Acute mesenteric ischemia and reperfusion: protective effects of recombinant soluble P-selectin glycoprotein ligand-1

The effects of recombinant soluble P-selectin glycoprotein ligand-1 (rsPSGL.Ig) were studied after 120 min of splanchnic artery occlusion and 120 min of reperfusion (SAO/R). SAO/R rats administered a low-affinity mutant form of rsPSGL.Ig exhibited signs of severe circulatory collapse with marked hypotension, a survival time of only 37+/-16 min, and significant increases in intestinal myeloperoxidase (MPO) activity (P<0.01). In addition, SAO/R rats given rsPSGL.Ig low-affinity mutant showed severe endothelial dysfunction characterized by a blunted vasorelaxation to the endothelium-dependent vasodilator acetylcholine in comparison to sham-operated controls (30+/-9% vs. 97+/-3%). Administration of rsPSGL.Ig (0.5 mg/kg) significantly improved mean arterial blood pressure and increased survival time to 107+/-13 min (P <0.01). rsPSGL.Ig treatment also resulted in a significant attenuation in both intestinal MPO activity as well as the SAO/R-induced decline in endothelium-dependent vasorelaxation of superior mesenteric artery rings (P<0.01). In addition, rsPSGL.Ig attenuated in vitro neutrophil adherence to thrombin-stimulated superior mesenteric artery endothelium to a comparable degree as a P-selectin monoclonal antibody. These data suggest that rsPSGL.Ig provides beneficial effects by preserving endothelial function and attenuating neutrophil-endothelial cell interactions in the splanchnic circulation following ischemia-reperfusion.