Neutrophil Recruitment in the Reperfused-Injured Rat Liver was Effectively Attenuated by Repertaxin,a Novel Allosteric Noncompetitive Inhibitor of Cxcl8 Receptors: A Therapeutic Approach for the Treatment of Post-Ischemic Hepatic Syndromes

Abstract

Hepatic reperfusion injury represents a crucial problem in several clinical situations including liver transplantation, extensive hepatectomy and hypovolemic shock with resuscitation. Repertaxin is a new non-competive allosteric blocker of interleukin-8 (CXCL8) receptors, which by locking CXCR1/R2 in an inactive conformation, prevents receptor signaling and polymorphonuclear leukocyte (PMN) Chemotaxis. The present study shows that repertaxin dramatically prevents rat post-ischemic hepatocellular necrosis (80% of inhibition) and PMN infiltration (96% of inhibition) at a clinically-relevant time (24 h) of reperfusion. Treatment with repertaxin by continuous infusion is demonstrated to be the optimal route of administration of the compound especially in view of its clinical threrapeutic use. Because repertaxin has proven to be safe and well tolerated in different animal studies and in phase I studies in human volunteers, it is in fact a candidate novel therapeutic agent for the prevention and treatment of hepatic post-ischemic injury.