward DJ, Roberson EC, Liptak MD, Cousins ME, Butnor KJ, Taatjes DJ, Budd RC, Irvin CG, Ho YS, Hakem R, Brown KK, Matsui R, Bachschmid MM, Gomez JL, Kaminski N, van der Vliet A, Janssen-Heininger Y (2018) Reducing protein oxidation reverses lung fibrosis. Nat Med 24:1128–1135. https://doi.org/10.1038/s41591-018-0090-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Kang YP, Lee SB, Lee JM, Kim HM, Hong JY, Lee WJ, Choi CW, Shin HK, Kim DJ, Koh ES, Park CS, Kwon SW, Park SW (2016) Metabolic profiling regarding pathogenesis of idiopathic pulmonary fibrosis. J Proteome Res 15:1717–1724. https://doi.org/10.1021/acs.jproteome.6b00156

    Article  CAS  PubMed  Google Scholar 

  83. Li L, Cai L, Zheng L, Hu Y, Yuan W, Guo Z, Li W (2018) Gefitinib inhibits bleomycin-induced pulmonary fibrosis via alleviating the oxidative damage in mice. Oxid Med Cell Longev 2018:8249693. https://doi.org/10.1155/2018/8249693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Kim SJ, Cheresh P, Jablonski RP, Morales-Nebreda L, Cheng Y, Hogan E, Yeldandi A, Chi M, Piseaux R, Ridge K, Michael HC, Chandel N, Scott BG, Kamp DW (2016) Mitochondrial catalase overexpressed transgenic mice are protected against lung fibrosis in part via preventing alveolar epithelial cell mitochondrial DNA damage. Free Radic Biol Med 101:482–490. https://doi.org/10.1016/j.freeradbiomed.2016.11.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Reddy NM, Kleeberger SR, Cho HY, Yamamoto M, Kensler TW, Biswal S, Reddy SP (2007) Deficiency in Nrf2-GSH signaling impairs type II cell growth and enhances sensitivity to oxidants. Am J Respir Cell Mol Biol 37:3–8. https://doi.org/10.1165/rcmb.2007-0004RC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Jablonski RP, Kim SJ, Cheresh P, Williams DB, Morales-Nebreda L, Cheng Y, Yeldandi A, Bhorade S, Pardo A, Selman M, Ridge K, Gius D, Budinger G, Kamp DW (2017) SIRT3 deficiency promotes lung fibrosis by augmenting alveolar epithelial cell mitochondrial DNA damage and apoptosis. FASEB J 31:2520–2532. https://doi.org/10.1096/fj.201601077R

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Sundaresan NR, Bindu S, Pillai VB, Samant S, Pan Y, Huang JY, Gupta M, Nagalingam RS, Wolfgeher D, Verdin E, Gupta MP (2015) SIRT3 blocks aging-associated tissue fibrosis in mice by deacetylating and activating glycogen synthase kinase 3beta. Mol Cell Biol 36:678–692. https://doi.org/10.1128/MCB.00586-15

    Article  CAS  PubMed  Google Scholar 

  88. Larson-Casey JL, He C, Carter AB (2020) Mitochondrial quality control in pulmonary fibrosis. Redox Biol 33:101426. https://doi.org/10.1016/j.redox.2020.101426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Hecker L, Vittal R, Jones T, Jagirdar R, Luckhardt TR, Horowitz JC, Pennathur S, Martinez FJ, Thannickal VJ (2009) NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury. Nat Med 15:1077–1081. https://doi.org/10.1038/nm.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Jarman ER, Khambata VS, Cope C, Jones P, Roger J, Ye LY, Duggan N, Head D, Pearce A, Press NJ, Bellenie B, Sohal B, Jarai G (2014) An inhibitor of NADPH oxidase-4 attenuates established pulmonary fibrosis in a rodent disease model. Am J Respir Cell Mol Biol 50:158–169. https://doi.org/10.1165/rcmb.2013-0174OC

    Article  CAS  PubMed  Google Scholar 

  91. Sato N, Takasaka N, Yoshida M, Tsubouchi K, Minagawa S, Araya J, Saito N, Fujita Y, Kurita Y, Kobayashi K, Ito S, Hara H, Kadota T, Yanagisawa H, Hashimoto M, Utsumi H, Wakui H, Kojima J, Numata T, Kaneko Y, Odaka M, Morikawa T, Nakayama K, Kohrogi H, Kuwano K (2016) Metformin attenuates lung fibrosis development via NOX4 suppression. Respir Res 17:107. https://doi.org/10.1186/s12931-016-0420-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Augsburger F, Filippova A, Rasti D, Seredenina T, Lam M, Maghzal G, Mahiout Z, Jansen-Durr P, Knaus UG, Doroshow J, Stocker R, Krause KH, Jaquet V (2019) Pharmacological characterization of the seven human NOX isoforms and their inhibitors. Redox Biol 26:101272. https://doi.org/10.1016/j.redox.2019.101272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was supported by the National Natural Science Foundation of China (31900817), the One Hundred Person Project of Hebei Province (E2018050011), Hebei Scientific Research Foundation for Returned Scholars (C201814), and Key Projects of Hebei Normal University (L2018Z07).

Author information

Author notes

  1. Yue Fang and Jingya Tian have contributed to this work equally and ranked alphabetically.

Authors and Affiliations

  1. Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, 20 East Road of 2nd South Ring, Yuhua District, Shijiazhuang, 050024, China

    Yue Fang, Jingya Tian, Yumei Fan & Pengxiu Cao

  2. Key Laboratory of Brain Functional Genomics of Ministry of Education, School of Life Sciences, East China Normal University, Shanghai, 200062, China

    Yue Fang

  3. College of Chemistry and Environmental Sciences, Hebei University, Baoding, China

    Jingya Tian

Authors
  1. Yue Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jingya Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yumei Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pengxiu Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YF and JT wrote the manuscript. YF and PC modified the manuscript and provided funding.

Corresponding authors

Correspondence to Yumei Fan or Pengxiu Cao.

Ethics declarations

Conflict of interest

The authors have no conflicts of interest to declare.

Ethical approval

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fang, Y., Tian, J., Fan, Y. et al. Latest progress on the molecular mechanisms of idiopathic pulmonary fibrosis. Mol Biol Rep 47, 9811–9820 (2020). https://doi.org/10.1007/s11033-020-06000-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-020-06000-6

Keywords

Search

Navigation