Zhuo Jinzhong, Liu Dongyu, Yu Qi, Hu Minxuan, Huang Haohua, Chen Yixin, Li Yanqun, Gao Yimei, Chen Weimou, Meng Xiaojin, Zou Fei, Zhang Jinming, Cai Shaoxi, Dong Hangming
Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Ganzhou People's Hospital, Ganzhou 341000, China.
Life Sci. 2024 Dec 15;359:123191. doi: 10.1016/j.lfs.2024.123191. Epub 2024 Oct 29.
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.
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.
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.
Our study demonstrates that IAA alleviates PF through multiple pathways, highlighting its potential as a therapeutic agent.
肺纤维化（PF）是一种持续进展的疾病，死亡率高且有效治疗选择有限。吲哚 - 3 - 乙酸（IAA）最初被认为是一种植物激素，也被鉴定为哺乳动物中由微生物群代谢产生的色氨酸衍生代谢物。IAA在各种疾病中已表现出抗氧化、抗炎和抗肿瘤作用，但其在PF中的作用仍不清楚。
使用博来霉素（BLM）诱导小鼠模型中的PF。在原代小鼠肺成纤维细胞（pMLF）中使用转化生长因子 - β1（TGF - β1）建立促纤维化体外细胞模型，并在A549细胞中建立体外细胞衰老模型。使用苏木精 - 伊红染色、免疫荧光染色、蛋白质印迹、SA - β - 半乳糖苷酶测定和网络药理学分析评估IAA对PF的治疗效果。此外，使用16S rRNA基因测序分析研究IAA对PF小鼠肺微生物群的影响。
我们观察到PF患者和小鼠模型中IAA水平均显著降低。此外，我们证明了IAA在减轻BLM诱导的小鼠模型中的PF方面具有治疗潜力，呈现剂量依赖性反应。从机制上讲，我们阐述了三个方面。首先，IAA通过抑制PI3K/AKT/mTOR途径促进自噬流，从而抑制肺成纤维细胞分化和细胞外基质（ECM）沉积。其次，IAA通过调节PI3K/AKT和HIF - 1途径减轻肺泡上皮细胞衰老。最后，IAA显示出通过调节肺微生物群的结构和组成来减轻PF的能力。
我们的研究表明，IAA通过多种途径减轻PF，突出了其作为治疗剂的潜力。
