Efeito da tolerância ao Lipopolissacarídeo (LPS) no desacoplamento mitocondrial da sepse

Abstract

Sepsis has organic dysfunctions due to a dysregulated inflammatory response that alters cellular functions. This cell damage occurs with significant changes to metabolic pathways and to cellular function. Uncoupling proteins (UCPs) are located in the inner mitochondrial membrane, playing roles that include heat production and regulation of the production of reactive oxygen species by mitochondria. Mitochondrial respiration results in proton extrusion (H+) outside the mitochondria and inside the intermembrane space, establishing the mitochondrial membrane potential. UCPs pump protons from the intermembrane space to the mitochondrial matrix and, thus, dissipate the proton gradient, reduce ATP production, and decrease superoxide production. Hence, UCPs play important roles in redox regulation and in mitochondrial and metabolic processes. This study has the purpose of evaluating the effects of LPS tolerance in mitochondrial uncoupling in an experimental model of sepsis, in addition to evaluating mitochondrial damage through the amount of mitochondria present in liver tissue and investigating oxygen consumption in mitochondria isolated from the liver tissue. Male, 7week-old, Balb/c mice were used, which underwent sepsis stimulation through cecal ligation and puncture (CLP) technique and induction of Escherichia coli lipopolysaccharide (LPS) tolerance. The animals were euthanized 24 hours after CLP procedure and the material was collected. The results found in this study show increased levels of UCP-1 in both groups undergoing CLP procedure, and tolerance did not change animal response. On the other hand, a reduction was seen in UCP-2 and UCP-3 levels both in the liver and in the heart of animals undergoing CLP procedure when compared to Control and Tolerant groups, also with no influence of tolerance on these UCPs. The quantification of mitochondrial DNA showed that there were no statistical differences when comparing the groups under analysis. Data showed a reduction in oxygen consumption in CLP group in State 2 when compared to Control and Tolerant groups, as well as a reduction in oxygen consumption in CLPT group in State 2 when compared to the Tolerant group, showing a deficit in oxidative metabolism in septic animals. Future studies with other periods may elucidate the metabolism cycle of UCPs in tolerance and in sepsis.