To determine whether immune disturbances during exertional heat injury (EHI) could be distinguished from those due to exercise (E), peripheral lymphocyte subset distributions and phytohemagglutinin-stimulated CD69 mitogen responses as discriminated by flow cytometry were studied in military recruits [18.7 +/- 0.3 (SE) yr old] training in warm weather. An E group (3 men and 3 women) ran 1.75-2 miles. During similar E, 11 recruits (10 men and 1 woman) presented with suspected EHI. EHI (40.4 +/- 0.3 degrees C) vs. E (38.6 +/- 0.2 degrees C) body temperature was significantly elevated (P < 0.05). Heat illness was largely classified as EHI, not heatstroke, because central nervous system manifestations were generally mild. Blood was collected at E completion or EHI onset (0 h) and 2 and 24 h later. At 0 h (EHI vs. E), suppressor, natural killer, and total lymphocyte counts were significantly elevated, helper and B lymphocyte counts remained similar, and the helper-to-suppressor ratio was significantly depressed. By 2 h, immune cell dynamics between groups were similar. From 0 to 24 h, T lymphocyte subsets revealed significantly reduced phytohemagglutinin responses (percent CD69 and mean CD69 fluorescent intensity) in EHI vs. E. Thus immune cell dynamics with EHI were distinguishable from E. Because heat stress as reported in exercise or heatstroke is associated with similar immune cell disturbances, these findings in EHI contributed to the suggestion that heat stress of varying severity shares a common pathophysiological process influencing the immune system.

Immune system cytokines induce vascular shock. Tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta), and bacterial endotoxin (E) circulate in human heatstroke to suggest that E release from a heat-damaged gut may stimulate cytokines that contribute to hypovolemia. However, immune activation by heat-induced tissue necrosis might stimulate cytokine generation in the absence of E. To evaluate this potential and heat stress effects on the anti-inflammatory cytokines, IL-1 receptor antagonist (IL-1ra) and IL-1 soluble receptor II (IL-1srII), a human whole blood (HWB) model was employed in which the presence or absence of E could be controlled. Using thermoelectric technology to regulate the HWB heat exposures, the temperature modulations of lethal heatstroke were precisely replicated (maximum temperature = 42.4 degrees C +/- 0.04 degrees C; thermal area = 52.3 degrees C +/- 1.5 degrees C per min). Cytokine and mRNA measurements employed enzyme-linked immunosorbant-based assay systems. Significant elevations in TNF-alpha, IL-1beta, interleukin 6 (IL-6), and IL-1ra resulted when HWB was exposed to E concentrations (10 ng/ml) reported to circulate in heatstroke. While E-stimulated IL-1ra was significantly decreased by the presence of prior heat stress (PPHS), E-stimulated IL-1beta, TNF-alpha, and IL-6 were not significantly altered by PPHS, but tended to be elevated. IL-1srII expression was unchanged by PPHS and/or E. PPHS in the absence of E did not induce cytokine responses, nor were there elevations in TNF-alpha or IL-1beta mRNA. Thus, some factor normally absent under in vitro conditions, like endotoxin, was required to provoke HWB cytokine expressions and the heat stress and E conditions that characterize heatstroke affected HWB cytokine metabolism to favor a proinflammatory environment.

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Environmental heat stress may result in loss of fluid from the vascular space, which can lead to circulatory shock. Since the endothelium serves as the blood vessel barrier between the vascular and interstitial spaces, direct heat damage to this tissue may contribute to such fluid loss. This study modeled heat influences on the actin cytoskeletal proteins that provide the tensile forces that sustain endothelial junctional integrity or barrier function. Heat effects on bovine aortic endothelial cell (BAEC) F-actin and F-actin stress fibers (FASFs) were correlated with intercellular permeability (IP). F-actin concentration and FASF distribution were analyzed by quantitation of the specific binding of rhodamine phalloidin (RP) to F-actin and by observing the fluorescence of RP-FASF complexes, respectively. Dextran fluorescein IP was determined. The IP was elevated (p < 0.05) at 43 degrees C, but not at 41 degrees C. At 43 degrees C, BAECs were rounded and had disrupted FASFs and diminished cell-to-cell apposition. Similar cells were seen at 41 degrees C, but these were interspersed among FASF-containing cells to sustain apposition. Thus, disruption of FASFs correlated with increases in IP. F-actin was increased (p < 0.05) after hyperthermia. Since G-actin is more susceptible to irreversible heat denaturation, F-actin sustainment may function to preserve the actin pool and prevent irrevocable loss of the blood vessel barrier after heat stress.