Leon LR, Helwig BG. Heat stroke: role of the systemic inflammatory response

U.S. Army Research Institute of Environmental Medicine, Thermal Mountain Medicine Division, Kansas St., Bldg 42, Natick, MA 01760-5007, USA.
Journal of Applied Physiology (Impact Factor: 3.06). 12/2010; 109(6):1980-8. DOI: 10.1152/japplphysiol.00301.2010
Source: PubMed


Heat stroke is a life-threatening illness that is characterized clinically by central nervous system dysfunction, including delirium, seizures, or coma and severe hyperthermia. Rapid cooling and support of multi-organ function are the most effective clinical treatments, but many patients experience permanent neurological impairments or death despite these efforts. The highest incidence of heat stroke deaths occurs in very young or elderly individuals during summer heat waves, with ∼ 200 deaths per year in the United States. Young, fit individuals may experience exertional heat stroke while performing strenuous physical activity in temperate or hot climates. Factors that predispose to heat stroke collapse include pre-existing illness, cardiovascular disease, drug use, and poor fitness level. For decades the magnitude of the hyperthermic response in heat stroke patients was considered the primary determinant of morbidity and mortality. However, recent clinical and experimental evidence suggests a complex interplay between heat cytotoxicity, coagulation, and the systemic inflammatory response syndrome (SIRS) that ensues following damage to the gut and other organs. Cytokines are immune modulators that have been implicated as adverse mediators of the SIRS, but recent data suggest a protective role for these proteins in the resolution of inflammation. Multi-organ system failure is the ultimate cause of mortality, and recent experimental data indicate that current clinical markers of heat stroke recovery may not adequately reflect heat stroke recovery in all cases. Currently heat stroke is a more preventable than treatable condition, and novel therapeutics are required to improve patient outcome.

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    • "Heat stress (HS) is a major environmental hazard for both humans and animals. Despite advances in the understanding of heat-related illnesses, there is no treatment against specific aspects of their pathophysiology, and protocols are limited to generic cooling and rehydration (Leon and Helwig 1985). Therefore, a better understanding of the biological consequences of HS is critical in order to develop effective treatment protocols and mitigation strategies. "
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    ABSTRACT: Proper insulin homeostasis appears critical for adapting to and surviving a heat load. Further, heat stress (HS) induces phenotypic changes in livestock that suggest an increase in insulin action. The current study objective was to evaluate the effects of HS on whole-body insulin sensitivity. Female pigs (57 ± 4 kg body weight) were subjected to two experimental periods. During period 1, all pigs remained in thermoneutral conditions (TN; 21°C) and were fed ad libitum. During period 2, pigs were exposed to: (i) constant HS conditions (32°C) and fed ad libitum (n = 6), or (ii) TN conditions and pair-fed (PFTN; n = 6) to eliminate the confounding effects of dissimilar feed intake. A hyperinsulinemic euglycemic clamp (HEC) was conducted on d3 of both periods; and skeletal muscle and adipose tissue biopsies were collected prior to and after an insulin tolerance test (ITT) on d5 of period 2. During the HEC, insulin infusion increased circulating insulin and decreased plasma C-peptide and nonesterified fatty acids, similarly between treatments. From period 1 to 2, the rate of glucose infusion in response to the HEC remained similar in HS pigs while it decreased (36%) in PFTN controls. Prior to the ITT, HS increased (41%) skeletal muscle insulin receptor substrate-1 protein abundance, but did not affect protein kinase B or their phosphorylated forms. In adipose tissue, HS did not alter any of the basal or stimulated measured insulin signaling markers. In summary, HS increases whole-body insulin-stimulated glucose uptake. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.
    Full-text · Article · Aug 2015
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    • "The surface-to-core temperature gradient increases during cold exposure, extending to subcutaneous and muscle tissues up to 4 cm deep (Webb 1992). Core temperature itself can increase by several degrees during fever (Singh and Hasday 2013), exertional/environmental hyperthermia (Leon and Helwig 2010), or as part of adverse drug reactions (Hopkins 2011). A decrease by several degrees may occur during accidental (Reed 1996) or therapeutic hypothermia (The Hypothermia after Cardiac Arrest StudyGroup 2002;Bernard et al. 2002), sepsis (Clemmer et al. 1992), trauma (Jurkovich et al. 1987), or certain drug intoxications (van Marum et al. 2007;Wilson and Waring 2007). "
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    ABSTRACT: Previous studies have revealed that clinically relevant changes in temperature modify clinically relevant gene expression profiles through transcriptional regulation. Temperature dependence of post-transcriptional regulation, specifically, through expression of miRNAs has been less studied. We comprehensively analyzed the effect of 24 h exposure to 32°C or 39.5°C on miRNA expression profile in primary cultured human small airway epithelial cells (hSAECs) and its impact on expression of a targeted protein, protein kinase C α (PKCα). Using microarray, and solution hybridization-based nCounter assays, with confirmation by quantitative RT-PCR, we found significant temperature-dependent changes in expression level of only five mature human miRNAs, representing only 1% of detected miRNAs. Four of these five miRNAs are the less abundant passenger (star) strands. They exhibited a similar pattern of increased expression at 32°C and reduced expression at 39.5°C relative to 37°C. As PKCα mRNA has multiple potential binding sites for three of these miRNAs, we analyzed PKCα protein expression in HEK 293T cells and hSAECs. PKCα protein levels were lowest at 32°C and highest at 39.5°C and specific miRNA inhibitors reduced these effects. Finally, we analyzed cell-cycle progression in hSAECs and found 32°C cells exhibited the greatest G1 to S transition, a process known to be inhibited by PKCα, and the effect was mitigated by specific miRNA inhibitors. These results demonstrate that exposure to clinically relevant hypothermia or hyperthermia modifies expression of a narrow subset of miRNAs and impact expression of at least one signaling protein involved in multiple important cellular processes. © 2015 Potla et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.
    Full-text · Article · May 2015 · RNA
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    • "It is not uncommon for liver biomarkers to be elevated the days following the event, however, with appropriate treatment these should return to normal values rapidly, usually within a week (Roberts, 2000; Roberts, 2006). In cases where appropriate treatment was not implemented, elevated levels of these biomarkers may be an indicator of possible organ failure that could precipitate death (Leon & Helwig, 2010; O'Connor et al., 2010; Wallace, Kriebel, Punnett, Wegman, & Amoroso, 2007). Because every case of EHS is different, recovery times can vary drastically. "
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    ABSTRACT: Exertional heat stroke (EHS) is one of the leading causes of sudden death in sport and physical activity. In American Football alone, there have been 46-documented EHS fatalities in the United States between 1995 and 2010. In 2003, National Collegiate Athletics Association mandated pre-season heat acclimatization guidelines, which successfully decreased the number of heat stroke fatalities in collegiate American football. However, despite the advancement in modern medical care and increased awareness in heat safety, lack of appropriate on-site medical care is still contributing to EHS seen especially in the youth level. It is well established in scientific literature that fatalities as a result of EHS are largely preventable with proper education on the knowledge of recognition, treatment, and prevention of EHS. This document provides a review of the current best medical practices and evidence on the epidemiology, pathophysiology, risk factors, recognition, treatment, prevention, and return to play recommendations for EHS, specifically as they relate to sport and physical activity Heat Stroke in Physical Activity and Sport. Available from: [accessed Dec 6, 2015].
    Full-text · Article · Dec 2014
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