Sacubitril/valsartan alleviates sepsis-induced acute lung injury via inhibiting GSDMD-dependent macrophage pyroptosis in mice
Sacubitril/valsartan alleviates sepsis-induced acute lung injury via inhibiting GSDMD-dependent macrophage pyroptosis in mice
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DOI：
10.1111/febs.16696
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发表时间：
2023-01-04
期刊：
影响因子：
5.4
通讯作者：
Li，Xu
中科院分区：
文献类型：
--
作者：
Wang，Jun;Li，Jierui;Li，Xu
脓毒症引起的急性肺损伤（ALI）是一种具有复杂发病机制的危及生命的疾病。据报道，巨噬细胞焦亡在ALI中起重要作用。虽然已经确定血管紧张素受体阻滞剂（ARB）可以减少脓毒症诱导的器官损伤，但沙库巴曲/缬沙坦（SV）治疗脓毒症的疗效在很大程度上尚未得到充分研究。在此，我们旨在研究SV在脓毒症诱导的ALI中的作用。采用盲肠结扎穿孔法（CLP）诱导多菌性脓毒症及相关ALI。随后评估SV在CLP小鼠中的治疗效果。Gasdermin D（GSDMD）−/−小鼠用于验证受SV影响的信号通路。在体外，小鼠骨髓源性巨噬细胞（BMDM）和Raw 264.7细胞在暴露于脂多糖和三磷酸腺苷后用SV处理。最后，从42名脓毒症患者获得的血清用于生化分析。与其他ARB相比，SV对巨噬细胞的抗炎作用更为显著。在体内，SV降低了CLP小鼠的死亡率，显著减轻了肺损伤，并防止了炎症反应。此外，SV抑制小鼠中GSDMD介导的巨噬细胞焦亡。在BMDM和Raw 264.7细胞中，验证了SV的抗炎和抗焦亡特性。SV处理以GSDMD依赖性方式有效抑制NLRP 3炎性体活化并防止巨噬细胞焦亡。此外，我们发现脓毒症患者血清血管紧张素II水平显著升高。总体而言，我们发现SV可能通过抑制GSDMD介导的巨噬细胞焦亡来预防CLP小鼠的ALI。因此，SV可能是治疗脓毒症诱导的ALI的可行药物。
Sepsis‐induced acute lung injury (ALI) is a life‐threatening disorder with intricate pathogenesis. Macrophage pyroptosis reportedly plays a vital role in ALI. Although it has been established that angiotensin receptor blockers (ARBs) can reduce sepsis‐induced organ injury, the efficacy of sacubitril/valsartan (SV) for sepsis has been largely understudied. Here, we aimed to investigate the role of SV in sepsis‐induced ALI. Caecal ligation and puncture (CLP) were used to induce polymicrobial sepsis and related ALI. The therapeutic effects of SV in CLP mice were subsequently assessed. Gasdermin D (GSDMD)−/−mice were used to validate the signalling pathways affected by SV.In vitro, mouse bone marrow‐derived macrophages (BMDMs) and Raw264.7 cells were treated with SV following exposure to lipopolysaccharide and adenosine triphosphate. Finally, the serum obtained from 42 septic patients was used for biochemical analysis. Compared to the other ARBs, SV yielded more pronounced anti‐inflammatory effects on macrophages.In vivo, SV decreased mortality rates, significantly reduced lung damage and prevented the inflammatory response in CLP mice. In addition, SV suppressed GSDMD‐mediated macrophage pyroptosis in mice. In BMDMs and Raw264.7 cells, the anti‐inflammatory and anti‐pyroptosis properties of SV were verified. SV treatment effectively inhibited NLRP3 inflammasome activation and prevented macrophage pyroptosis in a GSDMD‐dependent manner. Furthermore, we found that septic individuals had considerably higher serum angiotensin II levels. Overall, we found that SV might prevent ALI in CLP mice by inhibiting GSDMD‐mediated pyroptosis of macrophages. Thus, SV might be a viable drug for sepsis‐induced ALI.