Protective role of p-selectin glycoprotein ligand-1 (PSGL-1) during the early phase of ischemia- and ischemia/reperfusion (I/R)-induced intestinal mucosal barrier dysfunction

Background: All three select in family members (P.E and L) have been implicated as mediators of neutrophil migration through the endothelium during I/R injury. We hypothesized that PSGL-1, a homodimeric mucin which can bind all three selectins, would ameliorate intestinal mucosal and pulmonary capillary hyperpermeability in a rat model of superior mesenteric artery (SMA) occlusion and reperfusion. Methods: To investigate the role of selectins in intestinal I/R injury. PSGL-1 (0.4 mg/kg, i.v bolus) or vehicle (n=6/group) were administered 5 min prior to 60-min ischemia and 1 min prior to 60-min reperfusion. Five segments of small intestine were isolated at baseline (BL), 30- and 60-min ischemia (130 and 160, respectively), and 30- and 60-min reperfusion (R30 and R60, respectively). Intestinal permeability was assessed using an everted gut sac technique by measuring the mucosal-to-serosal clearance (nl/min/cm²) of fluorescently labelled dextran (MW=4 kDa: FD4). Serosal and mucosal blood flow (SBF and MBF, respectively) were monitored by Doppler Laser flowmetry. To evaluate remote lung injury. FD4 (5 mg/kg, i.v bolus) was given 30 min prior to SMA occlusion (n=6/group). Bronchoalveolar lavage (BAL) of right lung was obtained at the end of the R60 period for determination of BAL/plasma ratio (%BPR), white blood cell count (wbc: ×10⁴cells/ml), and protein concentration (μg/ml). Percent total water content (TW) of the left lung was also determined. Results: SBF and MBF were not significantly different between the two groups. Time Intestinal clearance PSGL-1 Vehicle BL 4.2±0.6 3.6±0.7 130 7.3±1.1*, a 23.0±1.7 a 160 31.6±6.9 a 47.1±4.7 a R30 26.2±3,8*, a 41.1±6.3 a R60 33.3±6.2 a 34.5±10.2 a Parameter Remote lung injury PSGL-1 Vehicle %BPR 1.6±0.4 1.8±0.5 wbc 3.7±1.3 5.2±2.2 protein 630.1±28.8 705±129.8 %TW 73.2±4.8 77.9±1.0*p<0.05, PSGL-1 vs vehicle: a p<0.05.vs BL Conclusion: These data support the idea that selectins play a role in the pathogenesis of I/R-induced gut mucosal hyperpermeability, but also suggest that other factors, not blocked by PSGL-1, are important as well.