PMID- 36471663 OWN - NLM STAT- MEDLINE DCOM- 20230420 LR - 20230420 IS - 1742-4658 (Electronic) IS - 1742-464X (Linking) VI - 290 IP - 8 DP - 2023 Apr TI - Sacubitril/valsartan alleviates sepsis-induced acute lung injury via inhibiting GSDMD-dependent macrophage pyroptosis in mice. PG - 2180-2198 LID - 10.1111/febs.16696 [doi] AB - 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. CI - (c) 2022 Federation of European Biochemical Societies. FAU - Wang, Jun AU - Wang J AUID- ORCID: 0000-0003-1680-7872 AD - Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China. AD - Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China. FAU - Li, Jierui AU - Li J AD - Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China. FAU - Lou, Anni AU - Lou A AD - Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China. FAU - Lin, Ying AU - Lin Y AD - Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China. FAU - Xu, Qihan AU - Xu Q AD - Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China. FAU - Cui, Wanfu AU - Cui W AD - Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China. FAU - Huang, Weichang AU - Huang W AD - Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China. FAU - Wang, Guozhen AU - Wang G AD - Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China. FAU - Li, Yang AU - Li Y AD - Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China. FAU - Sun, Jing AU - Sun J AD - Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China. FAU - Gong, Jiacheng AU - Gong J AD - Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China. FAU - Guo, Qiuping AU - Guo Q AD - Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China. FAU - Qiu, Hongshen AU - Qiu H AD - Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China. FAU - Meng, Ying AU - Meng Y AD - Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China. FAU - Li, Xu AU - Li X AD - Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China. AD - Ministry of Education, Key Laboratory of Hainan Trauma and Disaster Rescue, College of Emergency and Trauma, Hainan Medical University, Haikou, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230104 PL - England TA - FEBS J JT - The FEBS journal JID - 101229646 RN - 0 (Angiotensin Receptor Antagonists) RN - 0 (Angiotensin-Converting Enzyme Inhibitors) RN - 0 (Inflammasomes) RN - 0 (Lipopolysaccharides) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 17ERJ0MKGI (sacubitril) RN - 80M03YXJ7I (Valsartan) SB - IM MH - Animals MH - Mice MH - *Acute Lung Injury/drug therapy/etiology MH - Angiotensin Receptor Antagonists MH - Angiotensin-Converting Enzyme Inhibitors MH - Inflammasomes/metabolism MH - Lipopolysaccharides MH - Macrophages/metabolism MH - Mice, Inbred C57BL MH - NLR Family, Pyrin Domain-Containing 3 Protein/genetics MH - *Sepsis/complications/drug therapy MH - Valsartan/pharmacology OTO - NOTNLM OT - acute lung injury OT - macrophage OT - pyroptosis OT - sacubitril/valsartan OT - sepsis EDAT- 2022/12/07 06:00 MHDA- 2023/04/20 10:17 CRDT- 2022/12/06 01:43 PHST- 2022/10/25 00:00 [revised] PHST- 2022/07/21 00:00 [received] PHST- 2022/12/05 00:00 [accepted] PHST- 2023/04/20 10:17 [medline] PHST- 2022/12/07 06:00 [pubmed] PHST- 2022/12/06 01:43 [entrez] AID - 10.1111/febs.16696 [doi] PST - ppublish SO - FEBS J. 2023 Apr;290(8):2180-2198. doi: 10.1111/febs.16696. Epub 2023 Jan 4.