Microvascular Injury, Thrombosis, Inflammation, and Apoptosis in the Pathogenesis of Heatstroke

Abstract

Objective— Severe heatstroke is a leading cause of morbidity and mortality during heat waves. The pathogenesis of tissue injury, organ failure, and death in heatstroke is not well understood. Methods and Result— We investigated the pathways of heatstroke-induced tissue injury and cell death in anesthetized baboons ( Papio hamadyras ) subjected to environmental heat stress until core temperature attained 42.5°C (moderate heatstroke; n=3) or onset of severe heatstroke (n=4) signaled by a fall in systolic blood pressure to <90 mm Hg and rise in core temperature to 43.1±0.1°C. Three sham-heated animals served as controls. Light and electron microscopy revealed widespread hemorrhage and thrombosis, transmural migration of leukocytes, and microvascular endothelium injury in severe heatstroke. Immunohistology and ultrastructural analysis demonstrated increased staining of endothelial von Willebrand factor (vWF), tissue factor (TF), and endothelial leukocyte-platelet interaction. Extensive apoptosis was noted in spleen, gut, and lung, and in hematopoeitic cells populating these organs. Double-labeling studies colocalized active caspase-3 and TF with apoptotic cells. Findings in sham-heated animals were unremarkable. Conclusion— These data suggested that microvascular injury, thrombosis, inflammation, and apoptosis may play an important role in the pathogenesis of heatstroke injury.

Hsp-72, a candidate prognostic indicator of heatstroke

“…The degree of Hsp-72 expression paralleled the severity of liver injury and renal dysfunction as assessed by plasma liver enzyme activity and creatinine levels, respectively. This is also in agreement with previous clinical and experimental studies showing that in severe heatstroke; liver and jejunum are the sites of extensive damage compared with other organs, such as the lung (Bouchama et al 2005;Roberts et al 2008).…”

“…The mechanisms of MODS are not fully understood but include direct tissue injury and cell death from hyperthermia, sustained organ dysfunction and damage secondary to activation of the host inflammatory and coagulation responses (Bouchama and Knochel 2002;Bouchama et al 2005;Roberts et al 2008). Consequently, in spite of optimal cooling and supportive treatment in intensive care, the overall mortality can exceed 60%, because as yet, there is no specific treatment available (Misset et al 2006;Argaud et al 2007).…”

“…We have recently established that baboons subjected to environmental heat stress mimic the clinical spectrum from moderate to severe heatstroke seen in human heatstroke (Bouchama et al 2005;Roberts et al 2008). Baboons with moderate heatstroke display hyperthermia, neurologic alteration, and MODS, which subside after 72 h with full recovery, whereas baboons with severe heatstroke develop hypotension and rapidly progressing MODS that can culminate in death (Bouchama et al 2005;Roberts et al 2008).…”

“…Baboons with moderate heatstroke display hyperthermia, neurologic alteration, and MODS, which subside after 72 h with full recovery, whereas baboons with severe heatstroke develop hypotension and rapidly progressing MODS that can culminate in death (Bouchama et al 2005;Roberts et al 2008). The objectives of the present study were to use these two experimental baboon models of heatstroke to: (1) examine the expression of Hsp-60 and Hsc-70, together with inducible Hsp72; (2) determine whether Hsp-60 and Hsp-72 are released into the circulation, and if so, (3) analyze their time course and relation with biomarkers of cell injury, organ dysfunction, as well as death in heatstroke.…”

Effect of ulinastatin, a human urinary protease inhibitor, on heatstroke-induced apoptosis and inflammatory responses in rats

“…2). These observations were similar to those in baboons subjected to heatstroke (22). Furthermore, to further understand the mechanism of cell apoptosis, the expression of Bax, Bcl-2 and caspase-3 levels in heatstroke-induced rats was detected.…”