Toll-Like Receptor 4 and High-Mobility Group Box 1 Are Critical Mediators of Tissue Injury and Survival in a Mouse Model for Heatstroke

摘要: The molecular mechanisms that initiate the inflammatory response in heatstroke and their relation with tissue injury lethality are not fully elucidated. We examined whether endogenous ligands released by damaged/stressed cells such as high-mobility group box 1 (HMGB1) signaling through Toll-like receptor 4 (TLR4) may play a pathogenic role heatstroke. Mutant TLR4-defective (C3H/HeJ) wild type (C3H/HeOuJ) mice were subjected to heat stress an environmental chamber pre-warmed at 43.5°C until core temperature reached 42.7°C, which was taken onset of animals then allowed recover passively ambient temperature. A sham-heated served control. displayed more histological liver damage higher mortality compared (73% vs. 27%, respectively, P<0.001). Compared mice, mutant exhibited earlier plasma release markers systemic inflammation HMGB1 (206±105 63±21 ng/ml; P = 0.0018 209±100 46±32 P<0.0001), IL-6 (144±40 46±20 pg/ml; P<0.001 184±21 84±54 P = 0.04), IL-1β (27±4 1.7±2.3 P<0.0001 hour). Both strains early into circulation upstream responses remained elevated up 24 h. Specific inhibition activity DNA-binding Box (600 µg/mouse) protected against lethal effect (60% 18% GST protein, P = 0.04). These findings suggest protective for TLR4 host severe stress. They also is mediator inflammation, presence defective signaling.