Pirfenidone has been widely used in the treatment of idiopathic pulmonary fibrosis (IPF). However, the role of pirfenidone in LPS-induced acute lung injury (ALI) remains unclear. This study aims to investigate the protective effects of pirfenidone in ALI and to explore its underlying mechanism. Pirfenidone clearly reduces LPS-triggered ALI as indicated by significant pathological alterations, reduced oxidative stress and inflammatory responses in vivo. Furthermore, pirfenidone also blocks apoptosis of LPS-induced alveolar epithelial type II (ATII) cells through inhibition of endoplasmic reticulum (ER) stress and mitochondrial injury in vivo and in vitro. A lower expression level of BAP31, an ER transmembrane protein, was found to be associated with ALI followed LPS challenge. The reintroduction of BAP31 blunted LPS induced ER stress and mitochondrial damage and therefore alleviated ATII cell apoptosis, which correlated with pirfenidone treatment. Knockdown of BAP31 expression in pirfenidone treated ATII cells re-activated ER stress, mitochondrial damage and followed cellular apoptosis. In summary, this study confirms the beneficial effect of pirfenidone on ER stress and mitochondrial dysfunction mediated apoptosis via upregulation of BAP31. Our results demonstrated that pirfenidone may be considered as a potential agent for the treatment of ALI in the future.

吡非尼酮已广泛用于治疗特发性肺纤维化（IPF）。然而，吡非尼酮在 LPS 诱导的急性肺损伤 (ALI) 中的作用仍不清楚。本研究旨在探讨吡非尼酮对 ALI 的保护作用并探讨其潜在机制。吡非尼酮明显降低了 LPS 触发的 ALI，如显着的病理改变、减少的体内氧化应激和炎症反应所示。此外，吡非尼酮还通过在体内和体外抑制内质网 (ER) 应激和线粒体损伤来阻断 LPS 诱导的肺泡上皮 II 型 (ATII) 细胞的凋亡. 发现 BAP31（一种 ER 跨膜蛋白）的较低表达水平与 LPS 攻击后的 ALI 相关。BAP31 的重新引入减弱了 LPS 诱导的内质网应激和线粒体损伤，因此减轻了与吡非尼酮治疗相关的 ATII 细胞凋亡。抑制吡非尼酮处理的 ATII 细胞中 BAP31 的表达重新激活了内质网应激、线粒体损伤和细胞凋亡。总之，本研究证实了吡非尼酮通过 BAP31 上调对 ER 应激和线粒体功能障碍介导的细胞凋亡的有益作用。我们的结果表明，吡非尼酮可能被认为是未来治疗 ALI 的潜在药物。