Notch Signaling Regulates Pulmonary Fibrosis

Overview

Journal Front Cell Dev Biol

Specialty Cell Biology

Date 2024 Oct 25

PMID 39450276

Authors

Xinyue Zhang

Zhihao Xu

Qi Chen

Zhimin Zhou

Affiliations

Soon will be listed here.

Abstract

Pulmonary fibrosis is a progressive interstitial lung disease associated with aging. The pathogenesis of pulmonary fibrosis remains unclear, however, alveolar epithelial cell injury, myofibroblast activation, and extracellular matrix (ECM) accumulation are recognized as key contributors. Moreover, recent studies have implicated cellular senescence, endothelial-mesenchymal transition (EndMT), and epigenetic modifications in the pathogenesis of fibrotic diseases. Various signaling pathways regulate pulmonary fibrosis, including the TGF-β, Notch, Wnt, Hedgehog, and mTOR pathways. Among these, the TGF-β pathway is extensively studied, while the Notch pathway has emerged as a recent research focus. The Notch pathway influences the fibrotic process by modulating immune cell differentiation (e.g., macrophages, lymphocytes), inhibiting autophagy, and promoting interstitial transformation. Consequently, inhibiting Notch signaling represents a promising approach to mitigating pulmonary fibrosis. In this review, we discuss the role of Notch signaling pathway in pulmonary fibrosis, aiming to offer insights for future therapeutic investigations.

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References

Pagie S, Gerard N, Charreau B . Notch signaling triggered via the ligand DLL4 impedes M2 macrophage differentiation and promotes their apoptosis. Cell Commun Signal. 2018; 16(1):4. PMC: 5764024. DOI: 10.1186/s12964-017-0214-x. View

Zhao C, Li J, Yang J, Yang L, Chen P, Dou J . Inhibitor of γ-secretase alleviates middle ear inflammation by regulating Th2 response in OVA-mediated allergic OME in vivo. Immunobiology. 2019; 224(6):765-773. DOI: 10.1016/j.imbio.2019.08.010. View

Li L, Kao K, Liu Y, Lin C, Chen N, Lee C . Nintedanib reduces ventilation-augmented bleomycin-induced epithelial-mesenchymal transition and lung fibrosis through suppression of the Src pathway. J Cell Mol Med. 2017; 21(11):2937-2949. PMC: 5661114. DOI: 10.1111/jcmm.13206. View

Schaefer C, Ruhrmund D, Pan L, Seiwert S, Kossen K . Antifibrotic activities of pirfenidone in animal models. Eur Respir Rev. 2011; 20(120):85-97. PMC: 9487788. DOI: 10.1183/09059180.00001111. View

Amsen D, Helbig C, Backer R . Notch in T Cell Differentiation: All Things Considered. Trends Immunol. 2015; 36(12):802-814. DOI: 10.1016/j.it.2015.10.007. View

Shammout B, Johnson J . Pericytes in Chronic Lung Disease. Adv Exp Med Biol. 2019; 1147:299-317. DOI: 10.1007/978-3-030-16908-4_14. View

Bhaskaran M, Kolliputi N, Wang Y, Gou D, Chintagari N, Liu L . Trans-differentiation of alveolar epithelial type II cells to type I cells involves autocrine signaling by transforming growth factor beta 1 through the Smad pathway. J Biol Chem. 2006; 282(6):3968-76. DOI: 10.1074/jbc.M609060200. View

Wang X, Zhou J, Li X, Liu C, Liu L, Cui H . The Role of Macrophages in Lung Fibrosis and the Signaling Pathway. Cell Biochem Biophys. 2024; 82(2):479-488. DOI: 10.1007/s12013-024-01253-5. View

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

10.

Piera-Velazquez S, Jimenez S . Molecular mechanisms of endothelial to mesenchymal cell transition (EndoMT) in experimentally induced fibrotic diseases. Fibrogenesis Tissue Repair. 2012; 5(Suppl 1):S7. PMC: 3368755. DOI: 10.1186/1755-1536-5-S1-S7. View

11.

Fiuza U, Martinez Arias A . Cell and molecular biology of Notch. J Endocrinol. 2007; 194(3):459-74. DOI: 10.1677/JOE-07-0242. View

12.

Peng L, Wen L, Shi Q, Gao F, Huang B, Meng J . Scutellarin ameliorates pulmonary fibrosis through inhibiting NF-κB/NLRP3-mediated epithelial-mesenchymal transition and inflammation. Cell Death Dis. 2020; 11(11):978. PMC: 7666141. DOI: 10.1038/s41419-020-03178-2. View

13.

Ding Y, Fu X, Wang Q, Liu H, Wang H, Wu D . The Complex Interplay between Autophagy and NLRP3 Inflammasome in Renal Diseases. Int J Mol Sci. 2021; 22(23). PMC: 8657456. DOI: 10.3390/ijms222312766. View

14.

Wang Y, He F, Feng F, Liu X, Dong G, Qin H . Notch signaling determines the M1 versus M2 polarization of macrophages in antitumor immune responses. Cancer Res. 2010; 70(12):4840-9. DOI: 10.1158/0008-5472.CAN-10-0269. View

15.

Katsuragi Y, Ichimura Y, Komatsu M . p62/SQSTM1 functions as a signaling hub and an autophagy adaptor. FEBS J. 2015; 282(24):4672-8. DOI: 10.1111/febs.13540. View

16.

Wang F, Xia H, Yao S . Regulatory T cells are a double-edged sword in pulmonary fibrosis. Int Immunopharmacol. 2020; 84:106443. DOI: 10.1016/j.intimp.2020.106443. View

17.

Rangarajan S, Kurundkar A, Kurundkar D, Bernard K, Sanders Y, Ding Q . Novel Mechanisms for the Antifibrotic Action of Nintedanib. Am J Respir Cell Mol Biol. 2015; 54(1):51-9. PMC: 4742925. DOI: 10.1165/rcmb.2014-0445OC. View

18.

Liu X, Zhang Y, Shi M, Wang Y, Zhang F, Yan R . Notch1 regulates PTEN expression to exacerbate renal tubulointerstitial fibrosis in diabetic nephropathy by inhibiting autophagy via interactions with Hes1. Biochem Biophys Res Commun. 2018; 497(4):1110-1116. DOI: 10.1016/j.bbrc.2018.02.187. View

19.

Huang Y, Liu H, Yuan Y, Guo Y, Wan D, Pan S . Exercise Preconditioning Increases Beclin1 and Induces Autophagy to Promote Early Myocardial Protection via Intermittent Myocardial Ischemia-Hypoxia. Int Heart J. 2021; 62(2):407-415. DOI: 10.1536/ihj.20-597. View

20.

Hashimoto N, Phan S, Imaizumi K, Matsuo M, Nakashima H, Kawabe T . Endothelial-mesenchymal transition in bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol. 2009; 43(2):161-72. PMC: 2937229. DOI: 10.1165/rcmb.2009-0031OC. View