Department of Thoracic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, PR China.
Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200080, PR China.
Arch Biochem Biophys. 2020 Oct 30;693:108562. doi: 10.1016/j.abb.2020.108562. Epub 2020 Aug 28.
Previous studies have suggested that pyroptosis may play an important role in LPS-induced acute lung injury (ALI), but the exact mechanism of pyroptosis induction and the role of Angiotensin-converting enzyme 2 (ACE2)/Ang (1-7)/Mas axis in pyroptosis has not been investigated yet. The present study aimed to establish a mice model of ALI and clarify the involvement of pyroptosis and ACE2/Ang (1-7)/Mas axis. The results showed that LPS induced pyroptosis in lung, demonstrated by increased expression of Gasdermin D (GSDMD), cleaved GSDMD, IL-1β, and Caspase-1. Treatment of Ang (1-7) significantly reduced the severity of ALI and pyroptosis, while AngII significantly exaggerated them. Furthermore, ACE2 activator resorcinolnaphthalein (RES) significantly reduced the severity of ALI and pyroptosis, but ACE2 inhibitor MLN-4760 and Mas inhibitor A779 significantly exaggerated them, suggesting that the ACE2/Ang (1-7)/Mas axis was involved in the pyroptosis in LPS-induced ALI. In addition, Ang (1-7) and RES significantly decreased the levels of NLRP3, which were increased by AngII and A779. NLRP3 knockout significantly reduced the severity of ALI and pyroptosis. In conclusion, pyroptosis played an important role in ALI induced by LPS. The ACE2/Ang (1-7)/Mas axis negatively regulated the pyroptosis and protected mice against LPS-induced ALI through NLRP3 inhibition. The present study expanded our understating of the role of ACE2/Ang (1-7)/Mas axis in ALI by providing a novel explanation that it may regulate the pyroptosis in ALI.
先前的研究表明，细胞焦亡可能在脂多糖诱导的急性肺损伤（ALI）中发挥重要作用，但细胞焦亡的诱导机制以及血管紧张素转换酶 2（ACE2）/血管紧张素（1-7）/Mas 轴在细胞焦亡中的作用尚未得到研究。本研究旨在建立 ALI 小鼠模型，阐明细胞焦亡和 ACE2/血管紧张素（1-7）/Mas 轴的作用。结果表明，LPS 诱导肺细胞焦亡，表现为 Gasdermin D（GSDMD）、切割 GSDMD、IL-1β 和 Caspase-1 的表达增加。血管紧张素（1-7）的治疗显著减轻了 ALI 和细胞焦亡的严重程度，而血管紧张素 II（AngII）则显著加剧了它们的作用。此外，ACE2 激活剂间苯二酚萘酚（RES）显著减轻了 ALI 和细胞焦亡的严重程度，但 ACE2 抑制剂 MLN-4760 和 Mas 抑制剂 A779 则显著加剧了它们的作用，提示 ACE2/血管紧张素（1-7）/Mas 轴参与了 LPS 诱导的 ALI 中的细胞焦亡。此外，血管紧张素（1-7）和 RES 显著降低了 NLRP3 的水平，而 AngII 和 A779 则使其升高。NLRP3 敲除显著减轻了 ALI 和细胞焦亡的严重程度。综上所述，细胞焦亡在 LPS 诱导的 ALI 中发挥了重要作用。ACE2/血管紧张素（1-7）/Mas 轴通过抑制 NLRP3 负调控细胞焦亡，并通过抑制 NLRP3 负调控细胞焦亡来保护小鼠免受 LPS 诱导的 ALI。本研究通过提供一种新的解释，即 ACE2/血管紧张素（1-7）/Mas 轴可能调节 ALI 中的细胞焦亡，从而扩展了我们对 ACE2/血管紧张素（1-7）/Mas 轴在 ALI 中的作用的认识。
