Identification of therapeutic targets in a murine model of severe exertional heat stroke

Exertional heat stroke (EHS) is a potentially lethal condition resulting from high core body temperatures (TC) in combination with a systemic inflammatory response syndrome (SIRS) with varying degrees of severity across victims, and limited understanding of the underlying mechanism(s). We established a mouse model of severe EHS in an effort to identify mechanisms of hyperthermia / inflammation that may be responsible for organ damage. Mice were forced to run on a motorized wheel in a 37.5°C chamber until loss of consciousness and were either removed immediately (EHI; TCMax = 42.3 ± 0.2°C) or remained in the chamber an additional 20 minutes (EHS; TCMax = 42.5 ± 0.4°C). Exercise control mice (ExC) experienced identical procedures to EHS at 25°C. At 3h post-EHS, there was evidence for an immune / inflammatory response as elevated blood chemokine (IP-10, KC, MIP-1α, MIP-1β, MIP-2) and cytokine (G-CSF, IL-10, IL-6) levels peaked and were highest in EHS mice compared to EHI and ExC mice. Immunoblotting of organs susceptible to EHS damage indicated several kinases were sensitive to stress associated with heat / inflammation and exercise; specifically, phosphorylation of liver c-Jun N-terminal Kinase (JNK) at Threonine 183 / Tyrosine 185 immediately (0h) post-heating related to heat illness severity. We have established a mouse EHS model, and JNK [or its downstream target(s)] could underlie EHS symptomatology, allowing identification of molecular pathways or countermeasure targets to mitigate heat illness severity, enable complete recovery, and decrease overall EHS-related fatalities.

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