INDUCTION OF THE HEAT-SHOCK RESPONSE REDUCES MORTALITY-RATE AND ORGAN DAMAGE IN A SEPSIS-INDUCED ACUTE LUNG INJURY MODEL

Objective: To test the hypothesis that induction of heat shock proteins before the onset of sepsis could prevent or reduce organ injury and death in a rat model of intra-abdominal sepsis and sepsis-induced acute lung injury produced by cecal ligation and perforation. Design: Prospective, blind, randomized, controlled trial. Setting:: University research laboratory. Subjects: One-hundred forty-two adult Sprague-Dawley rats (weight range 200 to 300 g). Interventions: Production of intra-abdominal sepsis and exposure to heat stress. Animals were randomly divided into four groups: heated and septic, heated and sham-septic, unheated and septic, and unheated and sham-septic. Measurements and Main Results: We evaluated the mortality rate and pathologic changes in lung, heart, and liver at 18 hrs after cecal perforation, at 24 hrs after removal of the cecum, and at 7 days after perforation. Heated animals exhibited a maximum increase in heat shock protein of 72 kilodalton molecular weight protein concentrations in the lungs and heart 6 to 24 hrs after the hyperthermic stress. By 18 hrs after perforation, 25% of the septic, unheated animals had died whereas none of the septic heated animals had died (p <.005). Septic, heated animals showed a marked decrease in 7-day mortality rate (21%) compared with septic unheated animals (69%) (p <.01). Furthermore, septic heated animals showed less histologic evidence of lung: and liver damage than septic unheated animals. Conclusions: These data suggest that thermal pretreatment, associated with the synthesis of heat shock proteins, reduces organ damage and enhances animal survival in experimental sepsis-induced acute lung injury. Although the mechanisms by which heat shock proteins exert a protective effect are not well understood, these data raise interesting questions regarding the importance of fever in the protection of the whole organism during bacterial infection.