Suppression of endotoxin-induced fever in near-term pregnant rats is mediated by brain nitric oxide

Abstract

Begg DP, Kent S, McKinley MJ, Mathai ML. Suppression of endotoxin-induced fever in near-term pregnant rats is mediated by brain nitric oxide. Am J Physiol Regul Integr Comp Physiol 292: 2174-2178, 2007. First published March 1, 2007; doi:10.1152/ajpregu.00032.2007.-Over the last three decades, experiments in several mammalian species have shown that the febrile response to bacterial endotoxin is attenuated late in pregnancy. More recent evidence has established that the expression of nitric oxide synthase (NOS) enzymes is increased in the brain late in pregnancy. The current study investigated the possible role of brain nitric oxide in mediating the phenomenon of fever suppression. Core body temperature (T b) of near-term pregnant rats (day 19 and 20) was measured following inhibition of brain NOS and intraperitoneal injection of LPS (50 g/kg); they were compared with both day 15 pregnant and virgin animals. Intracerebroventricular injection with an inhibitor of NOS, N G -monomethyl-L-arginine citrate (L-NMMA; 280 g), in near-term pregnant rats restored the febrile response to LPS. As expected, near-term dams that received intracerebroventricular vehicle ϩ IP LPS did not increase T b, in contrast to the 1.0 Ϯ 0.2°C rise in Tb in dams treated with ICV L-NMMA ϩ IP LPS (P Ͻ 0.01). In virgin females and day 15 pregnant controls receiving this treatment, the increases in T b were 1.5 Ϯ 0.3°C and 1.6 Ϯ 0.4°C, respectively. Thus, blockade of brain NOS restored the febrile response to LPS in near-term dams; at 5 h postinjection, T b was 60 -70% of that observed in virgins and day 15 pregnant animals. Intracerebroventricular L-NMMA alone did not induce a significant change in Tb in any group. These results suggest that the mechanism underlying the suppression of the febrile response in near-term pregnancy is mediated by nitric oxide signaling in the brain. nitric oxide synthase; N G -monomethyl-L-arginine citrate; lipopolysaccharide; core body temperature; thermoregulation FEVER IS A REGULATED INCREASE in core body temperature (T b ) caused by initiation of heat-conserving and heat-producing systems. It plays a crucial role in the physiological response to infection by pathogens, improving the efficiency of lymphocytes and reducing the replication of many microorganisms (23). Fever can be caused by a number of different stimuli, such as infection with bacteria and viruses (27) or by stress (13,17). It has been widely documented that these factors result in the release of proinflammatory cytokines from macrophages (11). This results in the stimulation of central and peripheral cyclooxygenase (COX) enzymes that catalyze the synthesis of PGs (10). The enzymes COX-1 and COX-2 are the ratelimiting step in the production of PGs, and inhibition of COX blocks the febrile response (39). PGE 2 has been seen traditionally as the final step in the process of fever generation. The febrile response is integral to the body's defense against infection; however, if T b becomes excessively high, it endangers the host, as these temperatu...

Reversal of Diet-Induced Obesity Increases Insulin Transport into Cerebrospinal Fluid and Restores Sensitivity to the Anorexic Action of Central Insulin in Male Rats

“…They were shaved and positioned with the skull horizontal in a stereotaxic instrument (David Kopf Instruments, Tujunga, California), as previously described (26). After a small hole was drilled through the skull at a position 2.2 mm posterior to bregma, on the midline, the sagittal sinus was displaced laterally, and a stainless steel guide cannula (Plastics One, Roanoke, Virginia) was lowered 7.5 mm ventral to the dura.…”

Acute starvation alters lipopolysaccharide-induced fever in leptin-dependent and -independent mechanisms in rats

“…These results do not support a scenario that leptin recovers the fever maintenance via PGE 2 synthesis in the fasted rats. Likewise, leptin repletion did not affect the levels of MIP-1␤, endothelin-1, and NOS-1-3 mRNA and CSF 15-D-PGJ 2 , inflammatory mediators that were reported to modulate fever independently of PGE 2 (3,32,37,38). Taken together, we concluded that fasting attenuates the late phase of fever partly through the depression of inflammation, but the leptin-mediated fever recovery is dissociated from the pyrogenic inflammatory responses in the brain.…”

“…These results indicate that while the reduced fever response on fasting is partly attributable to an attenuated central PGE 2 production, the leptin-mediated recovery of fever is not. We also examined the levels of other inflammatory variables that were reported to contribute to the fever response independent of PGE 2 synthesis (3,7,12,37,38). Neither the levels of CSF 15-D-PGJ 2 , MIP-1␤, endothelin-1, NOS-1, NOS-2, nor NOS-3 mRNA was associated with the degree of sustained fever (Table 3).…”

Prenatal Immune Stress in Rats Dampens Fever during Adulthood

“…In our study this was not the case. The innate immune response is dampened at the late phase of pregnancy in many species [13,29,30,32,52], which could explain the lack of LPS-induced programming of thermoregulation. However, it has been recently noted that prenatal injection of LPS during late pregnancy was closely associated with a dampened proinflammatory response to LPS in offspring [53].…”

“…While early- to midterm pregnant rats mount a relatively strong febrile response to LPS, near-term pregnant rats show a rather suppressed fever [13,30,31,32,33]. The consequence of these varying maternal innate immune responses to infection throughout pregnancy on fetal development is underinvestigated.…”