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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.

SUBMITTER: Sun DS

PROVIDER: S-EPMC5078805 | biostudies-other | 2016 Oct

REPOSITORIES: biostudies-other

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

Sun Der-Shan DS Ho Pei-Hsun PH Chang Hsin-Hou HH

Scientific reports 20161025

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<sup>-/-</sup>) mutants, i ...[more]

PMID: 27779216

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Project description:Envenomation by the Hypnale hypnale in the Western Ghats of India (particularly in the Malabar region of Kerala) and the subcontinent island nation of Sri Lanka is known to inflict devastating mortality and morbidity. Currently, H. hypnale bites in India are devoid of anti-venom regimens. A detailed characterization of the venom is essential to stress the need for therapeutic anti-venom. Notably, the deleterious effects of this venom on human blood cells have largely remained less explored. Therefore, in continuation of our previous study, in the present study, we envisioned investigating the effect of venom on the morphological and physiological properties of red blood cells (RBCs). The venom readily induced deleterious morphological changes and, finally, the aggregation of washed RBCs. The aggregation process was independent of the ROS and the intracellular Ca2+ ion concentration. Confocal and scanning electron microscopy (SEM) images revealed the loss of biconcave morphology and massive cytoskeletal disarray. Crenation or serrated plasma membrane projections were evenly distributed on the surface of the RBCs. The venom did not cause the formation of methemoglobin in washed RBCs but was significantly induced in whole blood. Venom did not affect glucose uptake and Na+/K+ -ATPase activity but inhibited glucose 6 phosphate dehydrogenase activity and decreased the fluidity of the plasma membrane. Venom-induced RBC aggregates exhibited pro-coagulant activity but without affecting platelet aggregation. In pre-incubation or co-treatment studies, none of the bioactive compounds, such as melatonin, curcumin, fisetin, berberine, and quercetin, sugars such as mannose and galactose, and therapeutic polyvalent anti-venoms (Bharat and VINS) were inhibited, whereas only N-acetylcysteine and H. hypnale monovalent anti-venom could inhibit venom-induced deleterious morphological changes and aggregation of RBCs. In post-treatment studies, paradoxically, none of the bioactives and anti-venoms, including N-acetylcysteine and H. hypnale monovalent anti-venom, reversed the venom-induced RBC aggregates.

Dataset Information

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

Publications

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

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