Investigation of cardiac alterations that occur in poisoning by Tityus serrulatus scorpion venom

Author(s)

Mouzarllem Barros dos Reis

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2020-01-31

Examining board members

Lucia Helena Faccioli; Vania Luiza Deperon Bonato; Rita de Cassia Aleixo Tostes Passaglia

• Advisor: Lucia Helena Faccioli

Abstract

Tityus serrulatus envenomation induces local or systemic symptoms such as severe pain and inflammation. In severe manifestations, systemic reaction culminates in acute lung edema and cardiogenic shock, which can potentially lead to death. Our group demonstrated that pattern recognition receptors such as TLR2 and TLR4 in macrophages recognize T. serrulatus (TsV) venom resulting in the production of pro-inflammatory mediators such as cytokines and eicosanoids. In addition, mouse inoculation with TsV induces pulmonary edema and death mediated by activation of the NLRP3 inflammasome and IL-1β release by a process regulated by lipid mediators. However, the mechanisms responsible for cardiac manifestations during scorpionism are poorly understood. Thus, in this project employing wild-type animals (C57Bl / 6 or WT) or IL-1β receptor-deficient animals (Il1r1-/-) inoculated with a lethal dose of TsV (180 µg.kg-1), we evaluated cardiac function by echocardiogram and carotid cannulation technique, and we determined blood pressure, the production of inflammatory mediators in heart tissue and neurotransmitters release systemically. We observed that IL-1β and PGE2 production increased in cardiac tissue only in C57Bl/6 mice, and that IL-1β-mediated signaling is essential for changes in heart rate and blood pressure. Il1r1-/- or dexamethasone-treated WT animals do not experience a drop in blood pressure, heartbeat or echocardiographic changes, as well as in survival rate. In addition, we have shown that IL-1R receptor-dependent signaling is essential for PGE2 production, which in turn, via EP2/EP4 receptors, controls the release of acetylcholine, but not adrenaline or noradrenaline. In addition, we determined that cardiac fibroblasts, but not cardiomyocytes, produce IL-1β after venom stimulation in vitro. These data show that scorpion poisoning activates the IL-1β/IL-1R/PGE2/ACh axis and is responsible for acetylcholine release leading to cardiac dysfunction and mortality. Based on our results, we are proposing that in addition to the administration of anti-scorpion serum, additional high-dose corticosteroid therapy should be given soon after scorpion bite to prevent the release of inflammatory mediators and acetylcholine, thereby minimizing the risk of death in scorpionism. (AU)

• FAPESP's process: 17/02314-3 - Investigation of cardiac changes that occur in poisoning by Tityus serrulatus scorpion venom
• Grantee: Mouzarllem Barros dos Reis
• Support Opportunities: Scholarships in Brazil - Doctorate