Abstract Rationale Recruitment of polymorphonuclear (PMN) cells during acute inflammation constitutes a fundamental component of the innate immune response to triggers such as viral or bacterial pathogens. Selectins and their counter ligand P-selectin glycoprotein ligand-1 (PSGL-1), mediate the initial temporary binding of PMN cells to activate endothelial cells and promote platelet aggregation, intravascular thrombosis, microangiopathy, and increased vascular permeability during inflammation. We have previously shown that inhibition of P-selectin/PSGL-1 interactions mitigate lung inflammation and kidney injury in small animal rodent models of lung injury. We now utilize a clinically-relevant large animal porcine model of sepsis/ARDS to test the therapeutic effectiveness of TSGL-Ig, a novel recombinant tandem PSGL-1 immunoglobulin fusion molecule that competitively inhibits PSGL-1/P-selectin interactions. Methods Yucatan male minipigs exposed to IV/IT-delivered LPS/VILI (12 h) received IV PBS (control) or TSGL-Ig (1 mg/kg) 2 h after initiation of septic shock/VILI. Acute lung injury severity was assessed by bronchoalveolar lavage (BAL), physiological, histological, and biochemical parameters. Lung fluid balance was assessed by BAL protein, lung wet/dry ratios, and lung ultrasound B-line quantification. Results When compared to PBS, TSGL-Ig treatment 2 h after LPS/VILI significantly decreased BAL cell count (47% decrease) and protein (47.7 % decrease), p=0.009, p=0.01, respectively. Lung wet to dry ratio and number of B-lines on lung ultrasound were significantly decreased in TSGL-Ig treated minipigs compared to PBS. The amount of reduction in the static and dynamic compliances of the respiratory system was significantly attenuated by TSGL-Ig. Both plasma lipocalin-2 increases (biomarker of acute kidney injury) and the severity of tubular necrosis in renal tissues were significantly attenuated with TSGL-Ig. Conclusion These studies strongly validate the efficacy of TSGL-Ig to alleviate lung and multiorgan inflammation in a clinically-relevant large animal model of sepsis/ARDS. This abstract is funded by: NIH
Bime et al. (Fri,) studied this question.