ALDH2 缺乏通过线粒体功能障碍和成纤维细胞老化加剧肺纤维化

IF 4.7 2区 医学 Q1 PATHOLOGY American Journal of Pathology Pub Date : 2024-08-01 DOI:10.1016/j.ajpath.2024.04.008
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引用次数: 0

摘要

特发性肺纤维化(IPF)是一种致命的间质性肺病,其特点是成纤维细胞活化和细胞外基质(ECM)异常积聚。由于对成纤维细胞异常活化的机制了解不全面,有效的治疗开发受到了限制。在这里,我们将成纤维细胞中的乙醛脱氢酶 2 (ALDH2) 作为肺纤维化的潜在治疗靶点。在 IPF 患者和博莱霉素处理的小鼠中观察到了 ALDH2 表达的减少。ALDH2 缺乏会自发诱导老年小鼠肺部胶原蛋白堆积。此外,与对照小鼠相比,年轻的 ALDH2 基因敲除小鼠表现出博莱霉素诱导的肺纤维化加重,死亡率增加。机理研究发现,转化生长因子(TGF)-β1诱导和ALDH2耗竭构成了一个正反馈回路,加剧了成纤维细胞的活化。TGF-β1 通过 TGF-β 受体 1/Smad3 依赖性机制下调 ALDH2。随后 ALDH2 的缺乏导致成纤维细胞功能障碍,表现为线粒体自噬和衰老受损,导致成纤维细胞活化和 ECM 生成。ALDH2 的过表达明显抑制了成纤维细胞的活化,而 PTEN 诱导的推定激酶 1(PINK1)的敲除则会减弱这种效应,这表明 ALDH2 的促纤维化效应是 PINK1 依赖性的。此外,Alda-1 诱导的 ALDH2 激活可逆转年轻小鼠和老年小鼠已形成的肺纤维化。总之,ALDH2 的表达可抑制肺纤维化的发病机制。上调或激活 ALDH2 表达的策略可能是治疗肺纤维化的潜在疗法。
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Aldehyde Dehydrogenase 2 Deficiency Aggravates Lung Fibrosis through Mitochondrial Dysfunction and Aging in Fibroblasts

Idiopathic pulmonary fibrosis, a fatal interstitial lung disease, is characterized by fibroblast activation and aberrant extracellular matrix accumulation. Effective therapeutic development is limited because of incomplete understanding of the mechanisms by which fibroblasts become aberrantly activated. Here, we show aldehyde dehydrogenase 2 (ALDH2) in fibroblasts as a potential therapeutic target for pulmonary fibrosis. A decrease in ALDH2 expression was observed in patients with idiopathic pulmonary fibrosis and bleomycin-treated mice. ALDH2 deficiency spontaneously induces collagen accumulation in the lungs of aged mice. Furthermore, young ALDH2 knockout mice exhibited exacerbated bleomycin-induced pulmonary fibrosis and increased mortality compared with that in control mice. Mechanistic studies revealed that transforming growth factor (TGF)-β1 induction and ALDH2 depletion constituted a positive feedback loop that exacerbates fibroblast activation. TGF-β1 down-regulated ALDH2 through a TGF-β receptor 1/Smad3-dependent mechanism. The subsequent deficiency in ALDH2 resulted in fibroblast dysfunction that manifested as impaired mitochondrial autophagy and senescence, leading to fibroblast activation and extracellular matrix production. ALDH2 overexpression markedly suppressed fibroblast activation, and this effect was abrogated by PTEN-induced putative kinase 1 (PINK1) knockdown, indicating that the profibrotic effects of ALDH2 are PINK1- dependent. Furthermore, ALDH2 activated by N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide (Alda-1) reversed the established pulmonary fibrosis in both young and aged mice. In conclusion, ALDH2 expression inhibited the pathogenesis of pulmonary fibrosis. Strategies to up-regulate or activate ALDH2 expression could be potential therapies for pulmonary fibrosis.

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来源期刊
CiteScore
11.40
自引率
0.00%
发文量
178
审稿时长
30 days
期刊介绍: The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.
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