Key result
Genetic ablation of Tlr4, Nlrp3, and caspase-1 did not prevent cardiac dysfunction after high-grade polymicrobial sepsis in mice, despite preventing the increase in pro-inflammatory cytokines.
Why the study?
Does genetic ablation of Tlr4, Nlrp3, or caspase-1 prevent cardiac dysfunction in a mouse model of high-grade polymicrobial sepsis?
Does genetic ablation of Tlr4, Nlrp3, or caspase-1 prevent cardiac dysfunction in a mouse model of high-grade polymicrobial sepsis?
Genetic ablation of TLR4, NLRP3, and caspase-1 does not prevent sepsis-induced cardiac dysfunction in mice, suggesting these pathways are not feasible therapeutic targets for this condition.
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 toll-like receptor 4 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 colon ascendens stent peritonitis (CASP) model. The QJ interval was increased in wild-type C57BL/6J mice after CASP when compared with sham controls, a result paralleled by an increase in the cardiac action potential (AP) duration (APD). The decreases in ejection fraction (EF), left ventricle end diastolic volume, 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 cecal ligation and puncture. Despite developing cardiac dysfunction similar to wild types after CASP, Nlrp3 mice had reduced circulating levels of interleukin (IL)-1β, IL-6 and tumor necrosis factor-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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Alarcón et al. (2017) studied Severe sepsis / colon ascendens stent peritonitis-associated heart disease. Genetic ablation of Tlr4, Nlrp3, and caspase-1 vs. Wild-type C57BL/6J mice was evaluated on Cardiac dysfunction (ejection fraction, left ventricle end diastolic volume, stroke volume, and cardiac output). Genetic ablation of Tlr4, Nlrp3, and caspase-1 did not prevent cardiac dysfunction after high-grade polymicrobial sepsis in mice, despite preventing the increase in pro-inflammatory cytokines.
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