Akciğer Fibrozisinin Moleküler Mekanizmaları

Akciğer fibrozisi oldukça heterojen ve yaşamı tehdit eden bir hastalıktır. Akciğer fibrozisinin moleküler patogenezi üzerine yapılan çalışmalar daha çok hücre dışı matriks ve kollajen artışını düzenleyen mekanizmalara odaklanmıştır. Bu çalışmalar var olsa da, birçok farklı yeni çalışma da yapılmaktadır. Bu çalışmalar daha çok fibroblast aktivasyonunu ve farklılaşmasını düzenleyen mekanizmalara, fibrozisin nasıl başladığına ve nasıl ilerlediğine odaklanmaktadır. Bu derlemede özellikle akciğer fibrozisinin moleküler mekanizmaları üzerinde durulmuş ve mekanizmaları incelenmiştir.

Lung fibrosis molecular mechanisms

Lung fibrosis is a highly heterogeneous and life-threatening disease in patients. Studies on the molecular pathogenesis of lung fibrosis have more often focused on the mechanisms regulating the increase of extracellular matrix and collagen. Although these studies have been conducted in this way, many different new studies are also being conducted. These studies have focused more on the mechanisms regulating fibroblast activation and differentiation, how fibrosis starts and how it progresses. In this review, especially the molecular mechanisms of lung fibrosis are emphasized and examined.

___

  • 1. Selman M, King TE, Pardo A. American Thoracic Society; European Respiratory Society; American College of Chest Physicians. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann. Intern. Med. 2001; 134:136–151
  • 2. Katzen J, Beers MF. Contributions of alveolar epithelial cell quality control to pulmonary fibrosis. J. Clin. Investig. 2020; 130:5088–5099.
  • 3. Kirkwood TB. Understanding the odd science of aging. Cell. 2005; 120: 437–447.
  • 4. Kapetanaki MG, Mora AL, Rojas M. Influence of age on wound healing and fibrosis. J. Pathol. 2013; 229: 310–322.
  • 5. Wynn TA. Integrating mechanisms of pulmonary fibrosis. J. Exp. Med. 2011; 208: 1339–1350.
  • 6. Barkauskas CE, Noble PW. Cellular mechanisms of tissue fibrosis. 7. New insights into the cellular mechanisms of pulmonary fibrosis. Am. J. Physiol. Cell Physiol. 2014; 306: C987–C996.
  • 7. Wynn TA, Ramalingam TR. Mechanisms of fibrosis: Therapeutic translation for fibrotic disease. Nat. Med. 2012; 18: 1028–1040.
  • 8. Hecker L, Logsdon NJ, Kurundkar D, Kurundkar A, Bernard K, Hock T, Meldrum E, Sanders YY, Thannickal VJ. Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance. Sci. Transl. Med. 2014; 6: 231ra47.
  • 9. Betensley A, Sharif R, Karamichos D. A Systematic Review of the Role of DysfunctionalWound Healing in the Pathogenesis and Treatment of Idiopathic Pulmonary Fibrosis. J. Clin. Med. 2016; 6: 2.
  • 10. Coker RK, Laurent GJ, Shahzeidi S, Lympany PA, du Bois RM, Jeffery PK., McAnulty, RJ. Transforming growth factors-beta (1), -beta (2), and -beta (3) stimulate fibroblast procollagen production in vitro but are differentially expressed during bleomycin-induced lung fibrosis. Am. J. Pathol. 1997; 150: 981–991.
  • 11. Khalil N, O’Connor RN, Unruh HW, Warren PW, Flanders KC, Kemp A, Bereznay OH, Greenberg AH. Increased production and immunohistochemical localization of transforming growth factor-beta in idiopathic pulmonary fibrosis. Am. J. Respir. Cell Mol. Biol. 1991; 5: 155–162.
  • 12. Raghow B, Irish P, Kang AH. Coordinate regulation of transforming growth factor beta gene expression and cell proliferation in hamster lungs undergoing bleomycin-induced pulmonary fibrosis. J. Clin. Investig. 1989; 84: 1836–1842.
  • 13. Heldin CH, Miyazono K, ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 1997, 390, 465–471.
  • 14. Zhao J, Shi W, Wang YL, Chen H, Bringas P, Jr., Datto MB, Frederick JP, Wang XF, Warburton D. Smad3 deficiency attenuates bleomycin-induced pulmonary fibrosis in mice. Am. J. Physiol. Lung Cell Mol. Physiol. 2002, 282, L585–L593.
  • 15. Nakao, A.; Afrakhte, M.; Moren, A.; Nakayama, T.; Christian, J.L.; Heuchel, R.; Itoh, S.; Kawabata, M.; Heldin, N.E.; Heldin, C.H.; et al. Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature 1997, 389, 631–635.
  • 16. Hayashi H, Abdollah S, Qiu Y, Cai J, Xu YY, Grinnell BW, Richardson MA, Topper JN, Gimbrone MA Jr, Wrana JL et al. The MAD-related protein Smad7 associates with the TGF-beta receptor and functions as an antagonist of TGF-beta signaling. Cell 1997, 89, 1165–1173.
  • 17. Grimminger F, Gunther A, Vancheri C. The role of tyrosine kinases in the pathogenesis of idiopathic pulmonary fibrosis. Eur. Respir. J. 2015, 45, 1426–1433.
  • 18. Antoniades HN, Bravo MA, Avila RE, Galanopoulos T, Neville-Golden J, Maxwell M, Selman M. Platelet-derived growth factor in idiopathic pulmonary fibrosis. J. Clin. Investig. 1990, 86, 1055–1064.
  • 19. Martinet Y, Rom WN, Grotendorst GR, Martin GR, Crystal RG. Exaggerated spontaneous release of platelet-derived growth factor by alveolar macrophages from patients with idiopathic pulmonary fibrosis. N. Engl. J. Med. 1987, 317, 202–209. 20. Liu JY, Morris GF, Lei WH, Hart CE, Lasky JA, Brody AR. Rapid activation of PDGF-A and -B expression at sites of lung injury in asbestos-exposed rats. Am. J. Respir. Cell Mol. Biol. 1997, 17, 129–140.
  • 21. Hoyle GW, Li J, Finkelstein JB, Eisenberg T, Liu JY, Lasky JA, Athas G, Morris GF, Brody AR. Emphysematous lesions, inflammation, and fibrosis in the lungs of transgenic mice overexpressing platelet-derived growth factor. Am. J. Pathol. 1999, 154, 1763–1775.
  • 22. Yi ES, Lee H, Yin S, Piguet P, Sarosi I, Kaufmann S, Tarpley J, Wang NS, Ulich TR. Platelet-derived growth factor causes pulmonary cell proliferation and collagen deposition in vivo. Am. J. Pathol. 1996, 149, 539–548.
  • 23. Yoshida M, Sakuma-Mochizuki J. Abe, K et al. In vivo gene transfer of an extracellular domain of platelet-derived growth factor beta receptor by the HVJ-liposome method ameliorates bleomycin-induced pulmonary fibrosis. Biochem. Biophys. Res. Commun. 1999; 265: 503–508.
  • 24. Rom WN, Basset P, Fells GA, Nukiwa T, et al. Alveolar macrophages release an insulin-like growth factor I-type molecule. J. Clin. Investig. 1988; 82: 1685–1693.
  • 25. Bitterman PB, Adelberg S, Crystal RG. Mechanisms of pulmonary fibrosis. Spontaneous release of the alveolar macrophage-derived growth factor in the interstitial lung disorders. J. Clin. Investig. 1983; 72: 1801–1813. 26. Dees C, M. Tomcik, K. Palumbo-Zerr, et al., Arthritis Rheum, 2012; 64: 3006-3015.
  • 27. Koppikar P, Bhagwat N, Kilpivaara O, Manshouri T, Adli M, Hricik T et al. Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. Nature. 2012;489(7414):155-9.
  • 28. Dees, C, Chakraborty, D, Distler, JHW. Cellular and molecular mechanisms in fibrosis. Exp. Dermatol.. 2021; 30: 121– 131.
  • 29. Giacomelli C, Piccarducci R, Marchetti L, Romei C, Martini C. Pulmonary Fibrosis from Molecular Mechanisms to Therapeutic Interventions: Lessons from Post-COVID-19 Patients. Biochem. Pharmacol. 2021; 193: 114812.
  • 30. Bartis D, Mise N, Mahida RY, Eickelberg O, Thickett DR. Epithelial–Mesenchymal Transition in Lung Development and Disease: Does It Exist and Is It Important? Thorax. 2014; 69: 760–765.
  • 31. Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, Brumwell AN, et al. Alveolar Epithelial Cell Mesenchymal Transition Develops in Vivo during Pulmonary Fibrosis and Is Regulated by the Extracellular Matrix. Proc. Natl. Acad. Sci. USA 2006; 103; 13180–13185.
  • 32. Ye Z, Hu Y. TGF-β1: Gentlemanly Orchestrator in Idiopathic Pulmonary Fibrosis (Review). Int. J. Mol. Med. 2021; 48: 132.
  • 33. Akhmetshina A, Palumbo K, Dees C, Bergmann C, Venalis P, et al. Activation of Canonical Wnt Signalling Is Required for TGF-β-Mediated Fibrosis. Nat. Commun. 2012; 3: 735.
  • 34. Zhou B, Liu Y, Kahn M, Ann DK, Han A, Wang H et al. Interactions Between β-Catenin and Transforming Growth Factor-β 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: 7026–7038.
  • 35. Hill C, Li J, Liu D, Conforti F, Brereton CJ, Yao L, et al. Autophagy Inhibition-Mediated Epithelial–Mesenchymal Transition Augments Local Myofibroblast Differentiation in Pulmonary Fibrosis. Cell. Death Dis. 2019; 10: 591.
  • 36. Peng T, Frank DB, Kadzik RS, Morley MP, Rathi KS, Wang T, Zhou S, Cheng L, Lu M.M.; Morrisey EE. Hedgehog Actively Maintains Adult Lung Quiescence and Regulates Repair and Regeneration. Nature 2015, 526, 578–582.
  • 37. Wang C, Cassandras M, Peng T. The Role of Hedgehog Signaling in Adult Lung Regeneration and Maintenance. J. Dev. Biol. 2019, 7, 14.
  • 38. Bolaños AL, Milla CM, Lira JC, Ramírez R, Checa M, Barrera L, García-Alvarez J, Carbajal V, Becerril C, Gaxiola M. et al. Role of Sonic Hedgehog in Idiopathic Pulmonary Fibrosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 2012, 303, L978–L990.
  • 39. Fitch PM, Howie SEM, Wallace WAH. Oxidative Damage and TGF-β Differentially Induce Lung Epithelial Cell Sonic Hedgehog and Tenascin-C Expression: Implications for the Regulation of Lung Remodelling in Idiopathic Interstitial Lung Disease: SHH and Tenascin-C in Type-II Alveolar Cells. Int. J. Exp. Pathol. 2011, 92, 8–17.
  • 40. Stewart GA, Hoyne GF, Ahmad SA, Jarman E, Wallace WA, Harrison DJ, Haslett C, Lamb JR, Howie SE. Expression of the Developmental Sonic Hedgehog (Shh) Signalling Pathway Is up-Regulated in Chronic Lung Fibrosis and the Shh Receptor Patched 1 Is Present in Circulating T Lymphocytes. J. Pathol. 2003, 199, 488–495.
  • 41. Henke C, Marineili W, Jessurun J, Fox J, Harms D, Peterson M, Chiang L, Doran P. Macrophage production of basic fibroblast growth factor in the fibroproliferative disorder of alveolar fibrosis after lung injury. Am. J. Pathol. 1993, 143, 1189–1199.
  • 42. Inoue Y, King TE, Jr., Tinkle SS, Dockstader K, Newman LS. Human mast cell basic fibroblast growth factor in pulmonary fibrotic disorders. Am. J. Pathol. 1996; 149: 2037–2054.
  • 43. Romero Y, Bueno M, Ramirez R, Álvarez D, Sembrat JC, Goncharova EA, et al. MTORC1 Activation Decreases Autophagy in Aging and Idiopathic Pulmonary Fibrosis and Contributes to Apoptosis Resistance in IPF Fibroblasts. Aging Cell 2016; 15: 1103–1112.
  • 44. Wang Y, Huang G, Wang Z, Qin H, Mo B, Wang, C. Elongation Factor-2 Kinase Acts Downstream of P38 MAPK to Regulate Proliferation, Apoptosis and Autophagy in Human Lung Fibroblasts. Exp. Cell. Res. 2018; 363: 291–298.
  • 45. Ogawa T, Shichino S, Ueha S, Matsushima K. Macrophages in Lung Fibrosis. Int. Immunol. 2021; 33: 665–671.
  • 46. Phan THG, Paliogiannis P, Nasrallah GK, Giordo R, Eid AH et al. Emerging Cellular and Molecular Determinants of Idiopathic Pulmonary Fibrosis. Cell. Mol. Life Sci. 2021; 78: 2031–2057.
  • 47. Heukels P, Moor CC, von der Thüsen JH, Wijsenbeek MS, Kool M. Inflammation and Immunity in IPF Pathogenesis and Treatment. Respir. Med. 2019; 147: 79–91.
Osmangazi Tıp Dergisi-Cover
  • ISSN: 1305-4953
  • Yayın Aralığı: Yılda 6 Sayı
  • Başlangıç: 2013
  • Yayıncı: Eskişehir Osmangazi Üniversitesi Rektörlüğü
Sayıdaki Diğer Makaleler

Pediatrik Kutanöz Leishmania Olgularının Değerlendirilmesi

Merve İŞERİ NEPESOV, Yalçın KARA, Mahmut Can KIZIL, Hilal KAYA ERDOĞAN, Kursat Bora CARMAN, Nihal DOĞAN, Tercan US, Ömer KILIÇ, Ener Çağrı DİNLEYİCİ

Böbrek Nakli Yapılmış Hastalarda Servikal Sitoloji Bulguları ve Bu Bulguların Normal Bireylerle Karşılaştırılması

Alev OK ATILGAN, Merih TEPEOĞLU, Eda YILMAZ AKÇAY, Asuman Nihan HABERAL REYHAN, Esra KUŞCU, Handan ÖZDEMİR, Mehmet HABERAL

Akciğer Fibrozisinin Moleküler Mekanizmaları

Ayşe KOÇAK SEZGİN

Fournier Gangreni’nde Vakum Yardımlı Kapama (Vak)’nın Yara İyileşmesi ve Greft Uyumu Üzerine Etkisi

Burhan BAYLAN, Recep UZUN

Endoskopik Kulak Cerrahisi: 7 yıllık Tek Merkez Deneyimi

Ercan KAYA, Armağan İNCESU, Mehmet Özgür PINARBAŞLI, Furkan KAYA

Retropubik Radikal Prostatektomi Operasyonunda Peroperatif Kanama Miktarını ve Kan Transfüzyonu İhtiyacını Etkileyen Faktörler

Osman GERCEK, Veli Mert YAZAR, Murat Cengizhan ATİK, Kutay TOPAL

Büro Çalışanlarının Ergonomik Çalışma Koşulları ve Stres Algılarının Değerlendirilmesi: Bir Üniversite Örneği

Feyza Nehir ÖZNUR MUZ, Ali KILINÇ, Mine TEPETAŞ, Alaettin ÜNSAL, Didem ARSLANTAŞ

Böbreğin Berrak Hücreli Sarkomu: Oldukça Nadir Bir Olgu Sunumu

Emel TEKİN, Osman Furkan MÜLKEM, Ersin TÖRET

Senkron ve Metakron Hematolojik ve Onkolojik Tümörlerin Tek Merkez Deneyimi

Filiz YAVAŞOĞLU, Çiğdem ÖZDEMİR, Yiğit ŞENOL, Hacer DEMİR, Meltem BAYKARA

Tıp Fakültesi Öğrencileri ve Sağlık Uygulama ve Araştırma Hastanesi Personellerinin Ruhsal Bozukluklar Açısından Değerlendirilmesi: Bir Üniversite Örneği

Mine TEPETAŞ, Sevil AYDOĞAN GEDİK, Ayşegül MUTLU, Sevda SUNGUR, Tuğçe ARSLAN TORBA, Didem ARSLANTAŞ, Alaettin ÜNSAL