Polyunsaturated fatty acid-derived lipid mediator Resolvin D1 alleviates sepsis-induced disseminated intravascular coagulation via Caspase-1/Gasdermin D pyroptotic pathway

Wenyan Zhang; Suwas Bhandari; Yajun Ding; Jun Luo; Bo Feng; Yating Jiang; Ting Chen; Jinling Wei; Xiaodong Pan; Haixu Weng; Zhangna Ding; Jie Chen; Xi Chen; Yuqiang Gong; Hui Li; Shengwei Jin; Yu Hao

doi:10.1016/j.clnu.2024.04.020

Polyunsaturated fatty acid-derived lipid mediator Resolvin D1 alleviates sepsis-induced disseminated intravascular coagulation via Caspase-1/Gasdermin D pyroptotic pathway

Clin Nutr. 2024 Apr 20;43(6):1372-1383. doi: 10.1016/j.clnu.2024.04.020. Online ahead of print.

Authors

Wenyan Zhang¹, Suwas Bhandari¹, Yajun Ding¹, Jun Luo², Bo Feng¹, Yating Jiang¹, Ting Chen¹, Jinling Wei¹, Xiaodong Pan³, Haixu Weng⁴, Zhangna Ding⁴, Jie Chen⁵, Xi Chen⁶, Yuqiang Gong⁷, Hui Li⁸, Shengwei Jin⁹, Yu Hao¹⁰

Affiliations

¹ Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou 325027, China.
² Department of Pharmacy, Taizhou Women and Children's Hospital of Wenzhou Medical University, Taizhou 317599, China.
³ Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou 325027, China; Department of Emergency Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China.
⁴ Department of Critical Care Medicine, The Third Affiliated Hospital of Wenzhou Medical University, Ruian 325207, China.
⁵ Department of Emergency, Third Affiliated Hospital, Wenzhou Medical University, Ruian 325207, China.
⁶ Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou 325027, China.
⁷ Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China. Electronic address: gyq12120@163.com.
⁸ Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou 325027, China. Electronic address: judy198406@sina.com.
⁹ Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou 325027, China. Electronic address: jsw@wmu.edu.cn.
¹⁰ Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou 325027, China. Electronic address: haoyu8403@163.com.

PMID: 38678822
DOI: 10.1016/j.clnu.2024.04.020

Abstract

Background & aims: Sepsis-induced disseminated intravascular coagulation (DIC) is characterised by abnormal blood clotting resulting from severe infection, contributing to organ dysfunction in sepsis. Resolvin D1 (RvD1) is an endogenous lipid mediator, synthesised from the omega-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) through enzymatic processes involving 15-LOX and 5-LOX. RvD1 is recognised for its protective properties against various inflammatory conditions. This study aims to investigate its potential to modulate coagulation dysfunction in sepsis and to evaluate coagulation disorders in septic patients.

Methods: Sepsis models were established by intraperitoneal injection LPS (20 mg/kg) or cecal ligation and puncture (CLP) followed by injection of RvD1 (10 μg/kg) or saline. The impact of RvD1 on coagulation dysfunction was assessed by clotting time and coagulation indicators such as TAT, D-dimer, PAI-1, and fibrinogen. The activity of the coagulation system in vivo was observed by evaluating dynamic microcirculation, platelets and thrombin in mice using intravital microscopy. The effect of RvD1 on pyroptosis was investigated by measuring NOD-like receptor protein 3 (NLRP3), Caspase-1, Caspase-11, and Gasdermin D (GSDMD) levels via western blot. Caspase-1 knockout mice, GSDMD knockout mice and bone marrow-derived macrophages (BMDMs) were used to elucidate the underlying mechanisms. Lastly, the concentration of RvD1 in plasma from septic patients was quantified to explore its relationship with coagulation and pyroptosis.

Results: RvD1 significantly attenuated coagulation dysfunction in septic mice induced by LPS and CLP, and inhibited Caspase-1/GSDMD-dependent pyroptosis in septic mice and bone marrow-derived macrophages. In septic patients, the plasma concentrations of RvD1 was negatively correlated with both coagulation-related indicators and markers of GSDMD activation.

Conclusion: The results suggest that RvD1 can improve coagulation dysfunction in sepsis by regulating the Caspase-1/GSDMD pyroptotic pathway. Additionally, the concentration of RvD1 in septic patient plasma is related to prognosis and DIC development. RvD1 could be a potential biomarker and a promising therapeutic alternative in sepsis-induced DIC.

Keywords: Caspase-1; Disseminated intravascular coagulation; Pyroptosis; Resolvin D1; Sepsis.