Pulmonary fibrosis is a diverse group of lung disorders defined by varying degrees of fibrosis and inflammation in the pulmonary parenchyma. While it may be caused by a known disease, e.g., autoimmune or connective tissue disorder, drugs, hypersensitivity to inhaled organic antigens, or sarcoidosis, it also occurs to be idiopathic. When we examine the pathogenesis of lung fibrosis, we see that cellular aging plays a major role. Lung fibroblasts play an active role in the regeneration process. However, despite all the information, the pathogenesis of lung fibrosis is not clearly understood. It is not yet clear how senescent cells in the lung mingle and cause fibrosis. The pathogenesis of lung fibrosis will be understood more clearly following future studies.

1. Raghu G, Remy-Jardin M, Myers JL, et al. Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline. American Journal of Respiratory and Critical Care Medicine 2018; 198(5): e44–e68. doi: 10.1164/rccm.201807-1255ST.

2. Rabeyrin M, Thivolet F, Ferretti GR, et al. Usual interstitial pneumonia end-stage features from explants with radiologic and pathological correlations. Annals of Diagnostic Pathology 2015; 19(4): 269–276. doi: 10.1016/j.anndiagpath.2015.05.003.

3. Selman M, Pardo A. Revealing the pathogenic and aging-related mechanisms of the enigmatic idiopathic pulmonary fibrosis. An integral model. American Journal of Respiratory and Critical Care Medicine 2014; 189(10): 1161–1172. doi: 10.1164/rccm.201312-2221PP.

4. McHugh D, Gil J. Senescence and aging: Causes, consequences, and therapeutic avenues. Journal Cell of Biology 2017; 217(1): 65–77. doi: 10.1083/jcb.201708092.

5. Loaiza N, Demaria M. Cellular senescence and tumor promotion: Is aging the key? Biochimica et Biophysica Acta (BBA)—Reviews on Cancer 2016; 1865(2): 155–167. doi: 10.1016/j.bbcan.2016.01.007.

6. Sun N, Youle RJ, Finkel T. The mitochondrial basis of aging. Molecular Cell 2016; 61(5): 654–666. doi: 10.1016/j.molcel.2016.01.028.

7. Kuilman T, Michaloglou C, Mooi WJ, Peeper DS. The essence of senescence. Genes & Development 2010; 24(22): 2463–2479. doi: 10.1101/gad.1971610.

8. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Experimental Cell Research 1961; 25: 585–621. doi: 10.1016/0014-4827(61)90192-6.

9. Robles SJ, Adami GR. Agents that cause DNA double strand breaks lead to p16INK4a enrichment and the premature senescence of normal fibroblasts. Oncogene 1998; 16: 1113–1123. doi: 10.1038/sj.onc.1201862.

10. Martínez-Zamudio RI, Robinson L, Roux PF, Bischof O. SnapShot: Cellular senescence pathways. Cell 2017; 170: 816–816.e1. doi: 10.1016/j.cell.2017.07.049.

11. Muñoz-Espín D, Serrano M. Cellular senescence: From physiology to pathology. Nature Reviews Molecular Cell Biology 2014; 15(7): 482–496. doi: 10.1038/nrm3823.

12. Salama R, Sadaie M, Hoare M, Narita M. Cellular senescence and its effector programs. Genes & Development 2014; 28(2): 99–114. doi: 10.1101/gad.235184.113.

13. Salminen A, Kauppinen A, Kaarniranta K. Emerging role of NF-κB signaling in the induction of senescence-associated secretory phenotype (SASP). Cellular Signalling 2012; 24(4): 835–845. doi: 10.1016/j.cellsig.2011.12.006.

14. Liu T, De Los Santos FG, Zhao Y, et al. Telomerase reverse transcriptase ameliorates lung fibrosis by protecting alveolar epithelial cells against senescence. Journal of Biology Chemistry 2019; 294(22): 8861–8871. doi: 10.1074/jbc.RA118.006615.

15. Yao C, Guan X, Carraro G, et al. Senescence of alveolar type 2 cells drives progressive pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine 2021; 203(6): 707–717. doi: 10.1164/rccm.202004-1274OC.

16. Jiang C, Liu G, Luckhardt T, et al. Serpine 1 induces alveolar type II cell senescence through activating p53-p21-Rb pathway in fibrotic lung disease. Aging Cell 2017; 16(5): 1114–1124. doi: 10.1111/acel.12643.

17. Zhang Y, Huang W, Zheng Z, et al. Cigarette smoke-inactivated SIRT1 promotes autophagy-dependent senescence of alveolar epithelial type 2 cells to induce pulmonary fibrosis. Free Radical Biology and Medicine 2021; 166: 116–127. doi: 10.1016/j.freeradbiomed.2021.02.013.

18. Young AR, Narita M. Connecting autophagy to senescence in pathophysiology. Current Opinion in Cell Biology 2010; 22(2): 234–240. doi: 10.1016/j.ceb.2009.12.005.

19. Qiu T, Tian Y, Gao Y, et al. PTEN loss regulates alveolar epithelial cell senescence in pulmonary fibrosis depending on Akt activation. Aging 2019; 11(18): 7492–7509. doi: 10.18632/aging.102262.

20. Lehmann M, Hu Q, Hu Y, et al. Chronic WNT/β-catenin signaling induces cellular senescence in lung epithelial cells. Cellular Signalling 2020; 70: 109588. doi: 10.1016/j.cellsig.2020.109588.

21. Coppé JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: The dark side of tumor suppression. Annual Review of Pathology: Mechanisms of Disease 2010; 5: 99–118. doi: 10.1146/annurev-pathol-121808-102144.

22. Freund A, Orjalo AV, Desprez PY, Campisi J. Inflammatory networks during cellular senescence: Causes and consequences. Trends in Molecular Medicine 2010; 16(5): 238–246. doi: 10.1016/j.molmed.2010.03.003.

23. Lopes-Paciencia S, Saint-Germain E, Rowell MC, et al. The senescence-associated secretory phenotype and its regulation. Cytokine 2019; 117: 15–22. doi: 10.1016/j.cyto.2019.01.013.

24. Wiley CD, Brumwell AN, Davis SS, et al. Secretion of leukotrienes by senescent lung fibroblasts promotes pulmonary fibrosis. JCI Insight 2019; 4(24): e130056. doi: 10.1172/jci.insight.130056.

25. Rana T, Jiang C, Liu G, et al. PAI-1 regulation of TGF-β1-induced alveolar type II cell senescence, SASP secretion, and SASP-mediated activation of alveolar macrophages. American Journal of Respiratory Cell and Molecular Biology 2020; 62(3): 319–330. doi: 10.1165/rcmb.2019-0071OC.

26. Hu B, Ullenbruch MR, Jin H, et al. An essential role for CCAAT/enhancer binding protein β in bleomycin-induced pulmonary fibrosis. The Journal Pathology 2006; 211(4): 455–462. doi: 10.1002/path.2119.

27. Chilosi M, Carloni A, Rossi A, Poletti V. Premature lung aging and cellular senescence in the pathogenesis of idiopathic pulmonary fibrosis and COPD/emphysema. Translational Research 2013; 162(3): 156–173. doi: 10.1016/j.trsl.2013.06.004.

28. Xu Y, Mizuno T, Sridharan A, et al. Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis. JCI Insight 2016; 1(20): e90558. doi: 10.1172/jci.insight.90558.

29. Smirnova NF, Schamberger AC, Nayakanti S, et al. Detection and quantification of epithelial progenitor cell populations in human healthy and IPF lungs. Respiratory Research 2016; 17(1): 1–11. doi: 10.1186/s12931-016-0404-x.

30. Carraro G, Mulay A, Yao C, et al. Single-cell reconstruction of human basal cell diversity in normal and idiopathic pulmonary fibrosis lungs. American Journal of Respiratory and Critical Care Medicine 2020; 202(11): 1540–1550. doi: 10.1164/rccm.201904-0792OC.

31. De Pianto DJ, Heiden JAV, Morshead KB, et al. Molecular mapping of interstitial lung disease reveals a phenotypically distinct senescent basal epithelial cell population. JCI Insight 2021; 6(8): e143626. doi: 10.1172/jci.insight.143626.

32. Meyer K, Hodwin B, Ramanujam DP, et al. Essential role for premature senescence of myofibroblasts in myocardial fibrosis. Journal of the American College of Cardiology 2016; 67(17): 2018–2028. doi: 10.1016/j.jacc.2016.02.047.

33. Krizhanovsky V, Yon M, Dickins R, et al. Senescence of activated stellate cells limits liver fibrosis. Cell 2008; 134(4): 657–667. doi: 10.1016/j.cell.2008.06.049.

34. Jun JI, Lau LF. The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nature Cell Biology 2010; 12(7): 676–685. doi: 10.1038/ncb2070.

35. Kendall RT, Feghali-Bostwick CA. Fibroblasts in fibrosis: Novel roles and mediators. Frontiers in Pharmacology 2014; 5: 123. doi: 10.3389/fphar.2014.00123.

36. Schafer MJ, White TA, Iijima K, et al. Cellular senescence mediates fibrotic pulmonary disease. Nature Communications 2017; 8: 14532. doi: 10.1038/ncomms14532.

37. Hecker L, Logsdon NJ, Kurundkar D, et al. Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance. Science Translational Medicine 2014; 6(231): 231ra47. doi: 10.1126/scitranslmed.3008182.

38. Hohmann MS, Habiel DM, Coelho AL, et al. Quercetin enhances ligand-induced apoptosis in senescent idiopathic pulmonary fibrosis fibroblasts and reduces lung fibrosis in vivo. American Journal of Respiratory Cell and Molecular Biology 2019; 60(1): 28–40. doi: 10.1165/rcmb.2017-0289OC.

39. Álvarez D, Cárdenes N, Sellarés J, et al. IPF lung fibroblasts have a senescent phenotype. American Journal of Physiology–Lung Cellular and Molecular Physiology 2017; 313(6): L1164–L1173.

40. Ramos C, Montaño M, García-Alvarez J, et al. Fibroblasts from idiopathic pulmonary fibrosis and normal lungs differ in growth rate, apoptosis, and tissue inhibitor of metalloproteinases expression. American Journal of Respiratory Cell and Molecular Biology 2001; 24(1): 591–598. doi: 10.1165/ajrcmb.24.5.4333.

41. Acosta JC, Banito A, Wuestefeld T, et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nature Cell Biology 2013; 15(8): 978–990. doi: 10.1038/ncb2784.

42. Zank DC, Bueno M, Mora AL, Rojas M. Idiopathic pulmonary fibrosis: Aging, mitochondrial dysfunction, and cellular bioenergetics. Frontiers in Medicine 2018; 5: 10. doi: 10.3389/fmed.2018.00010.

43. Passos JF, Nelson G, Wang C, et al. Feedback between p21 and reactive oxygen production is necessary for cell senescence. Molecular Systems Biology 2010; 6: 347. doi: 10.1038/msb.2010.5.

44. Wiley CD, Velarde MC, Lecot P, et al. Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell Metabolism 2016; 23(2): 303–314. doi: 10.1016/j.cmet.2015.11.011.

45. Bueno M, Lai YC, Romero Y, et al. PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis. Journal of Clinical Investigation 2015; 125(2): 521–538. doi: 10.1172/JCI74942.

46. Mora AL, Bueno M, Rojas M. Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis. Journal of Clinical Investigation 2017; 127(2): 405–414. doi: 10.1172/JCI87440.

47. Xie N, Tan Z, Banerjee S, et al. Glycolytic reprogramming in myofibroblast differentiation and lung fibrosis. American Journal of Respiratory and Critical Care Medicine 2015; 192(12): 1462–1474. doi: 10.1164/rccm.201504-0780OC.

48. Caporarello N, Meridew JA, Jones DL, et al. PGC1α repression in IPF fibroblasts drives a pathologic metabolic, secretory and fibrogenic state. Thorax 2019; 74(8): 749–760. doi: 10.1136/thoraxjnl-2019-213064.

49. Kobayashi K, Araya J, Minagawa S, et al. Involvement of PARK2-mediated mitophagy in idiopathic pulmonary fibrosis pathogenesis. Journal of Immunology 2016; 197(2): 504–516. doi: 10.4049/jimmunol.1600265.

50. Sosulski ML, Gongora R, Danchuk S, et al. Deregulation of selective autophagy during aging and pulmonary fibrosis: The role of TGFβ1. Aging Cell 2015; 14(5): 774–783. doi: 10.1111/acel.12357.

51. Rajawat YS, Hilioti Z, Bossis I. Aging: Central role for autophagy and the lysosomal degradative system. Ageing Research Reviews 2009; 8(30): 199–213. doi: 10.1016/j.arr.2009.05.001.

52. Kuwano K, Araya J, Hara H, et al. Cellular senescence and autophagy in the pathogenesis of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Respiratory Investigation 2016; 54(6): 397–406. doi: 10.1016/j.resinv.2016.03.010.

53. Araya J, Kojima J, Takasaka N, et al. Insufficient autophagy in idiopathic pulmonary fibrosis. American Journal of Physiology–Lung Cellular and Molecular Physiology 2013; 304(1): L56–L69. doi: 10.1152/ajplung.00213.2012.

54. Patel AS, Lin L, Geyer A, et al. Autophagy in idiopathic pulmonary fibrosis. PLoS ONE 2012; 7(7): e41394. doi: 10.1371/journal.pone.0041394.

55. Ricci A, Cherubini E, Scozzi D, et al. Decreased expression of autophagic beclin 1 protein in idiopathic pulmonary fibrosis fibroblasts. Journal of Cellular Physiology 2013; 228(7): 1516–1524. doi: 10.1002/jcp.24307.

56. Nho RS, Hergert P. IPF fibroblasts are desensitized to type I collagen matrix-induced cell death by suppressing low autophagy via aberrant Akt/mTOR kinases. PLoS ONE 2014; 9(4): e94616. doi: 10.1371/journal.pone.0094616.

57. Cha SI, Groshong SD, Frankel SK, et al. Compartmentalized expression of c-FLIP in lung tissues of patients with idiopathic pulmonary fibrosis. American Journal of Respiratory Cell and Molecular Biology 2010; 42(2): 140–148. doi: 10.1165/rcmb.2008-0419OC.

58. Yanai H, Shteinberg A, Porat Z, et al. Cellular senescence-like features of lung fibroblasts derived from idiopathic pulmonary fibrosis patients. Aging 2015; 7(9): 664–672. doi: 10.18632/aging.100807.

59. Yosef R, Pilpel N, Tokarsky-Amiel R, et al. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nature Communications 2016; 7: 11190. doi: 10.1038/ncomms11190.

60. Milara J, Hernandez G, Ballester B, et al. The JAK2 pathway is activated in idiopathic pulmonary fibrosis. Respiratory Research 2018; 19(1): 24. doi: 10.1186/s12931-018-0728-9.

61. Xia H, Khalil W, Kahm J, et al. Pathologic caveolin-1 regulation of PTEN in idiopathic pulmonary fibrosis. The American Journal of Pathology 2010; 176(6): 2626–2637. doi: 10.2353/ajpath.2010.091117.

62. Nho RS, Peterson M, Hergert P, Henke CA. FoxO3a (forkhead box O3a) deficiency protects idiopathic pulmonary fibrosis (IPF) fibroblasts from type I polymerized collagen matrix-induced apoptosis via caveolin-1 (cav-1) and fas. PLoS ONE 2013; 8(4): e61017. doi: 10.1371/journal.pone.0061017.

63. Romero Y, Bueno M, Ramirez R, et al. MTORC1 activation decreases autophagy in aging and idiopathic pulmonary fibrosis and contributes to apoptosis resistance in IPF fibroblasts. Aging Cell 2016; 15(6): 1103–1112. doi: 10.1111/acel.12514.

64. Xia, H, Bodempudi V, Benyumov A, et al. Identification of a cell-of-origin for fibroblasts comprising the fibrotic reticulum in idiopathic pulmonary fibrosis. The American Journal of Pathology 2014; 184(5): 1369–1383. doi: 10.1016/j.ajpath.2014.01.012.

65. Habiel DM, Hohmann MS, Espindola MS, et al. DNA-PKcs modulates progenitor cell proliferation and fibroblast senescence in idiopathic pulmonary fibrosis. BMC Pulmonary Medicine 2019; 19(1): 1–16. doi: 10.1186/s12890-019-0922-7.

66. Yang L, Xia H, Smith KA, et al. A CD44/Brg1 nuclear complex confers mesenchymal progenitor cells with enhanced fibrogenicity in idiopathic pulmonary fibrosis. JCI Insight 2021; 6(9): e144652. doi: 10.1172/jci.insight.144652.

67. Kumar V, Fleming T, Terjung S, et al. Homeostatic nuclear RAGE-ATM interaction is essential for efficient DNA repair. Nucleic Acids Research 2017; 45(18): 10595–10613. doi: 10.1093/nar/gkx705.

68. Habiel DM, Camelo A, Espindola M, et al. Divergent roles for clusterin in lung injury and repair. Scientific Reports 2017; 7(1): 15444. doi: 10.1038/s41598-017-15670-5.

69. Yang L, Herrera J, Gilbertsen A, et al. IL-8 mediates idiopathic pulmonary fibrosis mesenchymal progenitor cell fibrogenicity. American Journal of Physiology–Lung Cellular and Molecular Physiology 2018; 314(1): L127–L136. doi: 10.1152/ajplung.00200.2017.

70. Hohmann MS, Habiel DM, Espindola MS, et al. Antibody-mediated depletion of CCR10 ＋ EphA3 ＋ cells ameliorates fibrosis in IPF. JCI Insight 2021; 6(11): e141061. doi: 10.1172/jci.insight.141061.

71. Vicente R, Mausset-Bonnefont AL, Jorgensen C, et al. Cellular senescence impact on immune cell fate and function. Aging Cell 2016; 15(3): 400–406. doi: 10.1111/acel.12455.

72. Murray MA, Chotirmall SH. The impact of immunosenescence on pulmonary disease. Mediators of Inflammation 2015; 2015: 692546. doi: 10.1155/2015/692546.

73. Shenderov K, Collins SL, Powell JD, Horton MR. Immune dysregulation as a driver of idiopathic pulmonary fibrosis. Journal of Clinical Investigation 2021; 131(2): e143226. doi: 10.1172/JCI143226.

74. Faner R, Rojas M, MacNee W, Agustí A. Abnormal lung aging in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine 2012; 186(4): 306–313. doi: 10.1164/rccm.201202-0282PP.

75. Linton PJ, Thoman ML. Immunosenescence in monocytes, macrophages, and dendritic cells: Lessons learned from the lung and heart. Immunology Letters 2014; 162(1): 290–297. doi: 10.1016/j.imlet.2014.06.017.

76. Aiello A, Farzaneh F, Candore G, et al. Immunosenescence and its hallmarks: How to oppose aging strategically? A review of potential options for therapeutic intervention. Frontiers in Immunology 2019; 10: 2247. doi: 10.3389/fimmu.2019.02247.

77. Desai O, Winkler J, Minasyan M, Herzog EL. The role of immune and inflammatory cells in idiopathic pulmonary fibrosis. Frontiers in Medicine 2018; 5: 43. doi: 10.3389/fmed.2018.00043.

78. Li X, An G, Wang Y, et al. Targeted migration of bone marrow mesenchymal stem cells inhibits silica-induced pulmonary fibrosis in rats. Stem Cell Research & Therapy 2018; 9(1): 335. doi: 10.1186/s13287-018-1083-y.

79. Cárdenes N, Álvarez D, Sellarés J, et al. Senescence of bone marrow-derived mesenchymal stem cells from patients with idiopathic pulmonary fibrosis. Stem Cell Research & Therapy 2018; 9(1): 257. doi: 10.1186/s13287-018-0970-6.

80. Parimon T, Hohmann MS, Yao C. Cellular senescence: Pathogenic mechanisms in lung fibrosis. International Journal of Molecular Sciences 2021; 22(12): 6214. doi: 10.3390/ijms22126214.

81. Jinnin M. Molecular pathogenesis of fibrosis in systemic sclerosis. Trends in Immunotherapy 2022; 6(1): 32–40. doi: 10.24294/ti.v6.i1.1453.