Metyrapone restores the febrile response to Escherichia coli LPS in pregnant rats

Abstract

Alexander BN, Fewell JE. Metyrapone restores the febrile response to Escherichia coli LPS in pregnant rats. Am J Physiol Regul Integr Comp Physiol 300: R1588 -R1595, 2011. First published April 13, 2011 doi:10.1152 doi:10. /ajpregu.00785.2010 an important component of the host's defense response to immune challenge, is absent or attenuated in rats near the term of pregnancy. The present experiments were carried out to determine the role of endogenous glucocorticoids in mediating the altered core temperature (Tc) response to exogenous pyrogen (i.e., Escherichia coli LPS). For the experiments, metyrapone-a glucocorticoid synthesis inhibitor-was administered to near-term pregnant rats prior to an EC100 dose of E. coli LPS. Administration of LPS following vehicle elicited a significant corticosterone response and resulted in a decrease in Tc (i.e., hypothermia). Prior administration of metyrapone, however, which abolished the corticosterone response and altered the pyrogenic/ cryogenic cytokine response to LPS, eliminated hypothermia and restored the febrile response. Our results provide evidence that endogenous glucocorticoids play a role in mediating the altered febrile response to immune stimuli observed in rats near the term of pregnancy.glucocorticoids; hypothermia; infection NUMEROUS PHYSIOLOGICAL CHANGES accompany the maternal adaptation to pregnancy in rats, including reversible changes in blood hormone concentrations (e.g., corticosterone) and basal thermoregulatory control, as well as the cytokine, prostanoid, and Tc responses to immune challenge (4,17,19,21,34). For example, Fofie and Fewell (21) observed that Tc responses to intraperitoneal administration of 160 g/kg Escherichia coli LPS (EC 100 in nonpregnant rats) are different in pregnant rats as early as day 10 of the 21-day gestational period compared with nonpregnant oophorectomized rats. In nonpregnant rats, 160 g/kg E. coli LPS elicits an increase in Tc (i.e., a fever) with a latency, magnitude, and duration of 1.5 h, 1.9°C, and at least 4.5 h, respectively (21). Accompanying the febrile response are significant increases in plasma IL-1␤, IL-6, TNF-␣, and IL-1ra (22). In pregnant rats, however, 160 g/kg E. coli LPS elicits a "regulated" decrease in Tc (i.e., hypothermia)-the magnitude and duration of which increase with increasing LPS dose and gestation-before a modest increase in Tc above baseline is recorded (21, 52); accompanying the hypothermia are significant increases in plasma TNF-␣, and IL-ra, but not IL-1␤ and IL-6 (22). The mechanism and consequences for the mother and fetus of this altered thermoregulatory component of the acute phase response remain largely unknown.It has long been known that glucocorticoids have an antipyretic action on natural fevers in man (27), and Coelho et al.(13) and Morrow et al. (38) have shown that endogenous glucocorticoids modulate bacterial pyrogen-induced fever in male rats. Furthermore, Moore and Fewell (36) have recently shown that oral administration of mifepristone (RU38486)-a progesterone and gl...

Hypometabolism and hypothermia in the rat model of endotoxic shock: independence of circulatory hypoxia

“…An important mechanistic implication of these findings is that by not supporting the hypothesis that hypothermia results from hypoxia in endotoxic shock, they favour the alternate hypothesis that the balance between fever and hypothermia in systemic inflammation is an inherent property of immune-to-brain signalling. The latter hypothesis has received some attention, and is partly supported by evidence suggesting the existence of distinct inflammatory pathways for the mediation of fever versus hypothermia in animal models of systemic inflammation (Paul et al 1999;Dogan et al 2002;Nautiyal et al 2009;Steiner et al 2009;Krall et al 2010;Alexander & Fewell, 2011). None the less, it should be noted that even if hypothermia in endotoxic shock is not caused by hypoxia, it could still serve as a pre-emptive strategy to avoid the development of hypoxia.…”

“…; Krall et al . ; Alexander & Fewell, ). None the less, it should be noted that even if hypothermia in endotoxic shock is not caused by hypoxia, it could still serve as a pre‐emptive strategy to avoid the development of hypoxia.…”

Sex steroid levels near the term of pregnancy do not alter lipopolysaccharide‐induced fever in oophorectomized rats

“…Tumour necrosis factor‐α appears to play an important role in mediating the early LPS‐induced regulated hypothermia in pregnant rats, because the core temperature response is abated if one eliminates the increase in TNF‐α by blocking the LPS‐induced corticosterone surge (Alexander & Fewell, ) or administers an antibody to tumour necrosis receptor I (which neutralizes its cell surface‐mediated activity) prior to administration of LPS (Fewell et al . ).…”

“…TNF‐α and IL‐ra) to pyrogenic cytokines (i.e. IL‐1β and IL‐6) and restores the late thermoregulatory response to E. coli LPS in pregnant rats (Alexander & Fewell, ).…”

“…Tumour necrosis factor-α appears to play an important role in mediating the early LPS-induced regulated hypothermia in pregnant rats, because the core temperature response is abated if one eliminates the increase in TNF-α by blocking the LPS-induced corticosterone surge (Alexander & Fewell, 2011) or administers an antibody to tumour necrosis receptor I (which neutralizes its cell surface-mediated activity) prior to administration of LPS (Fewell et al 2010). Tumour necrosis factor-α is released into the circulation of rats as a burst in response to LPS and appears relatively early in comparison to other cytokines, with a maximal serum concentration occurring at 60-90 min; furthermore, it is eliminated from the serum relatively quickly according to first-order kinetics, with a calculated half-life of 27 ± 7 min (Waage, 1987).…”