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Heat shock paradox: subsequent heat shock increases lethality of polymicrobial sepsis in vivo

Previous in vitro studies have shown that induction of the heat shock response (HSR) prior to an inflammatory stimulus is cytoprotective, whereas induction of HSR after an inflammatory stimulus can cause apoptosis (the heat shock paradox). We sought to determine whether induction of HSR in an animal model of sepsis caused similar, order-dependent effects on survival.

In pilot studies to calibrate the murine HSR, 20–25 g ND4 mice were anesthetized and immersed in a water bath for a total of 20 min to raise core body temperature to 37, 40 or 41.5°C (n = 3 per group). Livers were harvested 24 hours later. Western blot analyses for Heat Shock Protein-72 (HSP-72, a widely-accepted marker of HSR) showed the expression of HSP-72 at 41.5°C for 20 min but not at or below 40°C. This pattern is strain independent.

Next, the effect of HSR prior to or subsequent to cecal ligation and puncture via halothane anesthetic (CLP) upon survival was tested. 20–25 g male inbred C57-BL6 mice were randomized to one of six groups (n = 15#8211;20 per group) and heated for 20 min to either 37 or 41.5°C alone or in combination with CLP. Survival was 70% and 15% for HSR induction prior, or subsequent, to CLP respectively (P = 0.001). To exclude the possibility that the order-dependent response was strain specific, the study was repeated with outbred ND4 mice (n = 11–13 per group). In the ND4 mice, survival for HSR induction prior to CLP was 25% but following CLP was nil (P = 0.0001, Fig. 1).

Though beneficial and somehow protective when induced prior to insult, the heat shock response paradoxically increases mortality when activated after severe stress. This paradoxical potentiation of injury also appears independent of the specific strain. The susceptibility of infected animals to devastating HSR at 41.5 degrees may explain, at least in part, why human fevers are generally self-limited to 40 degrees or less.


Figure 1

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Wizorek, J., Cobb, J., Qui, Y. et al. Heat shock paradox: subsequent heat shock increases lethality of polymicrobial sepsis in vivo. Crit Care 5, P070 (2001).

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  • Heat Shock
  • Halothane
  • Core Body
  • Inflammatory Stimulus
  • Severe Stress