Idiopathic pulmonary fibrosis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]


Pulmonary fibrosis share the pathogenesis process of interstitial lung disease which involve the pulmonary parenchyma. Although the exact pathogenesis is not fully understood, there are many initiating factors which cause the pulmonary tissue injury. The primary features of the lung injury includes inflammation, fibrosis, and granulomas development.


Normal lung tissue

  • Lungs are composed normally of extracellular collagen which allows the lungs to exert their breathing efforts.
  • Different collagen types in the lung include the following:[1]
    • Type 1 and type 3 compose majority of the lung tissue
    • Type 2 is the primary component of the cartilage of the main bronchi
    • Type 4 forms the basement membrane
    • Type 5 forms the interstitial tissue
  • Normally, collagen is degraded and produced regularly to preserve the normal lung tissue.[2]
  • Collagen is produced by fibroblasts which also can degrade some of the collagen produced.
  • Metalloproteinases produced by fibroblasts, neutrophils, and macrophages plays a primary role in degradation of collagen.


  • Interstitial lung disease is a group of disorders that involve pulmonary parenchyma.
  • The exact pathogenesis of these disorders is not fully understood.
  • There are multiple initiating factors that cause pulmonary injury. However, immunopathogenic responses of lung tissue are quite similar.
  • There are two major histopathologic patterns in response to lung injury which include:

Algorithm showing pathophysiology of Interstitial Lung Disease[3]

Tissue injury in lungs
Parenchymal injury
Vascular injury
Mast cells in lungs in response to tissue injury
LPA6, LPA2, and LPA4 receptors[4]
Decreased sFRP-1 (secreted frizzled-related protein 1) in fibroblasts[5]
Secretes tryptase
Transforming growth factor-β (TGF-β)[6]
Insulin-like growth factor (IGF) signalling[5]
Reduced expression of angiogenic factors,
vascular endothelial growth factor (VEGF)[7]
Elevation of angiostatic factors,
pigment epithelium-derived factor[8]
Wnt/β-catenin signalling pathway[9][10]
PAR-2/protein kinase (PK)C-α/Raf-1/p44/42 signaling pathway[11]
Upregulation of Egr-1 (early growth response protein 1)[12]
IGF-binding protein 5 (IGFBP-5)[13]
IGF-binding protein 3 (IGFBP-3)
Loss of endothelial barrier function
Dysregulation of repair in lung tissue and activation of fibroblasts[14]
Regulates transforming growth factor-β (TGF-β)
Induction of syndecan-2 (SDC2)[15]
Activation,proliferation, and migration of fibroblast to the site of injury
Altered PTEN (phosphatase and tensin homologue)/Akt axis
Acquire contractile stress fibres
Inactivates Fox (forkhead box) O3a[16]
Protomyofibroblast, composed of cytoplasmic actins
Pleural mesothelial cells (PMCs)[17][18]
Downregulation of caveolin-1 (cav-1) and Fas expression[19]
De novo expression of α-smooth muscle actin (α-SMA)
TGF-β1-dependent mesothelial–mesenchymal transition
Fibroblast resistant to apoptosis[20]
Different ranges of contractions mediated by RhoA/Rho-associated kinase
Changes in intracellular calcium concentrations
Recruitement of fibrocytes in lungs
Lock step mechanism of cyclic and contractile events[22]
T-helper cell type 2 on site of injury[23][24]
Upregulation of C-X-C chemokine receptor type 4 (CXCR4)
on fibrocytes and its ligand
CXCL12 (stromal cell-derived factor 1)[25]
Excess extracellular matrix production
Exerting traction force
Migration of fibrocytes to the site of injury[26]
Tissue remodelling[27]
Alternate pathway activation of macrophages[28]
Lung Fibrosis

Gross pathology

  • The most important characteristics of idiopathic pulmonary fibrosis on gross pathology include:[29]
Honeycomb appearance of a fibrotic lung.
Source: Case courtesy of A.Prof Frank Gaillard, rID: 8621, via

Microscopic pathology


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  2. Laurent GJ (1982). "Rates of collagen synthesis in lung, skin and muscle obtained in vivo by a simplified method using [3H]proline". Biochem J. 206 (3): 535–44. PMC 1158621. PMID 7150261.
  3. Bagnato G, Harari S (2015). "Cellular interactions in the pathogenesis of interstitial lung diseases". Eur Respir Rev. 24 (135): 102–14. doi:10.1183/09059180.00003214. PMID 25726561.
  4. Ren Y, Guo L, Tang X, Apparsundaram S, Kitson C, Deguzman J; et al. (2013). "Comparing the differential effects of LPA on the barrier function of human pulmonary endothelial cells". Microvasc Res. 85: 59–67. doi:10.1016/j.mvr.2012.10.004. PMID 23084965.
  5. 5.0 5.1 Hsu E, Shi H, Jordan RM, Lyons-Weiler J, Pilewski JM, Feghali-Bostwick CA (2011). "Lung tissues in patients with systemic sclerosis have gene expression patterns unique to pulmonary fibrosis and pulmonary hypertension". Arthritis Rheum. 63 (3): 783–94. doi:10.1002/art.30159. PMC 3139818. PMID 21360508.
  6. Andersson CK, Mori M, Bjermer L, Löfdahl CG, Erjefält JS (2010). "Alterations in lung mast cell populations in patients with chronic obstructive pulmonary disease". Am J Respir Crit Care Med. 181 (3): 206–17. doi:10.1164/rccm.200906-0932OC. PMID 19926870.
  7. Ebina M, Shimizukawa M, Shibata N, Kimura Y, Suzuki T, Endo M; et al. (2004). "Heterogeneous increase in CD34-positive alveolar capillaries in idiopathic pulmonary fibrosis". Am J Respir Crit Care Med. 169 (11): 1203–8. doi:10.1164/rccm.200308-1111OC. PMID 14754760.
  8. Cosgrove GP, Brown KK, Schiemann WP, Serls AE, Parr JE, Geraci MW; et al. (2004). "Pigment epithelium-derived factor in idiopathic pulmonary fibrosis: a role in aberrant angiogenesis". Am J Respir Crit Care Med. 170 (3): 242–51. doi:10.1164/rccm.200308-1151OC. PMID 15117744.
  9. Königshoff M, Balsara N, Pfaff EM, Kramer M, Chrobak I, Seeger W; et al. (2008). "Functional Wnt signaling is increased in idiopathic pulmonary fibrosis". PLoS One. 3 (5): e2142. doi:10.1371/journal.pone.0002142. PMC 2374879. PMID 18478089.
  10. Lam AP, Flozak AS, Russell S, Wei J, Jain M, Mutlu GM; et al. (2011). "Nuclear β-catenin is increased in systemic sclerosis pulmonary fibrosis and promotes lung fibroblast migration and proliferation". Am J Respir Cell Mol Biol. 45 (5): 915–22. doi:10.1165/rcmb.2010-0113OC. PMC 3262680. PMID 21454805.
  11. Wygrecka M, Dahal BK, Kosanovic D, Petersen F, Taborski B, von Gerlach S; et al. (2013). "Mast cells and fibroblasts work in concert to aggravate pulmonary fibrosis: role of transmembrane SCF and the PAR-2/PKC-α/Raf-1/p44/42 signaling pathway". Am J Pathol. 182 (6): 2094–108. doi:10.1016/j.ajpath.2013.02.013. PMID 23562441.
  12. Yasuoka H, Hsu E, Ruiz XD, Steinman RA, Choi AM, Feghali-Bostwick CA (2009). "The fibrotic phenotype induced by IGFBP-5 is regulated by MAPK activation and egr-1-dependent and -independent mechanisms". Am J Pathol. 175 (2): 605–15. doi:10.2353/ajpath.2009.080991. PMC 2716960. PMID 19628764.
  13. Bhattacharyya S, Wu M, Fang F, Tourtellotte W, Feghali-Bostwick C, Varga J (2011). "Early growth response transcription factors: key mediators of fibrosis and novel targets for anti-fibrotic therapy". Matrix Biol. 30 (4): 235–42. doi:10.1016/j.matbio.2011.03.005. PMC 3135176. PMID 21511034.
  14. Sun Z, Gong X, Zhu H, Wang C, Xu X, Cui D; et al. (2014). "Inhibition of Wnt/β-catenin signaling promotes engraftment of mesenchymal stem cells to repair lung injury". J Cell Physiol. 229 (2): 213–24. doi:10.1002/jcp.24436. PMID 23881674.
  15. Ruiz XD, Mlakar LR, Yamaguchi Y, Su Y, Larregina AT, Pilewski JM; et al. (2012). "Syndecan-2 is a novel target of insulin-like growth factor binding protein-3 and is over-expressed in fibrosis". PLoS One. 7 (8): e43049. doi:10.1371/journal.pone.0043049. PMC 3416749. PMID 22900087.
  16. Nho RS, Peterson M, Hergert P, Henke CA (2013). "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. 8 (4): e61017. doi:10.1371/journal.pone.0061017. PMC 3620276. PMID 23580232.
  17. Mubarak KK, Montes-Worboys A, Regev D, Nasreen N, Mohammed KA, Faruqi I; et al. (2012). "Parenchymal trafficking of pleural mesothelial cells in idiopathic pulmonary fibrosis". Eur Respir J. 39 (1): 133–40. doi:10.1183/09031936.00141010. PMID 21737551.
  18. Nasreen N, Mohammed KA, Mubarak KK, Baz MA, Akindipe OA, Fernandez-Bussy S; et al. (2009). "Pleural mesothelial cell transformation into myofibroblasts and haptotactic migration in response to TGF-beta1 in vitro". Am J Physiol Lung Cell Mol Physiol. 297 (1): L115–24. doi:10.1152/ajplung.90587.2008. PMC 2711818. PMID 19411308.
  19. Del Galdo F, Sotgia F, de Almeida CJ, Jasmin JF, Musick M, Lisanti MP; et al. (2008). "Decreased expression of caveolin 1 in patients with systemic sclerosis: crucial role in the pathogenesis of tissue fibrosis". Arthritis Rheum. 58 (9): 2854–65. doi:10.1002/art.23791. PMC 2770094. PMID 18759267.
  20. Thannickal VJ, Horowitz JC (2006). "Evolving concepts of apoptosis in idiopathic pulmonary fibrosis". Proc Am Thorac Soc. 3 (4): 350–6. doi:10.1513/pats.200601-001TK. PMC 2231523. PMID 16738200.
  21. Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA (2002). "Myofibroblasts and mechano-regulation of connective tissue remodelling". Nat Rev Mol Cell Biol. 3 (5): 349–63. doi:10.1038/nrm809. PMID 11988769.
  22. Castella LF, Buscemi L, Godbout C, Meister JJ, Hinz B (2010). "A new lock-step mechanism of matrix remodelling based on subcellular contractile events". J Cell Sci. 123 (Pt 10): 1751–60. doi:10.1242/jcs.066795. PMID 20427321.
  23. Capelli A, Di Stefano A, Gnemmi I, Donner CF (2005). "CCR5 expression and CC chemokine levels in idiopathic pulmonary fibrosis". Eur Respir J. 25 (4): 701–7. doi:10.1183/09031936.05.00082604. PMID 15802346.
  24. Belperio JA, Dy M, Murray L, Burdick MD, Xue YY, Strieter RM; et al. (2004). "The role of the Th2 CC chemokine ligand CCL17 in pulmonary fibrosis". J Immunol. 173 (7): 4692–8. PMID 15383605.
  25. Andersson-Sjöland A, de Alba CG, Nihlberg K, Becerril C, Ramírez R, Pardo A; et al. (2008). "Fibrocytes are a potential source of lung fibroblasts in idiopathic pulmonary fibrosis". Int J Biochem Cell Biol. 40 (10): 2129–40. doi:10.1016/j.biocel.2008.02.012. PMID 18374622.
  26. Moore BB, Kolodsick JE, Thannickal VJ, Cooke K, Moore TA, Hogaboam C; et al. (2005). "CCR2-mediated recruitment of fibrocytes to the alveolar space after fibrotic injury". Am J Pathol. 166 (3): 675–84. doi:10.1016/S0002-9440(10)62289-4. PMC 1780139. PMID 15743780.
  27. Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G (2007). "The myofibroblast: one function, multiple origins". Am J Pathol. 170 (6): 1807–16. doi:10.2353/ajpath.2007.070112. PMC 1899462. PMID 17525249.
  28. Lohmann-Matthes ML, Steinmüller C, Franke-Ullmann G (1994). "Pulmonary macrophages". Eur Respir J. 7 (9): 1678–89. PMID 7995399.
  29. Wolters PJ, Collard HR, Jones KD (2014). "Pathogenesis of idiopathic pulmonary fibrosis". Annu Rev Pathol. 9: 157–79. doi:10.1146/annurev-pathol-012513-104706. PMC 4116429. PMID 24050627.
  30. Gross TJ, Hunninghake GW (2001). "Idiopathic pulmonary fibrosis". N Engl J Med. 345 (7): 517–25. doi:10.1056/NEJMra003200. PMID 11519507.

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