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

Abstract

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) À/À 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.

Role of the Renin Angiotensin Aldosterone System in the Pathogenesis of Sepsis-Induced Acute Kidney Injury: A Systematic Review

“…A similar study using a dual inhibitor of neprilysin and ACE on septic mice found consistent results, including decreased levels of pro-inflammatory cytokines and evidence of lung protection on histology [82]. Similar findings were seen using Sacubitril/valsartan, a dual inhibitor of neprilysin, and an ARB [83]. The inhibition of the RAAS, whether by gene knockout or the use of an antagonist, demonstrated improvements in several organs, including the heart, spleen, and lungs, and improved overall survival.…”

“…The use of RAAS antagonists as a therapeutic option in sepsis has recently been considered, with emerging studies that help form a greater understanding of the role of RAAS inhibitors in sepsis. Several studies observed decreased rates of S-AKI, renal tissue damage, and levels of pro-inflammatory cytokines and oxidative stress with the use of RAAS antagonists as treatment during sepsis [84][85][86], as well as evidence of their playing a protective role in other organs, including the lung [81][82][83], heart [78][79][80], and spleen [79]. RAAS inhibitors modulate the activity of angiotensin II and minimize its downstream effects on inflammation and coagulation.…”