Induction of the heat shock response reduces mortality rate and organ damage in a sepsis-induced acute lung injury model

OBJECTIVETo 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. DESIGNProspective, blind, randomized, controlled trial. SETTINGUniversity research laboratory. SUBJECTSOne-hundred forty-two adult Sprague-Dawley rats (weight range 200 to 300 g). INTERVENTIONSProduction of intra-abdominal sepsis and exposure to heat stress. Animals were randomly divided into four groupsheated and septic, heated and sham-septic, unheated and septic, and unheated and sham-septic. MEASUREMENTS AND MAIN RESULTSWe 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. CONCLUSIONSThese 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. (Crit Care Med 1994; 22:914–921)