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Current Respiratory Medicine Reviews

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ISSN (Print): 1573-398X
ISSN (Online): 1875-6387

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Review Article

Local Lung Fibroblast Autophagy in the Context of Lung Fibrosis Pathogenesis

Author(s): Basheer Abdullah Marzoog*

Volume 19, Issue 1, 2023

Published on: 26 December, 2022

Page: [6 - 11] Pages: 6

DOI: 10.2174/1573398X19666221130141600

Price: $65

Abstract

The current molecular advances in lung fibrosis pathogenesis distend beyond the cellular to involve subcellular and molecular levels. Lung fibrogenesis and autophagy impairment are tightly associated. Autophagy is involved in cell cycle control and regulation of the intracellular microenvironment. Degradation of impaired intracellular organelles and biproducts is crucial to maintaining a healthy cell and preventing its metaplasia / transdifferentiation to a pathological cell. Autophagy modifies the metabolism of alveolar epithelial cells, endothelial cells, and lung fibroblasts. Autophagy upregulation induces local lung fibroblast hyperactivity and fibrosis. Several molecular triggers were found to induce lung fibroblast autophagy including TGFβ by inhibition of the PI3K/AKT/mTOR. However, physiologically, a balance is retained between autophagy inducers and inhibitors. Each type of autophagy plays its role in the initiation and progression of lung fibrosis. The pathogenesis of pulmonary fibrosis is multifactorial and involves dysfunction / dysregulation of alveolar epithelial cells, fibroblasts, monocyte-derived macrophages, and endothelial cells. The deposition of extracellular matrix proteins, the remodeling of the lung architecture and the molecular changes include impaired glycolysis, mitochondrial oxidation, gene expression modification, altered phospholipid and sphingolipid metabolism, and dysregulated protein folding lead to reprogramming of lung fibroblast into myofibroblast and their activation. The paper thoroughly addresses the molecular triggers and inhibitors of lung fibroblast autophagy in lung fibrosis.

Keywords: Autophagy, pathogenesis, pulmonary fibrosis, cytokines, TGF-β1, pathogenetic therapy.

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Graphical Abstract

[1]
Marzoog BA, Vlasova TI. Myocardiocyte autophagy in the context of myocardiocytes regeneration: A potential novel therapeutic strategy. Egypt J Med Hum Genet 2022; 23(1): 41.
[http://dx.doi.org/10.1186/s43042-022-00250-8]
[2]
Marzoog BA, Vlasova TI. Beta-cell autophagy under the scope of hypoglycemic drugs; possible mechanism as a novel therapeutic target. Obes Metab 2022; 18(4): 465-70.
[http://dx.doi.org/10.14341/omet12778]
[3]
Ghavami S, Yeganeh B, Zeki AA, et al. Autophagy and the unfolded protein response promote profibrotic effects of TGF-β1 in human lung fibroblasts. Am J Physiol Lung Cell Mol Physiol 2018; 314(3): L493-504.
[http://dx.doi.org/10.1152/ajplung.00372.2017] [PMID: 29074489]
[4]
Kim MS, Baek AR, Lee JH, et al. IL-37 attenuates lung fibrosis by inducing autophagy and regulating TGF-β1 production in mice. J Immunol 2019; 203(8): 2265-75.
[http://dx.doi.org/10.4049/jimmunol.1801515] [PMID: 31519861]
[5]
Poon AH, Choy DF, Chouiali F, et al. Increased autophagy-related 5 gene expression is associated with collagen expression in the airways of refractory asthmatics. Front Immunol 2017; 8(MAR): 355.
[http://dx.doi.org/10.3389/fimmu.2017.00355] [PMID: 28424691]
[6]
Araya J, Kojima J, Takasaka N, et al. Insufficient autophagy in idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2013; 304(1): L56-69.
[http://dx.doi.org/10.1152/ajplung.00213.2012] [PMID: 23087019]
[7]
Patel AS, Lin L, Geyer A, et al. Autophagy in idiopathic pulmonary fibrosis. PLoS One 2012; 7(7): e41394.
[http://dx.doi.org/10.1371/journal.pone.0041394] [PMID: 22815997]
[8]
Ricci A, Cherubini E, Scozzi D, et al. Decreased expression of autophagic beclin 1 protein in idiopathic pulmonary fibrosis fibroblasts. J Cell Physiol 2013; 228(7): 1516-24.
[http://dx.doi.org/10.1002/jcp.24307] [PMID: 23444126]
[9]
Hill C, Li J, Liu D, et al. Autophagy inhibition-mediated epithelial–mesenchymal transition augments local myofibroblast differentiation in pulmonary fibrosis. Cell Death Dis 2019; 10(8): 591.
[http://dx.doi.org/10.1038/s41419-019-1820-x] [PMID: 31391462]
[10]
Wang K, Zhang T, Lei Y, et al. Identification of ANXA2 (annexin A2) as a specific bleomycin target to induce pulmonary fibrosis by impeding TFEB-mediated autophagic flux. Autophagy 2018; 14(2): 269-82.
[http://dx.doi.org/10.1080/15548627.2017.1409405] [PMID: 29172997]
[11]
Cabrera S, Maciel M, Herrera I, et al. Essential role for the ATG4B protease and autophagy in bleomycin-induced pulmonary fibrosis. Autophagy 2015; 11(4): 670-84.
[http://dx.doi.org/10.1080/15548627.2015.1034409] [PMID: 25906080]
[12]
Gui YS, Wang L, Tian X, et al. mTOR overactivation and compromised autophagy in the pathogenesis of pulmonary fibrosis. PLoS One 2015; 10(9): e0138625.
[http://dx.doi.org/10.1371/journal.pone.0138625] [PMID: 26382847]
[13]
Zhang L, Wang Y, Wu G, Xiong W, Gu W, Wang CY. Macrophages: Friend or foe in idiopathic pulmonary fibrosis? Respir Res 2018; 19(1): 170.
[http://dx.doi.org/10.1186/s12931-018-0864-2] [PMID: 30189872]
[14]
Marzoog BA. Pulmonary fibrosis; risk factors and molecular triggers, insight for neo therapeutic approach. Curr Respir Med Rev 2022; 18(4): 257-64.
[http://dx.doi.org/10.2174/1573398X18666220806124019]
[15]
Zehender A, Li YN, Lin NY, et al. TGFβ promotes fibrosis by MYST1-dependent epigenetic regulation of autophagy. Nat Commun 2021; 12(1): 1-19.
[http://dx.doi.org/10.1038/s41467-021-24601-y]
[16]
Pan P, Su L, Wang X, et al. Vimentin regulation of autophagy activation in lung fibroblasts in response to lipopolysaccharide exposure in vitro. Ann Transl Med 2021; 9(4): 304-4.
[http://dx.doi.org/10.21037/atm-20-5129] [PMID: 33708931]
[17]
Marzoog B. Lipid behavior in metabolic syndrome pathophysiology. Curr Diabetes Rev 2022; 18(6): e150921196497.
[http://dx.doi.org/10.2174/1573399817666210915101321] [PMID: 34525924]
[18]
Bernard M, Yang B, Migneault F, et al. Autophagy drives fibroblast senescence through MTORC2 regulation. Autophagy 2020; 16(11): 2004-16.
[http://dx.doi.org/10.1080/15548627.2020.1713640] [PMID: 31931659]
[19]
Romero Y, Bueno M, Ramirez R, et al. mTORC 1 activation decreases autophagy in aging and idiopathic pulmonary fibrosis and contributes to apoptosis resistance in IPF fibroblasts. Aging Cell 2016; 15(6): 1103-12.
[http://dx.doi.org/10.1111/acel.12514] [PMID: 27566137]
[20]
Li X, Zhang W, Cao Q, et al. Mitochondrial dysfunction in fibrotic diseases. Cell Death Discov 2020; 6(1): 1-14.
[http://dx.doi.org/10.1038/s41420-020-00316-9]
[21]
Larson-Casey JL, Deshane JS, Ryan AJ, Thannickal VJ, Carter AB. Macrophage Akt1 Kinase-mediated mitophagy modulates apoptosis resistance and pulmonary fibrosis. Immunity 2016; 44(3): 582-96.
[http://dx.doi.org/10.1016/j.immuni.2016.01.001] [PMID: 26921108]
[22]
Ramakrishnan RK, Bajbouj K, Hachim MY, et al. Enhanced mitophagy in bronchial fibroblasts from severe asthmatic patients. PLoS One 2020; 15(11): e0242695.
[http://dx.doi.org/10.1371/journal.pone.0242695] [PMID: 33253229]
[23]
Marzoog BA. Autophagy in cancer cell transformation: A potential novel therapeutic strategy. Curr Cancer Drug Targets 2022; 22(9): 749-56.
[http://dx.doi.org/10.2174/1568009622666220428102741] [PMID: 36062863]
[24]
Chang AL, Ulrich A, Suliman HB, Piantadosi CA. Redox regulation of mitophagy in the lung during murine Staphylococcus aureus sepsis. Free Radic Biol Med 2015; 78: 179-89.
[http://dx.doi.org/10.1016/j.freeradbiomed.2014.10.582] [PMID: 25450328]
[25]
Jiang F. Autophagy in vascular endothelial cells. Clin Exp Pharmacol Physiol 2016; 43(11): 1021-8.
[http://dx.doi.org/10.1111/1440-1681.12649] [PMID: 27558982]
[26]
Sheng Q, Xiao X, Prasadan K, et al. Autophagy protects pancreatic beta cell mass and function in the setting of a high-fat and high-glucose diet. Sci Rep 2017; 7(1): 16348.
[http://dx.doi.org/10.1038/s41598-017-16485-0] [PMID: 29180700]
[27]
Zummo FP, Krishnanda SI, Georgiou M, et al. Exendin-4 stimulates autophagy in pancreatic β-cells via the RAPGEF/EPAC-Ca 2+ -PPP3/calcineurin-TFEB axis. Autophagy 2021; 1-17.
[http://dx.doi.org/10.1080/15548627.2021.1956123] [PMID: 34338148]
[28]
Ajoolabady A, Wang S, Kroemer G, et al. Targeting autophagy in ischemic stroke: From molecular mechanisms to clinical therapeutics. Pharmacol Ther 2021; 225: 107848.
[http://dx.doi.org/10.1016/j.pharmthera.2021.107848] [PMID: 33823204]
[29]
Hill C, Wang Y. Autophagy in pulmonary fibrosis: Friend or foe? Genes Dis 2022; 9(6): 1594-607.
[http://dx.doi.org/10.1016/j.gendis.2021.09.008] [PMID: 36119644]
[30]
Pei X, Zheng F, Li Y, et al. Niclosamide ethanolamine salt alleviates idiopathic pulmonary fibrosis by modulating the PI3K-mTORC1 Pathway. Cells 2022; 11(3): 346.
[http://dx.doi.org/10.3390/cells11030346] [PMID: 35159160]
[31]
Lu Y, Zhong W, Liu Y, et al. Anti-PD-L1 antibody alleviates pulmonary fibrosis by inducing autophagy via inhibition of the PI3K/Akt/mTOR pathway. Int Immunopharmacol 2022; 104: 108504.
[http://dx.doi.org/10.1016/j.intimp.2021.108504] [PMID: 35026657]
[32]
Celada LJ, Kropski JA, Herazo-Maya JD, et al. PD-1 up-regulation on CD4+ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production. Sci Transl Med 2018; 10(460): eaar8356.
[http://dx.doi.org/10.1126/scitranslmed.aar8356] [PMID: 30257954]
[33]
Marzoog B. Occurrence and severity of adverse reactions of immune checkpoint inhibitors (PD-1 and PD L1) based on mordovian dispensary data analysis. Curr Cancer Ther Rev 2022; 18(1): 51-6.
[http://dx.doi.org/10.2174/1573394717666210805120525]
[34]
He J, Peng H, Wang M, et al. Isoliquiritigenin inhibits TGF-β1-induced fibrogenesis through activating autophagy via PI3K/AKT/mTOR pathway in MRC-5 cells. Acta Biochim Biophys Sin (Shanghai) 2020; 52(8): 810-20.
[http://dx.doi.org/10.1093/abbs/gmaa067] [PMID: 32638014]
[35]
Saito S, Zhuang Y, Shan B, et al. Tubastatin ameliorates pulmonary fibrosis by targeting the TGFβ-PI3K-Akt pathway. PLoS One 2017; 12(10): e0186615.
[http://dx.doi.org/10.1371/journal.pone.0186615] [PMID: 29045477]
[36]
Liu M, Su M, Tang D, Hao L, Xun XH, Huang Y. Ligustrazin increases lung cell autophagy and ameliorates paraquat-induced pulmonary fibrosis by inhibiting PI3K/Akt/mTOR and hedgehog signalling via increasing miR-193a expression. BMC Pulm Med 2019; 19(1): 35.
[http://dx.doi.org/10.1186/s12890-019-0799-5] [PMID: 30744607]
[37]
Tsubouchi K, Araya J, Minagawa S, et al. Azithromycin attenuates myofibroblast differentiation and lung fibrosis development through proteasomal degradation of NOX4. Autophagy 2017; 13(8): 1420-34.
[http://dx.doi.org/10.1080/15548627.2017.1328348] [PMID: 28613983]
[38]
Mu E, Wang J, Chen L, Lin S, Chen J, Huang X. Ketogenic diet induces autophagy to alleviate bleomycin-induced pulmonary fibrosis in murine models. Exp Lung Res 2021; 47(1): 26-36.
[http://dx.doi.org/10.1080/01902148.2020.1840667] [PMID: 33121292]
[39]
Sharma P, Alizadeh J, Juarez M, et al. Autophagy, apoptosis, the unfolded protein response, and lung function in idiopathic pulmonary fibrosis. Cells 2021; 10(7): 1642.
[http://dx.doi.org/10.3390/cells10071642] [PMID: 34209019]
[40]
Mahavadi P, Vidyasagar V, Saket A, et al. The Pathomechanistic role of autophagy in lung fibrosis. Diffuse parenchymal lung disease. Eur Respir J 2017; 50: OA478.
[http://dx.doi.org/10.1183/1393003.congress-2017.OA478]

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