医学
气体6
肺纤维化
博莱霉素
M2巨噬细胞
癌症研究
特发性肺纤维化
巨噬细胞极化
纤维化
流式细胞术
巨噬细胞
肺
免疫学
内科学
病理
生物
受体
化疗
受体酪氨酸激酶
生物化学
体外
作者
Dong Ha Kim,Ho Cheol Kim,Kyungtaek Im,In-Jeoung Baek,Yun Jung Choi,Hyeonjeong Lee,Dasom Kim,Chae Won Lee,JaeYi Jeong,K. Ban,Sang‐Yeob Kim,Wonjun Ji,Jae Cheol Lee,Hyun‐Yi Kim,Yoon Ji Lee,Yeongin Yang,Miyong Yun,Chang Choi,Jin Kyung Rho
出处
期刊:The European respiratory journal
[European Respiratory Society]
日期:2025-01-09
卷期号:65 (6): 2400615-2400615
被引量:19
标识
DOI:10.1183/13993003.00615-2024
摘要
Rationale Although a relationship between the growth arrest-specific 6 (GAS6)/anexelekto (AXL) pathway and pulmonary fibrosis has been suggested, the precise mechanisms and clinical implications of the AXL pathway in idiopathic pulmonary fibrosis are still unclear. Methods Constitutive and conditional AXL-knockout mice were generated and injected with bleomycin to induce pulmonary fibrosis. The expression of AXL and macrophage subtypes in bleomycin-injected mice and patients with idiopathic pulmonary fibrosis was analysed using flow cytometry. The therapeutic effects of the AXL inhibitors were examined. Results AXL-deficient mice were resistant to bleomycin-induced pulmonary fibrosis and had a lower degree of M2-like macrophage differentiation than wild-type mice. Interestingly, AXL expression in monocytes was enhanced according to the progression of bleomycin-induced pulmonary fibrosis, and these results were especially prominent in lymphocyte antigen 6C (Ly6C) high monocytes. Gene silencing or inhibitor treatment with AXL inhibited the differentiation of M2-like macrophages during bone marrow-derived macrophage differentiation. These results were confirmed through experiments using AXL fl/fl LysMCre+ mice and systems with depletion and reconstitution of macrophages. In line with these results, patients with severe idiopathic pulmonary fibrosis had high AXL expression in monocytes, high GAS6 levels and an enhanced population of M2-like macrophages compared to those with mild idiopathic pulmonary fibrosis. Lastly, treatment with AXL inhibitors ameliorated bleomycin-induced pulmonary fibrosis and improved survival rates. Conclusions The AXL pathway in classical monocytes contributes to pulmonary fibrosis progression through the induction of M2-like macrophage differentiation. Therefore, targeting AXL may be a promising therapeutic option for pulmonary fibrosis.
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