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Study of the pro-inflammatory capacity of exudates produced from the action of snake venom metalloproteinases in murine models

Abstract

The North Region of Brazil has the highest incidence of snakebite cases, with 52 cases per 100,000 inhabitants. Bothrops atrox is the snake that causes most snakebites in the Brazilian Amazon. Mortality from these accidents is low, however morbidity resulting from local effects is high. The local effects are mainly a result of the proteolytic action of snake venom metalloproteinases (SVMPs) which are the major toxins in B. atrox venom. Recently, two metalloproteinases of class P-I (Atroxlysin-Ia) and P-III (Bathroxragin) were isolated from the venom of B. atrox. Both are highly efficient in hydrolyzing extracellular matrix (ECM) proteins and, consequently, induce rapid hemorrhage and dermonecrosis. We have already shown that these two toxins and the products resulting from the in vitro hydrolysis of ECM proteins have the ability to induce an inflammatory response in murine models. In addition, we also observed the presence of endogenous factors with pro-inflammatory action such as DAMPs (damage-associated molecular patterns) in the blister content after envenomation in humans. However, little is known about how these molecules produced through proteolytic activity contribute to the severity and morbidity of the local condition. Even after serum therapy, a continuous worsening of the local condition is observed that can lead to loss of function and amputation, which suggests that hydrolysis is initiated soon after the bite and these secondary products of the venom action act synergistically with the toxins to induce an intense inflammatory process at the site. Therefore, our next step is to deepen our knowledge of the mechanisms involved in the local action of SVMPs present in B. atrox venom. We will analyze in vitro the mechanisms involved in the pro-inflammatory capacity of exudates generated after the direct action of Atroxlysin-Ia and Bathroxragin in the muscle tissue of murine models. For this, we are initially going to establish the experimental model for obtaining the exudate after the injection of these two isolated toxins in the gastrocnemius muscle of mice. Then we will identify by mass spectrometry the composition of the exudate and finally investigate the pro-inflammatory pathways that are being stimulated/activated after the treatment of cells of muscular and inflammatory lineages with the produced exudate. The pro-inflammatory evaluation will be performed by identifying, quantifying, and analyzing the gene expression profile of pro-inflammatory mediators in the cell culture supernatant. Thus, we aim to add more knowledge about the intricate process of local damage resulting from the action of SVMPs at the bite site after envenomation from Bothrops and support the search for therapies that help to reduce and improve local damage. (AU)

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