Small β2-Glycoprotein I Peptides Protect from Intestinal Ischemia Reperfusion Injury

Abstract

Intestinal ischemic events, which are followed by reperfusion, induce significant tissue damage and frequently result in multiple organ failure, with >70% mortality. Upon reperfusion, excessive inflammation leads to exacerbated tissue damage. Previous studies indicated that binding of the serum protein, β2-glycoprotein I, to the endothelium initiates a cascade of inflammatory molecules that is required for damage. We hypothesized that peptides derived from the binding domain (domain V) of β2-glycoprotein I would attenuate ischemia/reperfusion-induced damage and inflammation in a therapeutic manner. Using a mouse model of intestinal ischemia/reperfusion, we administered peptides either prior to ischemia or at clinically relevant time points during reperfusion and evaluated intestinal tissue damage and inflammation after 2 h of reperfusion. We demonstrate that multiple peptides attenuate injury and inflammation in a dose-dependent manner and, perhaps more significantly, are efficacious when administered up to 30 min after the onset of reperfusion. In addition, an all D-amino acid retro-inverso peptide was biologically active. Thus, the β2-glycoprotein I-derived peptides attenuate injury and inflammation when administered in a therapeutic manner in intestinal ischemia/reperfusion injury.