An Increase in Thermotolerance Is Associated with Elevated Levels of Heat Shock Protein 70 (HSP70) in a Mouse Exertional Heat Stroke Model

Abstract

Recent data from our laboratory showedthat one exertional heat stroke (EHS) exposure improved thermal tolerance inmice who were exposed to the same conditions again within 24 h. This was evident by longer average runningtime, higher thermal load, higher maximum core temperature, and less severehypothermia during the second EHS exposure and recovery compared to the first. Theaim of this study was to determine if traditional biomarkers of EHS severitywere reflective of the improved thermoregulatory performance observed during the second EHS. We collected blood and liver samples from male C57BL/6J mice at30 min and 3 h into recovery from a second EHS event that occurred 24 h after the initial EHS exposure. Mice displayed significantly lower circulating cytokines and chemokines 30 min (MIP‐1β, MIP‐2; P<0.05) and 3 h (G‐CSF,IL‐10, IP‐10, KC, MCP‐1; P<0.05) following the second vs. first EHS exposure. Plasma corticosterone was also significantly lower in mice 3 h after the second vs. first EHS (36458 vs. 262914 pg/ml, respectively; P=0.0005). Liver heat shock protein (HSP)70 was significantly elevated in mice 24 h after the first EHS and was further increased after the second EHS at 30 min (5‐fold) and 3 h(2‐fold) of recovery. The elevated levels of liver HSP70 protein correlated with a reduction in HSP70 gene expression at these time points, suggestive of a negative feedback loop. Although HSP70 is thought to protect against heat‐induced organ damage, aspartate aminotransferase (AST; a clinical biomarker of liver damage) was significantly higher 30 min after the second vs. first EHS exposure (994 U/L vs. 374 U/L, respectively; P<0.05). Taken together, our results suggest that one EHS event induces partial thermal tolerance in mice that improves performance in the heat 24 h later and may protect against systemic inflammation during the subsequent heat exposure, as evidenced by changes in the expression of pro‐ and anti‐inflammatory factors, such as cytokines, chemokines and corticosterone. Elevated liver HSP70 suggests protection against organ damage, but this interpretation needs to be validated with histological analysis of the liver since elevated AST levels suggest increased stress to this organ following the second EHS. Perhaps the adaptive responses of improved run time and thermal tolerance in the heat 24 h after the initial EHS come at the cost of additional organ damage. Author views not official US Army or DOD policy.