A MULTIPLE DAMAGE-ASSOCIATED MOLECULAR PATTERN-SCAVENGING COMPOUND OP18 ATTENUATES HEPATIC ISCHEMIA/REPERFUSION INJURY.

Abstract

Abstract: Introduction: Hepatic ischemia-reperfusion (I/R) can cause further liver injury through a cascade of complex cellular events. Damage-associated molecular patterns (DAMPs) released from stressed or damaged cells in the liver contribute to this pathology, leading to hyperinflammation, organ tissue damage, and high mortality. We have developed a novel compound, Opsonin Peptide 18, which exhibits strong binding affinity for multiple DAMPs, including extracellular cold-inducible RNA-binding protein, high-mobility group box 1, and histone H3, thereby enhancing the clearance of those DAMPs by phagocytic cells. In this study, we hypothesized that Opsonin Peptide 18 mitigates hepatic I/R injury by suppressing DAMPs-induced inflammation. Methods: Adult C57BL/6 mice were subjected to 70% hepatic ischemia for 60 min immediately followed by intraperitoneal ( i.p. ) administration of either formic acid in PBS (vehicle) or 0.2 mg/kg body weight OP18 (treatment). After 24 h, blood and liver tissues were collected for the measurement of systemic inflammatory markers, including cytokines, liver enzymes, chemokines, and myeloperoxidase activity. Liver tissue damage and cell death were evaluated histologically. The survival rate was monitored for 10 days post hepatic I/R. Results: In the hepatic I/R mouse model, OP18 treatment significantly decreased the elevated plasma levels of IL-6, TNFα, IL-1β, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase compared to vehicle group. Moreover, OP18 markedly decreased liver tissue mRNA levels of IL-6, TNFα, IL-1β, macrophage inflammatory protein-2, keratinocyte chemoattractant, and Z-DNA-binding protein 1, as well as myeloperoxidase activity. Histological analysis revealed that OP18 treatment significantly attenuated liver tissue damage and cell death in hepatic I/R mice. Furthermore, the administration of OP18 significantly improved the survival after hepatic I/R injury. Conclusions: OP18 mitigates inflammation and tissue damage following hepatic I/R injury and improves survival. Thus, OP18 has potential as a promising therapeutic strategy for hepatic I/R injury.