CIRP contributes to multiple organ damage in acute pancreatitis by increasing endothelial permeability.

Abstract

Acute pancreatitis can lead to systemic inflammation and multiple organ damage. Increased endothelial permeability is a hallmark of systemic inflammation. Several studies have demonstrated that cold-inducible RNA-binding protein (CIRP) functions as a proinflammatory factor in various diseases. However, its role in endothelial barrier dysfunction during acute pancreatitis remains unknown. To study this, acute pancreatitis was induced by two hourly intraperitoneal injections of 4.0 g/kg L-arginine in wild-type (WT) or CIRP knockout mice. Our results showed that CIRP levels in the pancreas, small intestine, lung, and liver were upregulated at 72 h after the induction of acute pancreatitis in WT mice. CIRP deficiency significantly attenuated tissue injury, edema, and extravasation of Evans blue in the pancreas, small intestine, lung, and liver at 72 h after L-arginine injection. Administration of C23, a specific antagonist of CIRP, at 2 h after the last injection of L-arginine also produced similar protective effects as CIRP knockout in mice. In vitro studies showed that recombinant CIRP caused a significant reduction in transcellular electric resistance in HUVEC monolayers. Immunocytochemical analysis of endothelial cells exposed to CIRP revealed an increased formation of actin stress fibers. VE-cadherin and β-catenin staining showed intercellular gaps were formed in CIRP-stimulated cells. Western blot analysis showed that CIRP induced SRC phosphorylation at TYR416. Exposure to the SRC inhibitor PP2 reduced CIRP-induced endothelial barrier dysfunction in HUVEC monolayers. In conclusion, blocking CIRP mitigates acute pancreatitis-induced multiple organ damage by alleviating endothelial hyperpermeability. Targeting CIRP may be a potential therapeutic option for acute pancreatitis.