Translational studies on the importance of metalloproteinases in envenoming by Bothrops atrox in patients from the North region of Brazil

Abstract

The northern region of Brazil is responsible for the highest incidence and severity of ophidian accidents in the country. Bothrops atrox snake is responsible for the largest number of cases, presenting a composition of venom rich in Metalloproteinases (SVMPs). SVMPs have the ability to hydrolyze and bind extracellular matrix proteins (ECMs), which trigger most of the local lesions that occur in human envenomings. Recently, we isolate Atroxlysin-1a from B. atrox venom, a P-I class SVMPs with high capacity in hydrolyzing ECM proteins and, consequently, to induce hemorrhagic and dermonecrotic activities, which is unusual to this class of SVMPs. The hydrolysis of ECM components could generate endogenous pro-inflammatory factors such as damage-associated molecular patterns (DAMPs). In this project, we aim to improve the knowledge about the mechanisms involved in the local effects induced by SVMPs present in B. atrox venom and to validate the experimental evidences in human accidents. For this, we will analyze the production and the pro-inflammatory capacity of endogenous mediators in the exudates obtained in experimental models. Subsequently, we will analyze the importance of SVMPs in a translational and clinical context analyzing the contents of blisters and abscesses of patients bitten by B. atrox in the region of Manaus, AM, in order to confirm the generation of such endogenous factors in human accidents. Thus, this project aims to improve understanding of the action of SVMPs on local effects on human envenomings by Bothrops snakes, and may lead to therapeutic alternatives for use parallel to serum therapy.