Indole-3-acetic acid attenuates pulmonary fibrosis by modulating lung microbiota, inhibiting fibroblast activation, and alleviating alveolar epithelial cell senescence.

Autor: Zhuo J; Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China., Liu D; Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China., Yu Q; Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China., Hu M; Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China., Huang H; Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China., Chen Y; Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China., Li Y; Ganzhou People's Hospital, Ganzhou 341000, China., Gao Y; Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China., Chen W; Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China., Meng X; School of Public Health, Southern Medical University, Guangzhou 510515, China., Zou F; School of Public Health, Southern Medical University, Guangzhou 510515, China., Zhang J; Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Electronic address: 1107020638@qq.com., Cai S; Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Electronic address: hxkc@smu.edu.cn., Dong H; Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Electronic address: dhm@smu.edu.cn.
Jazyk: angličtina
Zdroj: Life sciences [Life Sci] 2024 Dec 15; Vol. 359, pp. 123191. Date of Electronic Publication: 2024 Oct 29.
DOI: 10.1016/j.lfs.2024.123191
Abstrakt: Aim: Pulmonary fibrosis (PF) is a relentlessly progressive disorder characterized by high mortality and limited effective therapeutic options. Indole-3-acetic acid (IAA), originally recognized as a plant hormone, is also identified as a tryptophan-derived metabolite catabolized from microbiota in mammals. IAA has exhibited antioxidative, anti-inflammatory, and anti-tumor effects in various disorders, yet its role in PF remains elusive.
Main Methods: Bleomycin (BLM) was employed to induce PF in a mouse model. TGF-β1 was utilized in primary mouse lung fibroblasts (pMLFs) to establish a pro-fibrotic in vitro cellular model, and in A549 cells to create an in vitro cellular senescence model. The therapeutic effects of IAA on PF were evaluated using hematoxylin-eosin staining, immunofluorescence staining, western blotting, SA-β-gal assay, and network pharmacology analysis. Additionally, the effect of IAA on lung microbiota of PF was investigated using 16S rRNA gene sequencing analysis.
Key Findings: we observed a significant reduction in IAA levels in both PF patients and mouse models. Moreover, we demonstrated the therapeutic potential of IAA in alleviating PF in BLM-induced mouse models, showing a dose-dependent response. Mechanistically, we delineated three perspectives. Firstly, IAA promoted autophagic flux by inhibiting the PI3K/AKT/mTOR pathway, thereby suppressing lung fibroblast differentiation and extracellular matrix (ECM) deposition. Secondly, IAA attenuated alveolar epithelial cell senescence by modulating the PI3K/AKT and HIF-1 pathways. Lastly, IAA displayed the ability to mitigate PF by modulating the structure and composition of lung microbiota.
Significance: Our study demonstrates that IAA alleviates PF through multiple pathways, highlighting its potential as a therapeutic agent.
Competing Interests: Declaration of competing interest There are no interests to declare.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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