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.


METHODS
Prospective, blind, randomized, controlled trial.


METHODS
University research laboratory.


METHODS
One-hundred forty-two adult Sprague-Dawley rats (weight range 200 to 300 g).


METHODS
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.


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.
Villar
J
J
Department of Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
Ribeiro
S P
SP
Mullen
J B
JB
Kuliszewski
M
M
Post
M
M
Slutsky
A S
AS
D000818:Animals; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D006979:Hyperthermia, Induced; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D008970:Molecular Weight; D009102:Multiple Organ Failure / Q000209:etiology / Q000401:mortality / Q000473:pathology / Q000517:prevention & control; D011446:Prospective Studies; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D012772:Shock, Septic / Q000150:complications / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D013312:Stress, Physiological / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
D006360:Heat-Shock Proteins