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Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Anesthesiology 2014 ; 121 (6): 1236-47 Nephropedia Template TP
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Importance of Toll-like Receptor 2 in Mitochondrial Dysfunction during Polymicrobial Sepsis #MMPMID25272245
Gong Y; Zou L; Feng Y; Li D; Cai J; Chen D; Chao W
Anesthesiology 2014[Dec]; 121 (6): 1236-47 PMID25272245show ga
BACKGROUND: Toll-like receptor 2 (TLR2) contributes to sepsis pathogenesis such as deleterious systemic inflammation, cardiac dysfunction, and high mortality in animal studies. Mitochondrial dysfunction is a key molecular event that is associated with organ injury in sepsis. The role of TLR2 in sepsis-induced mitochondrial dysfunction remains unclear. METHODS: Intracellular hydrogen peroxide (H2O2) and mitochondrial superoxide (O2?), mitochondrial membrane potential (??m) and intracellular adenosine triphosphate (ATP) were measured in peritoneal leukocytes. A mouse model of polymicrobial sepsis was generated by cecum ligation and puncture (CLP). Wild-type and TLR2-deficient (TLR2?/?) mice were subjected to sham or CLP. Mitochondrial functions including reactive oxygen species (ROS), ??m, intracellular ATP, and complex III activity were measured. RESULTS: TLR2/1 activation by Pam3Cys enhanced intracellular H2O2 and mitochondrial O2- production in leukocytes, but had no effect on mitochondrial ??m and ATP production. The effect was specific for TLR2/1 as TLR3 or TLR9 ligands did not induce ROS production. Polymicrobial sepsis induced mitochondrial dysfunction in leukocytes, as demonstrated by increased H2O2 and mitochondrial O2? production (CLP vs. sham; H2O2: 3,173 ± 498, n = 5 vs. 557 ± 38, n = 4; O2?: 707 ± 66, n = 35 vs. 485 ± 35, n = 17, mean fluorescence intensity, mean ± SEM), attenuated complex III activity (13 ± 2, n = 16 vs. 30 ± 3, n = 7, milli-optical densities per minute, mOD/min), loss of mitochondrial ??m, and depletion of intracellular ATP (33 ± 6, n = 11 vs. 296 ± 29, n = 4, nmol/mg protein). In comparison, there was significant improvement in mitochondrial function in septic TLR2?/? mice as evidenced by attenuated mitochondrial ROS production, better- maintained mitochondrial ??m and higher cellular ATP production. CONCLUSIONS: TLR2 signaling plays a critical role in mediating mitochondrial dysfunction in peritoneal leukocytes during polymicrobial sepsis.