Sepsis is among the most devastating events in intensive care units. As a complication of sepsis, acute lung injury (ALI) is common and highly associated with poor outcome. The present study demonstrated that abnormal mitochondrial dynamics play a pivotal role in lipopolysaccharide (LPS)-induced ALI. Inhibiting the mitochondrial fission with the specific inhibitor-1 (Mdivi-1) ameliorated ALI as assessed by hematoxylin and eosin (H&E) staining and wet/dry ratio. Furthermore, Mdivi-1 reduced mitogen-activated protein kinases (MAPKs) activation, oxidative stress and apoptosis in the lungs. Plasma pro-inflammation cytokines were also reduced significantly in Mdivi-1-treated mice. In vitro study revealed that Mdivi-1 protected the macrophages from LPS-induced MAPKs activation, oxidative stress and cell apoptosis. Mdivi-1 also inhibited the release of pro-inflammatory cytokines. Morphological analysis showed that Mdivi-1 rescued the macrophages from LPS-induced mitochondrial fragmentation. Moreover, LPS treatment induced significant phosphorylation of Drp1 at Ser616, dephosphorylation at Ser637 and translocation of Drp1 from the cytoplasm to mitochondria, while Mdivi-1 inhibited those effects. Thus, modification of fission to rebuild mitochondrial homeostasis may offer an innovative opportunity for developing therapeutic strategies against ALI.

脓毒症是重症监护病房中最具破坏性的事件。作为败血症的并发症，急性肺损伤（ALI）很常见，并且与不良预后高度相关。本研究表明异常的线粒体动力学在脂多糖（LPS）诱导的ALI中起关键作用。通过苏木精和曙红（H＆E）染色和干/湿比评估，用特异性抑制剂-1（Mdivi-1）抑制线粒体裂变可改善ALI。此外，Mdivi-1减少了肺中的丝裂原活化蛋白激酶（MAPK）活化，氧化应激和细胞凋亡。在Mdivi-1治疗的小鼠中，血浆促炎细胞因子也显着减少。体外研究表明，Mdivi-1保护巨噬细胞免受LPS诱导的MAPKs活化，氧化应激和细胞凋亡的影响。Mdivi-1还抑制促炎细胞因子的释放。形态分析表明，Mdivi-1从LPS诱导的线粒体片段解救中拯救了巨噬细胞。此外，LPS处理诱导了Ser616处Drp1的显着磷酸化，Ser637处的去磷酸化以及Drp1从细胞质到线粒体的转运，而Mdivi-1抑制了这些作用。因此，裂变的改造以重建线粒体的稳态可能为开发针对ALI的治疗策略提供了创新的机会。