Heat stroke is a life-threatening illness that affects all segments of society, including the young, aged, sick, and healthy. The recent high death toll in France (Dorozynski, 2003) and the death of high-profile athletes has increased public awareness of the adverse effects of heat injury. However, the etiology of the long-term consequences of this syndrome remains poorly understood such that preventive/treatment strategies are needed to mitigate its debilitating effects.
Cytokines are important modulators of the
acute phase response (APR) to stress,
infection, and
inflammation. Current data implicating
cytokines in
heat stroke responses are mainly from correlation studies showing elevated plasma levels in
heat stroke patients and experimental animal models. Correlation data fall far short of revealing the mechanisms of
cytokine actions such that additional research to determine the role of these endogenous substances in the
heat stroke syndrome is required. Furthermore,
cytokine determinations have occurred mainly at end-stage
heat stroke, such that the role of these substances in progression and long-term recovery is poorly understood. Despite several studies implicating
cytokines in
heat stroke pathophysiology, few studies have examined the protective effect(s) of
cytokine antagonism on the morbidity and mortality of
heat stroke. This is particularly surprising since
heat stroke responses resemble those observed in the endotoxemic syndrome, for which a role for endogenous
cytokines has been strongly implicated. The implication of
cytokines as mediators of
endotoxemia and the presence of circulating
endotoxin in
heat stroke patients suggests that much knowledge can be gained from applying our current understanding of endotoxemic pathophysiology to the study of
heat stroke.
Heat shock proteins (HSPs) are highly conserved
proteins that function as
molecular chaperones for denatured
proteins and reciprocally modulate
cytokine production in response to stressful stimuli. HSPs have been shown repeatedly to confer protection in
heat stroke and injury models. Interactions between HSPs and
cytokines have received considerable attention in the literature within the last decade such that a complex pathway of interactions between
cytokines, HSPs, and
endotoxin is thought to be occurring in vivo in the orchestration of the APR to heat injury. These data suggest that much of the pathophysiologic changes observed with
heat stroke are not a consequence of heat exposure, per se, but are representative of interactions among these three (and presumably additional) components of the innate immune response. This chapter will provide an overview of current knowledge regarding
cytokine, HSP, and
endotoxin interactions in
heat stroke pathophysiology. Insight is provided into the potential therapeutic benefit of
cytokine neutralization for mitigation of
heat stroke morbidity and mortality based on our current understanding of their role in this syndrome.