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HEAT STROKE: BIOMARKERS OF LONG TERM INJURY AND RECOVERY

HEAT STROKE: BIOMARKERS OF LONG TERM INJURY AND RECOVERY. Lisa R. Leon, Ph.D. Thermal & Mountain Medicine Division US Army Research Institute of Environmental Medicine. Thermoregulatory “Instability”. Hypothermia and Recurrent Fever Despite Treatment ― damage not detected in

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HEAT STROKE: BIOMARKERS OF LONG TERM INJURY AND RECOVERY

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  1. HEAT STROKE: BIOMARKERS OF LONG TERM INJURY AND RECOVERY Lisa R. Leon, Ph.D. Thermal & Mountain Medicine Division US Army Research Institute of EnvironmentalMedicine

  2. Thermoregulatory “Instability” Hypothermia and Recurrent Fever Despite Treatment ― damage not detected in hypothalamus Sepsis Criteria Tc < 36.5°C = Hypothermia Tc > 38.5°C = Fever Malamud, Haymaker & Custer. Mil. Surg., 1946 Leithead & Lind. Heat Stress & Heat Disorders, 1964

  3. Cytokines Correlate with Morbidity / Mortality Correlative data: High circulating cytokine / cytokine receptor levels in heat stroke patients & animal models IL-1, IL-1, IL-1ra, IL-6, IL-10, IL-12, IFN, TNFa, sIL-6R, sTNFr Bouchama et al. J. Appl Physiol., 1991

  4. PBMC Gene Expression Changes Sonna et al. J. Appl. Physiol., 2004 Gene expression is time-dependent Long-term changes unknown Gene Expression = Protein Expression

  5. Understanding the Long-Term Consequences of Heat Stroke Exertional Heat Stroke, Military Population Ratio of mortality rates for HI to APX subjects. TAIHOD database Wallace et al. Environ. Res., 2007

  6. Mechanisms of Long-Term Heat Injury Systemic Inflammatory Response Syndrome (SIRS) A Cytokine Storm Heat stress is the precipitatingevent ― long-term sequelae due to pathophysiological responses to tissue injury / sepsis Bouchama & Knochel. N. Eng. J. Med., 2002

  7. Knowledge Gaps ― Are circulating proteins (e.g., cytokines) appropriate biomarkers of tissue injury / recovery of function? ― What is correlation of thermoregulatory / cardiovascular changes with multi-organ injury / recovery? ― What is the time course of tissue injury / reset during long-term heat stroke recovery? homeostasis vs. stress-responsiveness

  8. Romanovsky & Blatteis. J. Appl. Physiol., 1996 Rodent Models of Heat Stroke to Study Long-Term Tissue Injury / Reset Previous Experimental Limitations: ―restraint / anesthesia ―thermoregulatory inhibitors ― cytokine stimulants ―prevent study of long-term changes ―heat shock rather than heat ‘stroke’ ―mortality as an endpoint

  9. Heat Stroke Induces Hypothermia / Fever Conscious Mouse Heat Stroke Model Biomarkers: ―Hypothermia ― sensitive biomarker of heat severity ― critical to survival (humans?) ―Fever ―inappropriate biomarker of heat severity ― infection response (GI leakage)

  10. Cytokine Milieu Changes During 24h Recovery 11 cytokines measured, 4 detected Conclusions: Cytokine milieu changes over course of recovery ― increased cytokine production associated with Tc “instability” Undetected cytokines (e.g., TNFa) ― cell associated effects Leon et al. J. Appl. Physiol., 2006

  11. ++IL-6 IL-12p40 IL-1b, IL-6, IL-10 Cytokine:Soluble Receptor Relationship

  12. ++IL-6 IL-12p40 IL-1b, IL-6, IL-10 Cytokine:Soluble Receptor Relationship

  13. Increased Heat Stroke Mortality in Cytokine Knockout Mice IL-6 Knockout Mice TNFR Knockout Mice Leon LR. J. Therm. Biol., 2006 ― permissive actions critical ― IL-6 highest at hypothermia depth ― TNF not detected in plasma

  14. Tissue Injury Progression in Heat Stroke Survivors 9 Organs Examined: Brain, heart, lung, liver, spleen, kidney, small intestine, large intestine, muscle Adapted from: Leon et al. J. Appl. Physiol. 2006

  15. Breakdown in Integration of Thermoregulatory Control Mechanisms Cerebellum Heat Control ― No damage in cerebellum

  16. Breakdown in Integration of Thermoregulatory Control Mechanisms Regulated hypothermia with improper integration of sensory afferent (Tc) signals Tissue injury improperly reflects tissue function Behavioral analysis is window into tissue function Moved to 31°C

  17. Early Liver Cytoprotective Functions Time Course of HSP70 Expression Liver * * ― Liver damage undetectable through 24-h of recovery ― Similar HSP70 response in the heart ― undetectable damage * Leon LR. Prog. Brain Res., 2007

  18. Early Liver Acute Phase Response Liver IL-6 Expression at Hypothermia Heat Stroke Control IL-6 staining confined to the centrolobular region, an area associated with acute phase protein synthesis. Leon LR. Prog. Brain Res., 2007

  19. Liver Damage in Long-Term Survivors Day 3 Hypothermia Renal damage “fatty liver” Leon LR. Prog. Brain Res., 2007 Time required to re-establish homeostatic function / tolerate severe heat strain unknown

  20. Multi-Variable Analysis Using a Conscious Rat Heat Stroke Model ―Tc, BP, HR collected every 1-minute through 10-days of recovery ― Tissue injury visually assessed at day 10 recovery Radiotelemetry

  21. Thermoregulatory / Cardiovascular Instability in Heat Stroke Survivor

  22. Renal Damage in Heat Stroke Survivor Recovery Day 10 Control Heat Core temperature, HR, BP show normal circadian rhythmicity from day 8-10 recovery

  23. Conclusions ―Tc, HR, BP, protein, & tissue injury responses dysregulated from one another during recovery ― Time to reset unknown ― Tc, HR, BP are insensitive measures of recovery / reset ― Circulation / tissue injury measures not always reflective of tissue function ― Restoration of homeostatic function may not reflect ability to tolerate subsequent exercise heat strain

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