TLR4 and NLRP3 Caspase 1- IL-1β- Axis are not Involved in Colon Ascendens Stent Peritonitis (Casp)-Associated Heart Disease

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Abstract

Hemodynamic collapse and myocardial dysfunction are among the major causes of death in severe sepsis. The purpose of this study was to assess the role played by TLR4 and by the NLRP3 inflammasome in the cardiac dysfunction that occurs after high-grade polymicrobial sepsis. We performed the colon ascendens stent peritonitis (CASP) surgery in Tlr4-/-, Nlrp3-/- and caspase-1-/- mice. We also assessed for the first time the electrical heart function in the CASP model. The QJ interval was increased in wild-type C57BL/6J mice after CASP when compared to sham controls, a result paralleled by an increase in the cardiac action potential duration (APD). The decreases in ejection fraction (EF), left-ventricle end diastolic volume (LVEDV), stroke volume, and cardiac output found after CASP were similar among all groups of mice. Similar heart response was found when Nlrp3-/- mice were submitted to high-grade CLP. Despite developing cardiac dysfunction similar to wild-types after CASP, Nlrp3-/- mice had reduced circulating levels of IL-1β, IL-6 and TNF-α. Our results demonstrate that the genetic ablation of Tlr4, Nlrp3, and caspase-1 does not prevent the cardiac dysfunction, despite preventing the increase in pro-inflammatory cytokines, indicating that these are not feasible targets to therapy in high-grade sepsis.

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