INDUCTION OF THE HEAT-SHOCK RESPONSE PREVENTS TISSUE-INJURY DURING ACUTE-INFLAMMATION OF THE RAT ILEUM

Objectives: To determine if prior total body hyperthermia protected ag ainst subsequent acute ileitis induced by the cytotoxic lectin, ricin, in rats. The time course of heat shock mRNA and protein expression in the ileum was determined. The effects of heat stress on small intesti nal mucosal integrity, arachidonic acid metabolism, and neutrophilic i nfiltrate were compared in heated and nonheated rats receiving vehicle or ricin intraluminally. The effect of hyperthermia on the circulatin g neutrophil superoxide production was also evaluated. Design: Prospec tive, randomized, controlled trial. Setting: University research labor atory. Subjects: Forty-one adult, male Sprague-Dawley rats, weighing 1 50 to 250 g, and 32 adult, inbred, male Fisher 344 rats, weighing 175 to 250 g. Interventions: Exposure to whole body hyperthermia and produ ction of acute ileitis. Sprague-Dawley rats were divided randomly into four experimental groups: nonheated control group, heated control gro up, nonheated ricin group (1 mg/mL water, intraluminal), and heated ri cin group. Sprague-Dawley rats in a separate study were assigned to se ven groups based on the time of removal of the terminal ileum followin g hyperthermia: 0 min, or 1, 2, 4, 8, 12, and 24 hrs. Inbred Fisher 34 4 rats were allocated to the heated and nonheated groups for periphera l neutrophil superoxide generation studies. Measurements and Main Resu lts: Whole body hyperthermia to a rectal temperature of 41 degrees C t o 42 degrees C for 15 to 20 mins: a) was associated with marked mucosa l cytoprotection against subsequent ricin-induced ileitis (Injury grad e [from 0 = normal to 5 = severe]: 0.4 +/- 0.1 vs. 2.5 +/- 0.2, p<.001 ); b) prevented the ricin-induced reduction in villus height to crypt depth ratio (2.4 +/- 0.1 vs. 1.9 +/- 0.1, p <.01); and c) significantl y reduced the number of infiltrating neutrophils when compared with no nheated ricin-treated rats (11 +/- 2 vs. 32 +/- 3 neutrophils/high-pow er field, p<.001). The hyperthermia-induced peak increase in heat shoc k protein (HSP)-70 mRNA at 2 hrs preceded that of HSP 70i at 4 hrs. He at shock significantly reduced the ricin-induced increase in both basa l (8.0 +/- 1.9 vs. 33.0 +/- 8.1 pg of leukotriene B-4/mg protein, p<.0 5) and ionophore-stimulated (16.0 +/- 4.9 vs. 80.0 +/- 15.5 pg of leuk otriene B-4/mg protein, p <.001) generation of ileal leukotriene B-4, but did not alter the cyclooxygenase product, prostaglandin E(2). Hype rthermia did not alter peripheral neutrophil superoxide production. Co nclusions: This study assessed the effects of heat shock in the normal and acutely inflamed intestine. These data suggest that heat stress a nd increased expression of HSP 70i protect against acute intestinal in flammation. This protection is associated with significant reductions in ileal leukotriene B-4 generation and neu trophilic infiltrate. Hype rthermia did not alter circulating neutrophil superoxide production. T hus, the mechanism of heat stress protection against acute ileitis may involve local intestinal inhibition of leukotriene B-4 production and subsequent neutrophilic infiltration without altering the ability of systemic neutrophils to be activated.