A multi-damage-associated molecular pattern targeting opsonic peptide attenuates gut ischemia/reperfusion-induced lung injury.

Abstract

Gut ischemia-reperfusion induces the release of damage-associated molecular patterns (DAMPs), exacerbating inflammation and organ injury and reducing survival. We recently developed a multi-damage-associated molecular pattern scavenging molecule, named opsonic peptide 18, which promotes the clearance of multiple damage-associated molecular patterns by phagocytes. The present study aims to investigate the therapeutic potential of opsonic peptide 18 in gut ischemia-reperfusion-induced lung injury. Male C57BL6/J mice underwent superior mesenteric artery occlusion and were treated with intraperitoneal opsonic peptide 18 or vehicle at the time of reperfusion. Blood and lungs were collected 4 hours after gut ischemia-reperfusion. Systemic levels of interleukin-6, alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase were determined. The pulmonary gene expression of cytokines (interleukin-6, interleukin-1β) and chemokines (macrophage-inflammatory protein-2, keratinocyte-derived chemokine) was also assessed. In addition, lung myeloperoxidase activity, tissue injury, and cell death were determined. Mice were monitored for 72 hours after gut ischemia-reperfusion for assessment of overall survival rate. Opsonic peptide 18 treatment significantly decreased serum interleukin-6, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase levels by 45%, 32%, 59%, and 48%, respectively, compared with the vehicle-treated group in gut ischemia-reperfusion mice. Furthermore, opsonic peptide 18 administration decreased mRNA levels of interleukin-6, interleukin-1β, inducible NO synthase, keratinocyte-derived chemokine, and macrophage-inflammatory protein-2 in the lungs by 73.2%, 75.3%, 77.5%, 63.9%, and 64.3%, respectively. Opsonic peptide 18 attenuated myeloperoxidase activity, histologic tissue injury, and cell death in the lungs. Administration of opsonic peptide 18 significantly improved the survival of gut ischemia-reperfusion mice. Opsonic peptide 18, a novel multi-damage-associated molecular pattern scavenger, reduces inflammation and mitigates gut ischemia-reperfusion-induced lung injury. Simultaneous targeting of multiple damage-associated molecular patterns is as a promising therapeutic strategy to alleviate gut ischemia-reperfusion-induced lung inflammation and injury.