Section of Pulmonary, Critical Care and Sleep Medicine, Dept of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
Dept of Pulmonary and Critical Care Medicine, and Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Eur Respir J. 2021 Apr 15;57(4). doi: 10.1183/13993003.00652-2020. Print 2021 Apr.
Danger signals, or damage-associated molecular patterns (DAMPs), instigate mitochondrial innate immune responses wherein mitochondrial antiviral signaling protein (MAVS) functions as a key platform molecule to mediate them. The role of MAVS in the pathogenesis of idiopathic pulmonary fibrosis (IPF), however, has not yet been identified. Whether MAVS signalling can be modulated by currently existing drugs has also not been explored.We used an established model of pulmonary fibrosis to demonstrate that MAVS is a critical mediator of multiple DAMP signalling pathways and the consequent lung fibrosis after bleomycin-induced injury After bleomycin injury, MAVS expression was mainly observed in macrophages. Multimeric MAVS aggregation, a key event of MAVS signalling activation, was significantly increased and persisted in bleomycin-injured lungs. A proapoptotic BH3 mimetic, ABT-263, attenuated the expression of MAVS and its signalling and, consequently, the development of experimental pulmonary fibrosis. In contrast, the therapeutic effects of nintedanib and pirfenidone, two drugs approved for IPF treatment, were not related to the modulation of MAVS or its signalling. Multimeric MAVS aggregation was significantly increased in lungs from IPF patients as well.MAVS may play an important role in the development of pulmonary fibrosis, and targeting MAVS with BH3 mimetics may provide a novel and much needed therapeutic strategy for IPF.
危险信号或损伤相关分子模式（DAMPs）引发线粒体固有免疫反应，其中线粒体抗病毒信号蛋白（MAVS）作为关键平台分子介导这些反应。然而，MAVS 在特发性肺纤维化（IPF）发病机制中的作用尚未确定。目前已有的药物是否可以调节 MAVS 信号也尚未得到探索。我们使用已建立的肺纤维化模型证明，MAVS 是多种 DAMPs 信号通路的关键介质，也是博来霉素诱导损伤后肺纤维化的关键介质。在博来霉素损伤后，MAVS 表达主要在巨噬细胞中观察到。多聚 MAVS 聚集，是 MAVS 信号激活的关键事件，在博来霉素损伤的肺中显著增加并持续存在。一种促凋亡 BH3 模拟物 ABT-263 可减弱 MAVS 的表达及其信号转导，从而减轻实验性肺纤维化的发生。相比之下，两种批准用于 IPF 治疗的药物尼达尼布和吡非尼酮的治疗效果与 MAVS 或其信号的调节无关。IPF 患者的肺中也明显增加了多聚 MAVS 聚集。MAVS 可能在肺纤维化的发展中起重要作用，用 BH3 模拟物靶向 MAVS 可能为 IPF 提供一种新的、非常需要的治疗策略。
