Soluble P-selectin rescues viper venom-induced mortality through anti-inflammatory properties and PSGL-1 pathway-mediated correction of hemostasis

Abstract

Venomous snakebites are lethal and occur frequently worldwide each year, and receiving the antivenom antibody is currently the most effective treatment. However, the specific antivenom might be unavailable in remote areas. Snakebites by Viperidae usually lead to hemorrhage and mortality if untreated. In the present study, challenges of rattlesnake (Crotalus atrox) venom markedly increased the circulating soluble P-selectin (sP-sel) level, but not P-selectin (P-sel, Selp-/-) mutants, in wild-type mice. Because sP-sel enhances coagulation through the P-selectin ligand 1 (PSGL-1, Selplg) pathway to produce tissue factor-positive microparticles, we hypothesized that increasing the plasma sP-sel level can be a self-rescue response in hosts against snake venom-mediated suppression of the coagulation system. Confirming our hypothesis, our results indicated that compared with wild-type mice, Selp-/- and Selplg-/- mice were more sensitive to rattlesnake venom. Additionally, administration of recombinant sP-sel could effectively reduce the mortality rate of mice challenged with venoms from three other Viperidae snakes. The antivenom property of sP-sel is associated with improved coagulation activity in vivo. Our data suggest that the elevation of endogenous sP-sel level is a self-protective response against venom-suppressed coagulation. The administration of recombinant sP-sel may be developed as a new strategy to treat Viperidae snakebites.