Heat stroke biomarkers of long term injury and recovery
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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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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 EnvironmentalMedicine


Heat stroke biomarkers of long term injury and recovery

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


Heat stroke biomarkers of long term injury and recovery

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


Heat stroke biomarkers of long term injury and recovery

PBMC Gene Expression Changes

Sonna et al. J. Appl. Physiol., 2004

Gene expression is time-dependent

Long-term changes unknown

Gene Expression = Protein Expression


Heat stroke biomarkers of long term injury and recovery

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


Heat stroke biomarkers of long term injury and recovery

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


Heat stroke biomarkers of long term injury and recovery

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


Heat stroke biomarkers of long term injury and recovery

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


Heat stroke biomarkers of long term injury and recovery

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)


Heat stroke biomarkers of long term injury and recovery

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


Heat stroke biomarkers of long term injury and recovery

++IL-6

IL-12p40

IL-1b, IL-6, IL-10

Cytokine:Soluble Receptor Relationship


Heat stroke biomarkers of long term injury and recovery

++IL-6

IL-12p40

IL-1b, IL-6, IL-10

Cytokine:Soluble Receptor Relationship


Heat stroke biomarkers of long term injury and recovery

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


Heat stroke biomarkers of long term injury and recovery

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


Heat stroke biomarkers of long term injury and recovery

Breakdown in Integration of Thermoregulatory

Control Mechanisms

Cerebellum

Heat

Control

― No damage in cerebellum


Heat stroke biomarkers of long term injury and recovery

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


Heat stroke biomarkers of long term injury and recovery

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


Heat stroke biomarkers of long term injury and recovery

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


Heat stroke biomarkers of long term injury and recovery

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


Heat stroke biomarkers of long term injury and recovery

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


Heat stroke biomarkers of long term injury and recovery

Thermoregulatory / Cardiovascular

Instability in Heat Stroke Survivor


Heat stroke biomarkers of long term injury and recovery

Renal Damage in Heat Stroke Survivor

Recovery Day 10

Control

Heat

Core temperature, HR, BP show normal circadian

rhythmicity from day 8-10 recovery


Heat stroke biomarkers of long term injury and recovery

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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