Protection from lethal endotoxic shock after testosterone depletion is linked to chromosome X.

Men are considered more susceptible to sepsis after severe injury than are women, which has been attributed to a suppressing effect of male sex steroids on the inflammatory response. Moreover, the effect of sex steroids on the inflammatory process depends on the genetic background. The present study examined the genetic contribution to survival after endotoxic shock in mice depleted of testosterone by surgical castration. Six-week-old male mice, from strains A/J, AKR/J, C57BL/6J (B6), BALBc/J, DBA/2J, and C3H/HeN, were castrated (CX) or nonoperated (NoOp). Two weeks after surgery, mice were injected intraperitoneally with Escherichia coli lipopolysaccharide (15 mg/kg) and the frequency of mortality was monitored. CX A/J mice showed a significantly higher survival rate than NoOp mice, but this protective effect was not observed in the other strains. Administration of 5-alpha-dihydrotestosterone to CX A/J mice reverted the protection by CX. The protective effect of CX was also observed in crosses of female A/J and male B6 (AXB), but not female B6 and male A/J (BXA), suggesting that protection is linked to the A/J X chromosome. This possibility was corroborated by using consomic mice containing A/J chromosome X and the remaining chromosomes from B6. These results suggest that testosterone is a negative factor in the recovery from endotoxic shock, depending on the genetic background.

Accelerated recovery after endotoxic challenge in heat shock-pretreated mice.

The inflammatory response induced by bacterial lipopolysaccharide (LPS) has profound metabolic and physiological effects. Thus hepatic glucose production is depressed after LPS administration, which is, at least in part, due to the downregulation of phosphoenolpyruvate carboxykinase (PEPCK) expression. PEPCK is a key regulatory enzyme of the gluconeogenic pathway. Expression of heat shock proteins (hsps) is a well-conserved response to stress correlated with protection from subsequent insults including inflammation. In this study, the expression of PEPCK was observed to be preserved after injection of LPS in heat shock-pretreated mice. Protection of PEPCK expression was limited to the time after heat shock treatment that displayed hsp70. Comparison of the transcription rate and mRNA levels of PEPCK after LPS injection between mice that were heat shock pretreated or not indicated that the preservation of PEPCK expression was not due to initial protection from the LPS challenge. On the contrary, it was mediated by a rapid recovery after the LPS insult at the level of transcription. These observations suggest that the mechanism of heat shock-mediated protection (stress tolerance) after LPS challenge is due to an increase in the capacity of the organism to recover rather than deterrence from the insult.