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A Physiological Systems Approach to Human and Mammalian Thermoregulation

Time course of cytokine, corticosterone, and tissue injury responses in mice during heat strain recovery

Thermal and Mountain Medicine Division, United States Army Research Institute of Environmental Medicine, Natick, Massachusetts

Submitted 25 August 2005 ; accepted in final form 15 October 2005

Elevated circulating cytokines are observed in heatstroke patients, suggesting a role for these substances in the pathophysiological responses of this syndrome. Typically, cytokines are determined at end-stage heatstroke such that changes throughout progression of the syndrome are poorly understood. We hypothesized that the cytokine milieu changes during heatstroke progression, correlating with thermoregulatory, hemodynamic, and tissue injury responses to heat exposure in the mouse. We determined plasma IL-1, IL-1, IL-2, IL-4, IL-6, IL-10, IL-12p40, IL-12p70, IFN-, macrophage inflammatory protein-1, TNF-, corticosterone, glucose, hematocrit, and tissue injury during 24 h of recovery. Mice were exposed to ambient temperature of 39.5 ± 0.2°C, without food and water, until maximum core temperature (T_c,Max) of 42.7°C was attained. During recovery, mice displayed hypothermia (29.3 ± 0.4°C) and a feverlike elevation at 24 h (control = 36.2 ± 0.3°C vs. heat stressed = 37.8 ± 0.3°C). Dehydration (10%) and hypoglycemia (65–75% reduction) occurred from T_c,Max to hypothermia. IL-1, IL-2, IL-4, IL-12p70, IFN-, TNF-, and macrophage inflammatory protein-1 were undetectable. IL-12p40 was elevated at T_c,Max, whereas IL-1, IL-6, and IL-10 inversely correlated with core temperature, showing maximum production at hypothermia. IL-6 was elevated, whereas IL-12p40 levels were decreased below baseline at 24 h. Corticosterone positively correlated with IL-6, increasing from T_c,Max to hypothermia, with recovery to baseline by 24 h. Tissue lesions were observed in duodenum, spleen, and kidney at T_c,Max, hypothermia, and 24 h, respectively. These data suggest that the cytokine milieu changes during heat strain recovery with similarities between findings in mice and those described for human heatstroke, supporting the application of our model to the study of cytokine responses in vivo.

heatstroke; hypothermia; fever; systemic inflammatory response

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