Protective effect of ethyl pyruvate on gut barrier function through regulations of ROS-related NETs formation during sepsis.

Abstract

BACKGROUND:

Sepsis impairs the function of the intestinal barrier through neutrophil extracellular traps (NETs). Reactive oxygen species (ROS)-induced activation of mitogen-activated protein kinase (MAPK) is involved in NET formation. Ethyl pyruvate (EP), a potent and effective ROS scavenger, ameliorates sepsis-associated intestinal barrier dysfunction, but the detailed mechanism is unknown. The current study aimed to explore the eff ;ects of EP on sepsis-induced intestinal barrier dysfunction and whether ROS and NETs were involved.

METHODS:

A sepsis model was induced in mice by intraperitoneal injection of LPS (10 mg/kg). The mice were divided into 4 groups: (1) sham group; (2) LPS group; (3) DNase-1 + LPS group; and (4) EP + LPS group. EP or DNase-1 was intraperitoneally injected after the LPS model was established. After 24 h, the small intestine and blood were collected for analysis. Human neutrophils were harvested and incubated with phorbol-12-myristate-13-acetate (PMA) or PMA + EP, and ROS and NET generation was measured.

RESULTS:

EP significantly decreased proinflammatory cytokines and MPO-DNA in the LPS model. In addition, EP suppressed NET formation in the intestines of endotoxemic mice. The decrease in NETs induced by EP or DNase-1 alleviated histopathological damage, intestinal cell apoptosis and increased tight junction expression. In vitro, the treatment of EP abolished PMA-induced ROS production and NET formation which could be reversed by H2O2 treatment. Meanwhile, EP also abolished MAPK ERK1/2 and p38 activation during PMA-induced NET formation.

CONCLUSION:

This study was the first to demonstrate that EP alleviated NET formation and sepsis-induced intestinal damage through blockage of ROS mediated MAPK ERK1/2 and p38 activation.

• Authors: Xinyu Wang, Shilong Sun, Zehua Duan, Chao Yang, Chengnan Chu, Kai Wang, Baochen Liu, Weiwei Ding, Weiqin Li, Jieshou Li
• Journal: Molecular immunology (Mol Immunol) Vol. 132 Pg. 108-116 (04 2021) ISSN: 1872-9142 [Electronic] England
• PMID: 33581408 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Ltd. All rights reserved.

Chemical References

• Protective Agents
• Pyruvates
• Reactive Oxygen Species
• ethyl pyruvate
• Hydrogen Peroxide
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases

Topics

• Animals
• Extracellular Traps (drug effects, metabolism)
• Hydrogen Peroxide (metabolism)
• Intestine, Small (drug effects, metabolism)
• MAP Kinase Signaling System (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Mitogen-Activated Protein Kinases (metabolism)
• Neutrophils (drug effects, metabolism)
• Protective Agents (pharmacology)
• Pyruvates (pharmacology)
• Reactive Oxygen Species (metabolism)
• Sepsis (drug therapy, metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)