Our laboratory has previously shown decreased mortality rates and the attenuation of lung injury in rats exposed to heat stress (H) 18 h prior to induction of sepsis. In the present study, we examined the hypothesis that heat stress would protect lungs against ventilator-induced lung injury. Male Sprague-Dawley rats were anesthetized and randomly allocated to receive either sham treatment or exposure to heat (rectal temperature 41 degrees C, for 15 min). The lungs were harvested 18 h later, a pressure-volume (P- V) curve was constructed, and the lungs were either lavaged for cytokine and surfactant analyses (preventilation data) or were mechanically ventilated with VT 40 ml/kg in a warmed, humidified chamber. After 2 h of mechanical ventilation, another P-V curve was constructed and the lungs were lavaged for cytokine and surfactant analyses (postventilation data). Mechanical ventilation in control lungs produced a 47% decrease in chord compliance, an increase in lung lavage levels of tumor necrosis factor (TNF)-alpha (722 +/- 306 pg/ml), interleukin (IL)-1beta (902 +/- 322 pg/ml), and macrophage inflammatory protein-2 (MIP-2) (363 +/- 104 pg/ml) as compared with low levels of cytokines detected in preventilation data, and no change in percentage of surfactant large aggregates (LA). In contrast, in mechanically ventilated lungs from animals that were exposed to heat stress we observed a smaller decrease in chord compliance (17%), a significant attenuation in cytokine levels (TNF-alpha 233 +/- 119 pg/ml; IL-1beta 124 +/- 53 pg/ml; MIP-2 73 +/- 52 pg/ml; p < 0.05) and a significant increase in percentage LA compared with control animals. We conclude that exposing animals to heat stress confers protection against the effects of an injurious form of mechanical ventilation, by a mechanism that may involve attenuation of cytokines and preservation of some surfactant properties.