160. Role of SVMPs, Matrikines and TLR4 in Snake Venom Induced Edema and Inflammation

Abstract

Background: Snake venom metalloproteinases have long been known to be potent agents of extracellular matrix and significant information has been gained in terms of understanding the mechanistic basis for how such degradation leads to hemorrhage and tissue damage. However, little is known regarding whether the products of ECM degradation may also contribute to the pathophysiology of envenomation. Methods: Both in vitro and in vivo experiments were performed to determine whether SVMP degraded ECM could induce edema and inflammation. Additional studies to elucidate the mechanism of action were also undertaken. Results: Venom SVMPs were demonstrated to degrade ECM to produce matrikines which could induce edema and inflammation in vivo and up-regulate chemokines in tissue culture. Antagonism of the toll-like receptor 4 (TLR4) could attenuate these activities. Discussion: It has been recognized that some ECM proteolytic products can activate TLR4 receptors to produce edema and inflammation in certain diseases. The ability of SVMPs to similarly produce ECM matrikines to contribute to the venom-induced edema and inflammation associated with envenomation is a significant novel finding which in turn suggests additional therapeutic routes to attenuate morbidity and dead associated with snake envenomation. Conclusions: SVMP degraded ECM products can function as matrikines to contribute to envenomation pathophysiology via a matrikine-TLR4 mediated pathway to induce edema and inflammation in the prey. These studies suggest a more complex, nuanced role for SVMPs in venom induced pathophysiology than previously recognized and that novel approaches to therapeutic treatment of envenomation focused on this pathway may attenuate edema and inflammation associated morbidities in patients.