Activation of GPR81 aggravated intestinal ischemia/reperfusion injury-induced acute lung injury via HMGB1-mediated neutrophil extracellular traps formation

• Published in: International journal of immunopathology and pharmacology 2023-08, Vol.37, p.3946320231193832
• Main Authors: Yili, Sun, Xinyi, Dai, Kerui, Fan, Kun, Chen, Yang, Yongqiang, Zhang, Li, Hu, Kai
• Format: Article
• Language: English
• Subjects: Alveoli; Citrulline; Enzyme-linked immunosorbent assay; G protein-coupled receptors; Histone H3; Histones; HMGB1 protein; Hyperlactatemia; Interleukin 6; Intestine; Ischemia; Lavage; Leukocytes (neutrophilic); Lungs; Microvasculature; Neutrophils; Original; Peroxidase; Reperfusion
• ISSN: 0394-6320; 2058-7384; 2058-7384
• DOI: 10.1177/03946320231193832

Introduction Intestinal ischemia/reperfusion (II/R) injury is a life-threatening situation accompanied by severe organ injury, especially acute lung injury (ALI). A great body of evidence indicates that II/R injury is usually associated with hyperlactatemia. G-protein-coupled receptor 81 (GPR81), a receptor of lactate, has been recognized as a regulatory factor in inflammation, but whether it was involved in II/R injury-induced ALI is still unknown. Methods To establish the II/R injury model, the superior mesenteric artery of the mice was occluded gently by a microvascular clamp for 45 min to elicit intestinal ischemia and then a 90-min reperfusion was performed. Broncho-alveolar lavage fluid (BALF) and lung tissues were obtained to evaluate the lung injury after II/R. The pulmonary histopathological alteration was evaluated by H&E staining. The concentration of proteins, the number of infiltrated cells, and the level of IL-6 were measured in BALF. The formation of neutrophil extracellular traps (NETs) was evaluated by the level of double-stranded DNA (dsDNA) and myeloperoxidase- double-stranded DNA (MPO-dsDNA) complex in BALF, and the content of citrullinated histone H3 (Cit-H3) in lung tissue. The level of HMGB1 in the BALF and plasma was measured by enzyme linked immunosorbent assay (ELISA). Results Administration of the GPR81 agonist 3,5-dihydroxybenzoic acid (DHBA) aggravated II/R injury-induced lung histological abnormalities, upregulated the concentration of proteins, the number of infiltrated cells, and the level of IL-6 in BALF. In addition, DHBA treatment increased the level of dsDNA and MPO-dsDNA complex in BALF, and promoted the elevation of Cit-H3 in lung tissue and the release of HMGB1 in BALF and plasma. Conclusion After induction of ALI by II/R, the administration of DHBA aggravated ALI through NETs formation in the lung.