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LUCHINI, L. S. G. Role of the Complement System in the inflammatory process caused by a class P1 metalloproteinase from Bothrops pirajai venom: Analysis in the ex vivo model of human whole blood. 2016. 72 p. Masthers thesis (Immunology) – Institute of Biomedical Sciences, University of São Paulo, São Paulo, 2016. The genus Bothrops, Viperidae family, comprises snakes that are responsible for about 80% of the envenomations in Brazil. These venoms are composed by a complex mixture of molecules, such as metalloand serine proteinases, desintegrins, phospholipases, lectins, peptides, among others. The local effects of the envenomations include edema, hemorrhage and necrosis, which can lead to permanent damage and produce systemic manifestations such as intravascular coagulation, shock, acute renal failure and systemic hemorrhage. Studies of our group have shown that the venom of Bothrops pirajai is able to activate the complement system (C), suggesting that this activation may contribute to the worsening of symptoms. Thus, considering the importance of Complement system in the inflammatory process and the role of metalloproteinases in Bothrops envenomations, the aim of this study was to analyze the generation of biologically active fragments from this system, as well as the leukocyte activation, induced by a class PI metalloproteinase purified from B. pirajai’s venom (PI-Bp), using the human whole blood model (ex vivo). In this model, cells and plasma mediators are present and are able to interact, which allows the better understanding of the systemic inflammatory events induced by a toxin. The results showed that PI-Bp was able to promote an increase in the expression of CD11b, CD14, C3aR, C5aR, TLR2 and TLR4 markers in leukocytes. In addition, the blood treatment with this toxin promoted generation of anaphylatoxins and TCC in the plasma. Tests were also carried out with samples of human whole blood treated with PBS (negative control), LPS (positive control) or PI-BP, in the presence or absence of Compstatin, an inhibitor of C3 component from the Complement System. Inhibition of the component C3 by compstatin significantly reduced the production of anaphylatoxins and TCC in blood plasma treated with the toxin, as well as the expression of membrane markers related to complement, such as CD11b, C3aR and C5aR on leukocytes. PI-Bp was able to induce increased production of the cytokines IL-10, IL-6, IL-1β and the chemokines IL-8, MCP-1 and MIG, in the human whole blood model. The addition of compstatin, to the reactions, caused a significant reduction in the production of IL-10, IL-1β, IL-8 MCP-1 and IL-8 in the cells treated with PI-Bp. Considering these results, it is possible to conclude that IP-Bp is able to activate the complement system, which leads to an increase in the inflammatory process. The data obtained with the use of compstatin indicate that Complement inhibition may significantly control the inflammatory process initiated by the toxin in the human whole blood model.

Papel do sistema complemento no processo inflamatório causado por uma metaloproteinase de classe PI, do veneno da serpente &lt;i&gt;Bothrops pirajai&lt;/i&gt;: análise em modelo &lt;i&gt;ex vivo&lt;/i&gt; de sangue total humano.