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]
Overview
Pathophysiology
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 most of the lung tissue
- Type 2 is the main 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 have the main role in degrading collagen.
Pathogenesis
- 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:
- Inflammation and fibrosis pattern
- Granulomatous pattern
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 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fibroblasts | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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] | Myofibroblasts[21] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 | Interleukin-13 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Migration of fibrocytes to the site of injury[26] | Tissue remodelling[27] | Alternate pathway activation of macrophages[28] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Lung Fibrosis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Genetics
Microscopic pathology
- The microscopic feature associated with idiopathic pulmonary fibrosis is named as "Usual Interstitial Pneumonia (UIP)".[29]
- The histologic findings in UIP include the following:
- Proliferation of mesenchymal cells
- Areas of different fibrosis degree
- Dense deposition of collagen fibers
- Overproduction of extracellular matrix
- Poor differentiated pulmonary architecture
- Honeycomb cysts (subpleural cysts)
Gross pathology
- The most important characteristics of idiopathic pulmonary fibrosis on gross pathology are:[30]
- Inferior lobes fibrosis
- Cobblestone appearance of the pleura
- Honeycomb appearance of the lung
- Airspaces enlargement
- Fibrotic retraction of the airways
Case courtesy of A.Prof Frank Gaillard, <a href="https://radiopaedia.org/">Radiopaedia.org</a>. From the case <a href="https://radiopaedia.org/cases/8621">rID: 8621</a> via www.radiopaedia.org
References
- ↑ van der Rest M, Garrone R (1991). "Collagen family of proteins". FASEB J. 5 (13): 2814–23. PMID 1916105.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 5.0 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Lohmann-Matthes ML, Steinmüller C, Franke-Ullmann G (1994). "Pulmonary macrophages". Eur Respir J. 7 (9): 1678–89. PMID 7995399.
- ↑ Gross TJ, Hunninghake GW (2001). "Idiopathic pulmonary fibrosis". N Engl J Med. 345 (7): 517–25. doi:10.1056/NEJMra003200. PMID 11519507.
- ↑ 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.