, 1989). Once occurring in capillary vessels, the hydrolysis of basement membrane proteins would result in the mechanical weakening of capillary wall, that would render to the hydrostatic pressure and tangential shear stress, resulting in the disruption of the vessel integrity and the consequent blood extravasation ( Gutierrez et al., 2005). However, catalytic activity is apparently similar in hemorrhagic

and non-hemorrhagic SVMPs, indicating that the hydrolysis of basement membrane substrates is not the only mechanism acting on vascular damage induced by the hemorrhagic toxins. Using jararhagin as a prototype of highly hemorrhagic SVMP, our group has been studying the mechanisms related to hemorrhage, focusing on the interaction of SVMPs with ECM proteins. Using neutralizing monoclonal antibodies, a fine correlation was observed between collagen binding Selleck beta-catenin inhibitor and hemorrhagic activity (Tanjoni et al., 2003a). This hypothesis was emphasized since the high affinity binding of jararhagin to type I collagen and type IV collagen was not observed for berythrativase, a non-hemorrhagic P-III SVMP isolated from Bothrops erythromelas venom ( Moura-da-Silva et al., 2008). Attempting to clarify the hypothesis that hemorrhagic lesion induced

by jararhagin could be related to its binding to collagens, Baldo et al. VE-821 purchase (2010) investigated the tissue distribution and degradation of ECM proteins induced Tideglusib by jararhagin and BnP1, a weakly hemorrhagic SVMP from P-I class, using a mouse skin as model. Injection of Alexa488-labeled jararhagin revealed fluorescent staining around capillary vessels and co-localization

with basement membrane type IV collagen. In opposition, BnP1 did not accumulate in the tissues. Besides, the strong hemorrhage induced by jararhagin was accompanied by hydrolysis of collagen fibers in the hypodermis and a marked degradation of type IV collagen at the vascular basement membrane ( Baldo et al., 2010). Injection of jararhagin in gastrocnemious muscle also induced a pronounced reduction in the immunostaining of type IV collagen ( Escalante et al., 2006) confirming the hydrolysis of collagens by jararhagin in vivo. In contrast, injection of BnP1 in mice skin did not disrupt collagen fibers or type IV collagen ( Baldo et al., 2010). These data demonstrate a particular tissue distribution of hemorrhagic toxins accumulating at the basement membrane of capillary vessels and small venules ( Fig. 1). Binding and disrupting of collagen structure would enhance detachment of endothelial cells and weakening of the capillary vessel resulting in the strong local hemorrhagic activity of P-III SVMPs ( Baldo et al., 2010). The hypothesis that jararhagin could play an important role in venom-induced local tissue damage through activation of endogenous inflammatory mediators was also approached by our group.