Insights into the Pathogenesis of Pulmonary Fibrosis from Genetic Diseases

Overview

Journal Am J Respir Cell Mol Biol

Specialties Cell Biology
Molecular Biology

Date 2022 Mar 16

PMID 35294321

Authors

Joanna Y Wang

Lisa R Young

Affiliations

Soon will be listed here.

Abstract

Pulmonary fibrosis is a disease process associated with significant morbidity and mortality, with limited therapeutic options owing to an incomplete understanding of the underlying pathophysiology. Mechanisms driving the fibrotic cascade have been elucidated through studies of rare and common variants in surfactant-related and telomere-related genes in familial and sporadic forms of pulmonary fibrosis, as well as in multisystem Mendelian genetic disorders that present with pulmonary fibrosis. In this translational review, we outline insights into the pathophysiology of pulmonary fibrosis derived from genetic forms of the disease, with a focus on model systems, shared cellular and molecular mechanisms, and potential targets for therapy.

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References

Keller R, Gagne K, Usmani G, Asdourian G, Williams D, Hofmann I . CTC1 Mutations in a patient with dyskeratosis congenita. Pediatr Blood Cancer. 2012; 59(2):311-4. PMC: 3374040. DOI: 10.1002/pbc.24193. View

Strikoudis A, Cieslak A, Loffredo L, Chen Y, Patel N, Saqi A . Modeling of Fibrotic Lung Disease Using 3D Organoids Derived from Human Pluripotent Stem Cells. Cell Rep. 2019; 27(12):3709-3723.e5. PMC: 6594401. DOI: 10.1016/j.celrep.2019.05.077. View

Young L, Gulleman P, Short C, Tanjore H, Sherrill T, Qi A . Epithelial-macrophage interactions determine pulmonary fibrosis susceptibility in Hermansky-Pudlak syndrome. JCI Insight. 2016; 1(17):e88947. PMC: 5070955. DOI: 10.1172/jci.insight.88947. View

Nathan N, Giraud V, Picard C, Nunes H, Dastot-Le Moal F, Copin B . Germline SFTPA1 mutation in familial idiopathic interstitial pneumonia and lung cancer. Hum Mol Genet. 2016; 25(8):1457-67. DOI: 10.1093/hmg/ddw014. View

Minagawa S, Araya J, Numata T, Nojiri S, Hara H, Yumino Y . Accelerated epithelial cell senescence in IPF and the inhibitory role of SIRT6 in TGF-β-induced senescence of human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2011; 300(3):L391-401. PMC: 3284316. DOI: 10.1152/ajplung.00097.2010. View

Chen R, Zhang K, Chen H, Zhao X, Wang J, Li L . Telomerase Deficiency Causes Alveolar Stem Cell Senescence-associated Low-grade Inflammation in Lungs. J Biol Chem. 2015; 290(52):30813-29. PMC: 4692211. DOI: 10.1074/jbc.M115.681619. View

ODwyer D, Armstrong M, Trujillo G, Cooke G, Keane M, Fallon P . The Toll-like receptor 3 L412F polymorphism and disease progression in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2013; 188(12):1442-50. DOI: 10.1164/rccm.201304-0760OC. View

Hancock L, Hennessy C, Solomon G, Dobrinskikh E, Estrella A, Hara N . Muc5b overexpression causes mucociliary dysfunction and enhances lung fibrosis in mice. Nat Commun. 2018; 9(1):5363. PMC: 6299094. DOI: 10.1038/s41467-018-07768-9. View

Hoffman T, van der Vis J, van der Smagt J, Massink M, Grutters J, van Moorsel C . Pulmonary fibrosis linked to variants in the gene, encoding the telomere protein TPP1. Eur Respir J. 2019; 54(6). DOI: 10.1183/13993003.00809-2019. View

10.

Cheong N, Zhang H, Madesh M, Zhao M, Yu K, Dodia C . ABCA3 is critical for lamellar body biogenesis in vivo. J Biol Chem. 2007; 282(33):23811-7. DOI: 10.1074/jbc.M703927200. View

11.

Tomer Y, Wambach J, Knudsen L, Zhao M, Rodriguez L, Murthy A . The common ABCA3 variant disrupts AT2 cell quality control and increases susceptibility to lung injury and aberrant remodeling. Am J Physiol Lung Cell Mol Physiol. 2021; 321(2):L291-L307. PMC: 8410113. DOI: 10.1152/ajplung.00400.2020. View

12.

Lehmann M, Hu Q, Hu Y, Hafner K, Costa R, van den Berg A . Chronic WNT/β-catenin signaling induces cellular senescence in lung epithelial cells. Cell Signal. 2020; 70:109588. PMC: 8968687. DOI: 10.1016/j.cellsig.2020.109588. View

13.

Stanley S, Gable D, Wagner C, Carlile T, Hanumanthu V, Podlevsky J . Loss-of-function mutations in the RNA biogenesis factor NAF1 predispose to pulmonary fibrosis-emphysema. Sci Transl Med. 2016; 8(351):351ra107. PMC: 5351811. DOI: 10.1126/scitranslmed.aaf7837. View

14.

Maguire J, Mulugeta S, Beers M . Endoplasmic reticulum stress induced by surfactant protein C BRICHOS mutants promotes proinflammatory signaling by epithelial cells. Am J Respir Cell Mol Biol. 2010; 44(3):404-14. PMC: 3095939. DOI: 10.1165/rcmb.2009-0382OC. View

15.

van Moorsel C, van Oosterhout M, Barlo N, de Jong P, van der Vis J, Ruven H . Surfactant protein C mutations are the basis of a significant portion of adult familial pulmonary fibrosis in a dutch cohort. Am J Respir Crit Care Med. 2010; 182(11):1419-25. DOI: 10.1164/rccm.200906-0953OC. View

16.

Terry R, SPERRY W, BRODOFF B . Adult lipidosis resembling Niemann-Pick's disease. Am J Pathol. 1954; 30(2):263-85. PMC: 1942466. View

17.

Mushiroda T, Wattanapokayakit S, Takahashi A, Nukiwa T, Kudoh S, Ogura T . A genome-wide association study identifies an association of a common variant in TERT with susceptibility to idiopathic pulmonary fibrosis. J Med Genet. 2008; 45(10):654-6. DOI: 10.1136/jmg.2008.057356. View

18.

Bullard J, Wert S, Whitsett J, Dean M, Nogee L . ABCA3 mutations associated with pediatric interstitial lung disease. Am J Respir Crit Care Med. 2005; 172(8):1026-31. PMC: 1403838. DOI: 10.1164/rccm.200503-504OC. View

19.

Alder J, Stanley S, Wagner C, Hamilton M, Hanumanthu V, Armanios M . Exome sequencing identifies mutant TINF2 in a family with pulmonary fibrosis. Chest. 2014; 147(5):1361-1368. PMC: 4420184. DOI: 10.1378/chest.14-1947. View

20.

Patel A, Lin L, Geyer A, Haspel J, An C, Cao J . Autophagy in idiopathic pulmonary fibrosis. PLoS One. 2012; 7(7):e41394. PMC: 3399849. DOI: 10.1371/journal.pone.0041394. View