Sacubitril/valsartan alleviates sepsis‐induced acute lung injury via inhibiting GSDMD‐dependent macrophage pyroptosis in mice

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. Here, we show that sacubitril/valsartan (SV) reduces the levels of local and systemic inflammatory cytokines, histological damage, inflammatory cell infiltration and pyroptosis in the sepsis‐induced acute lung injury (ALI) mouse model used. SV reduces NLRP3 inflammasome activation, which in sepsis promotes Gasdermin D (GSDMD)‐mediated macrophage pyroptosis. Additionally, we discovered that SV blocked the GSDMD pathway‐linked pyroptosis in macrophages. Overall, we established the crucial protective role of SV in sepsis‐induced ALI.