Role of endotoxin and cytokines in the systemic inflammatory response to heat injury

Abstract

Environmental heat exposure represents one of the most deadly natural hazards in the United States. Heat stroke is a life-threatening illness that affects all segments of society with few effective treatment strategies to mitigate the long-term debilitating consequences of this syndrome. Although the etiologies of heat stroke are not fully understood, the long-term sequelae are thought to be due to a systemic inflammatory response syndrome (SIRS) that ensues following heat-induced tissue injury. Endotoxin and cytokines have been implicated as key mediators of the heat-induced SIRS, based almost exclusively on correlative data that show high circulating concentrations of these substances in heat stroke patients and animal models. However, endotoxin and cytokine neutralization studies have not consistently supported this hypothesis indicating that the mechanisms of heat stroke morbidity / mortality remain poorly understood. This review discusses the current understanding of the role of endotoxin and cytokines in heat-induced SIRS. Insight is provided into genetic conditions that may predispose to heat stroke and potential therapeutic strategies that may be efficacious against the adverse consequences of this debilitating illness.

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

“…Neutralizing studies in animal models of heatstroke have established that this systemic inflammation has a significant role but it remains unclear whether it is beneficial or deleterious. As shown previously, inhibition of the inflammatory response with administration of IL-1 receptor antagonist [8], anti-inflammatory steroids [12] or recombinant activated protein C [7], [10] prevented organ damage and improved survival while other studies using IL-6 and tumor necrosis factor (TNF) receptors knockout mice [9] or primate models [11] reported enhanced mortality. One of the reasons that might explain these conflicting findings is that the molecular mechanisms that initiate and propagate the inflammatory response to heat stress are not known, although earlier studies have suggested that lipopolysaccharide (LPS) leaking into the systemic circulation from heat damaged gut is the primary stimulus [3], [9].…”

“…Clinical and experimental studies consistently demonstrated the presence of a systemic inflammatory response to heat stress that correlated with severity and outcome [5], [6], [7], [8], [9], [10], [11], [12]. Neutralizing studies in animal models of heatstroke have established that this systemic inflammation has a significant role but it remains unclear whether it is beneficial or deleterious.…”

Time Course of Physiological and Psychological Responses in Humans during a 20-Day Severe-Cold–Acclimation Programme

“…Cortisol can weaken the activity of the immune system [36], [20]. The immune function seems to be stimulated by acute stress, but is suppressed by chronic stress [14], [55], [40], [26]. This dual response can be beneficial for some types of immune responses, but deleterious for other types.…”

Pathophysiology and pathological findings of heatstroke in dogs

“…25 Similarly, the role of Hsp27 in protection of actin microfilament cytoskeleton under stress conditions may be important not only in individual cell tolerance to stress through cytoskeletal stabilization but may also be integral to the protection of the whole organism through the maintenance of endothelial and epithelial barrier integrity. 25,47 In fact, systemic endotoxemia and elevations in circulating cytokines have been demonstrated to occur during heatstroke, [48][49][50] and in this respect, reduction of gut flora by means of nonabsorbable antibiotics or administration of anti-endotoxin antibodies have been observed to allow animals to tolerate higher core temperatures. 51,52 HSP-associated heat adaptation of the whole organism may also involve endotoxin tolerance, since cells and animals become endotoxin tolerant after Hsp70 accumulation.…”

“…Widespread endothelial damage may also result in tissue thromboplastin and factor XII release, with consequent activation of the coagulation and complement cascades, which may culminate in systemic inflammatory response syndrome (SIRS) and widespread microthrombosis and hemorrhagic diathesis as a result of disseminated intravascular coagulation (DIC). 1,6,50,66,71 Thrombocytopenia, which is a common finding in canine heatstroke, may be due to direct heat damage to megakaryocytes or platelets, or may be associated with DIC. Hepatic damage due to thermal injury and prolonged splanchnic hypoperfusion may also further exacerbate hemostatic abnormalities.…”