Age-Dependent Inflammatory Microenvironment Mediates Alveolar Regeneration

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2024 Mar 28

PMID 38542450

Authors

Rui Quan

Chenhong Shi

Bing Fang

Yanan Sun

Taiqi Qu

Xifan Wang

Ran Wang

Yiran Zhang

Fazheng Ren

Yixuan Li

Affiliations

Soon will be listed here.

Abstract

Lung aging triggers the onset of various chronic lung diseases, with alveolar repair being a key focus for alleviating pulmonary conditions. The regeneration of epithelial structures, particularly the differentiation from type II alveolar epithelial (AT2) cells to type I alveolar epithelial (AT1) cells, serves as a prominent indicator of alveolar repair. Nonetheless, the precise role of aging in impeding alveolar regeneration and its underlying mechanism remain to be fully elucidated. Our study employed histological methods to examine lung aging effects on structural integrity and pathology. Lung aging led to alveolar collapse, disrupted epithelial structures, and inflammation. Additionally, a relative quantification analysis revealed age-related decline in AT1 and AT2 cells, along with reduced proliferation and differentiation capacities of AT2 cells. To elucidate the mechanisms underlying AT2 cell functional decline, we employed transcriptomic techniques and revealed a correlation between inflammatory factors and genes regulating proliferation and differentiation. Furthermore, a D-galactose-induced senescence model in A549 cells corroborated our omics experiments and confirmed inflammation-induced cell cycle arrest and a >30% reduction in proliferation/differentiation. Physiological aging-induced chronic inflammation impairs AT2 cell functions, hindering tissue repair and promoting lung disease progression. This study offers novel insights into chronic inflammation's impact on stem cell-mediated alveolar regeneration.

References

Serrao K, Fortenberry J, Owens M, HARRIS F, Brown L . Neutrophils induce apoptosis of lung epithelial cells via release of soluble Fas ligand. Am J Physiol Lung Cell Mol Physiol. 2001; 280(2):L298-305. DOI: 10.1152/ajplung.2001.280.2.L298. View

KUHN 3rd C . Cytochemistry of pulmonary alveolar epithelial cells. Am J Pathol. 1968; 53(5):809-33. PMC: 2013527. View

Braman S, Skloot G . Pulmonary Disease in the Aging Patient. Clin Geriatr Med. 2017; 33(4):xi-xii. DOI: 10.1016/j.cger.2017.08.001. View

Danahay H, Pessotti A, Coote J, Montgomery B, Xia D, Wilson A . Notch2 is required for inflammatory cytokine-driven goblet cell metaplasia in the lung. Cell Rep. 2015; 10(2):239-52. DOI: 10.1016/j.celrep.2014.12.017. View

Finn J, Sottoriva K, Pajcini K, Kitajewski J, Chen C, Zhang W . Dlk1-Mediated Temporal Regulation of Notch Signaling Is Required for Differentiation of Alveolar Type II to Type I Cells during Repair. Cell Rep. 2019; 26(11):2942-2954.e5. PMC: 6464111. DOI: 10.1016/j.celrep.2019.02.046. View

John-Schuster G, Gunter S, Hager K, Conlon T, Eickelberg O, Yildirim A . Inflammaging increases susceptibility to cigarette smoke-induced COPD. Oncotarget. 2015; 7(21):30068-83. PMC: 5058664. DOI: 10.18632/oncotarget.4027. View

Olajuyin A, Zhang X, Ji H . Alveolar type 2 progenitor cells for lung injury repair. Cell Death Discov. 2019; 5:63. PMC: 6368612. DOI: 10.1038/s41420-019-0147-9. View

Zacharias W, Frank D, Zepp J, Morley M, Alkhaleel F, Kong J . Regeneration of the lung alveolus by an evolutionarily conserved epithelial progenitor. Nature. 2018; 555(7695):251-255. PMC: 6020060. DOI: 10.1038/nature25786. View

Teramura T, Onodera Y . Stem cell depletion by inflammation-associated miR-155. Aging (Albany NY). 2018; 10(1):17-18. PMC: 5811257. DOI: 10.18632/aging.101374. View

10.

Cevenini E, Monti D, Franceschi C . Inflamm-ageing. Curr Opin Clin Nutr Metab Care. 2012; 16(1):14-20. DOI: 10.1097/MCO.0b013e32835ada13. View

11.

Chung M, Bujnis M, Barkauskas C, Kobayashi Y, Hogan B . Niche-mediated BMP/SMAD signaling regulates lung alveolar stem cell proliferation and differentiation. Development. 2018; 145(9). PMC: 5992594. DOI: 10.1242/dev.163014. View

12.

Moliva J, Rajaram M, Sidiki S, Sasindran S, Guirado E, Pan X . Molecular composition of the alveolar lining fluid in the aging lung. Age (Dordr). 2014; 36(3):9633. PMC: 4082594. DOI: 10.1007/s11357-014-9633-4. View

13.

Katsura H, Kobayashi Y, Tata P, Hogan B . IL-1 and TNFα Contribute to the Inflammatory Niche to Enhance Alveolar Regeneration. Stem Cell Reports. 2019; 12(4):657-666. PMC: 6450459. DOI: 10.1016/j.stemcr.2019.02.013. View

14.

Iwasaki A, Foxman E, Molony R . Early local immune defences in the respiratory tract. Nat Rev Immunol. 2016; 17(1):7-20. PMC: 5480291. DOI: 10.1038/nri.2016.117. View

15.

Meiners S, Eickelberg O, Konigshoff M . Hallmarks of the ageing lung. Eur Respir J. 2015; 45(3):807-27. DOI: 10.1183/09031936.00186914. View

16.

Birck C, Ginolhac A, Pavlou M, Michelucci A, Heuschling P, Grandbarbe L . NF-κB and TNF Affect the Astrocytic Differentiation from Neural Stem Cells. Cells. 2021; 10(4). PMC: 8068246. DOI: 10.3390/cells10040840. View

17.

Seitz D, Perl M, Mangold S, Neddermann A, Braumuller S, Zhou S . Pulmonary contusion induces alveolar type 2 epithelial cell apoptosis: role of alveolar macrophages and neutrophils. Shock. 2008; 30(5):537-44. DOI: 10.1097/SHK.0b013e31816a394b. View

18.

Li X, Lai Y, Li J, Zou M, Zou C . Oxidative stress destabilizes protein arginine methyltransferase 4 via glycogen synthase kinase 3β to impede lung epithelial cell migration. Am J Physiol Cell Physiol. 2017; 313(3):C285-C294. PMC: 5625095. DOI: 10.1152/ajpcell.00073.2017. View

19.

Riemondy K, Jansing N, Jiang P, Redente E, Gillen A, Fu R . Single cell RNA sequencing identifies TGFβ as a key regenerative cue following LPS-induced lung injury. JCI Insight. 2019; 5. PMC: 6538357. DOI: 10.1172/jci.insight.123637. View

20.

Choi J, Park J, Tsagkogeorga G, Yanagita M, Koo B, Han N . Inflammatory Signals Induce AT2 Cell-Derived Damage-Associated Transient Progenitors that Mediate Alveolar Regeneration. Cell Stem Cell. 2020; 27(3):366-382.e7. PMC: 7487779. DOI: 10.1016/j.stem.2020.06.020. View