Veneno da serpente Bothrops jararacussu induz uma resposta inflamatória local dependente de protanóides e da migração de neutrófilos

Abstract

Local tissue reactions provoked by Bothrops venoms are characterized by edema, hemorrhage, pain, and inflammation; however, the mechanisms of tissue damage vary depending upon the species of snake. This mechanistic variability reduces the efficacy of antivenom treatment. Considering the diversity of intraspecific pathophysiological responses, we investigated the mechanisms and mediators involved in the local inflammatory response induced by the Bothrops jararacussu venom (VBjsu). Female Swiss mice were injected with either saline or VBjsu (0.125-8 µg/paw). In a subset of VBjsu-treated mice, loratadine (an H1 receptor antagonist), compound 48/80 (for mast cell depletion), capsaicin (for C-fiber desensitization), infliximab (an anti-TNF-α antibody), indomethacin (a non-specific COX inhibitor), celecoxib (a selective COX-2 inhibitor) or fucoidan (a P- and L-selectins modulator) were administered before VBjsu treatment. Paw edema was measured by plethysmography. In addition, paw tissues were collected for the measurement of myeloperoxidase (MPO) activity, TNF-α and IL-1 levels, and COX-2 immunoexpression. The direct chemotactic effect of VBjsu was also studied using a Boyden chamber assay, and the in vitro calcium dynamic in neutrophils was investigated using confocal microscopy. VBjsu caused concentration- and time-dependent edematogenic responses and increased the local production of TNF-α and IL-1β as well as COX-2 expression vs. saline group (P<0.05). Both edema and neutrophil migration were prevented by pretreatment with cyclooxygenase inhibitors (indomethacin or celecoxib) or by the P- and L-selectins modulator, fucoidan vs. VBjsu (P<0.05). Furthermore, VBjsu induced a direct in vitro neutrophil chemotaxis by increasing intracellular calcium vs. RPMI (P<0.05). Therefore, VBjsu induces an early onset edema dependent upon prostanoid production and neutrophil migration.