The northern region of Brazil is responsible for the largest incidence of snakebite accidents in the country. The accidents in the region have worst prognosis due to the difficulty of moving fast on hospital for treatment, and also the low capacity of antivenoms to neutralize the local effects. Bothrops atrox is the specie responsible for the majority of snakebites in the Amazon and the venom present a rich composition in metalloproteases P-III and P-I classes, with hydrolysis, recognition and binding capacity, mainly to extracellular matrix proteins (ECM), which is a requirement for the hemorrhagic and necrotic effect. Recently, we isolated from B. atrox venom a P-I class metalloproteases, Atroxlisin-Ia, which presents a peculiar high hemorrhagic activity for this class of toxin and also induces a fast injury in the skin on experimental animals. These activities were attributed to the toxin's high ability to hydrolyze extracellular matrix proteins, particularly laminin, type IV collagen and nidogen. As a consequence, hydrolysis could generate damage-associated molecular patterns (DAMPs), fragments of components of the extracellular matrix that act as pro-inflammatory factor. Therefore, in this project, we will focus two aspects: first, to elucidate the mechanisms involved in the exacerbated hydrolysis of ECM components by Atroxlisin-Ia, by analyzing the interaction between the toxin and extracellular matrix by high resolution microscopy attempting to detect ultrastructural alterations endowing the hydrolysis observed in vitro and in vivo. We also sought to analyze the production of DAMPs in exudates obtained in experimental models and also in material collected from the local tissues of patients injured by B. atrox in the Manaus region presenting severe local complications. Thus, we will investigate the role of Metalloproteases in the local damage in human envenoming, and correlate if the DAMPs would worsen the local damages in snakebite.
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