Effects of sarin on temperature and activity of rats as a model for gulf war syndrome neuroregulatory functions.

Coexposure to subclinical levels of nerve gas and to heat stress may have induced some of the clinical symptoms of the Gulf War Syndrome. We tested the hypothesis that single or repeated subclinical exposure to sarin, particularly under conditions of heat stress, would impair regulation of body temperature and locomotor activity. Male F344 rats were housed at 25 degrees C or under mild heat stress at 32 degrees C and were exposed 1 h/day for 1, 5, or 10 days to 0, 0.2, or 0.4 mg/m(3) of sarin in a nose-only exposure system. Body temperature and activity were monitored continuously by telemetry during exposure and 1 month postexposure. Exposed rats showed no clinical symptoms of toxicity such as tremors, despite evidence of reduced red blood cell cholinesterase activity. Heat stress consistently elevated body temperature in unexposed animals, particularly during the dark period when animals are most active. Inhalation of sarin gas at the two subclinical levels did not affect body temperature acutely in a biologically meaningful manner after the first exposure nor after 5 or 10 repeated exposures, either at thermoneutral ambient temperature or during chronic heat stress. There were no consistent effects of sarin or housing temperature on activity. The data suggest that subclinical levels of sarin have minimal effects on temperature regulation and locomotor activity under these observation conditions.

Role of alpha(2)-macroglobulin in fever and cytokine responses induced by lipopolysaccharide in mice.

Alpha(2)-macroglobulin (alpha(2)M) is not only a proteinase inhibitor in mammals, but it is also a specific cytokine carrier that binds pro- and anti-inflammatory cytokines implicated in fever, including interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha). To define the role of alpha(2)M in regulation of febrile and cytokine responses, wild-type mice and mice deficient in alpha(2)M (alpha(2)M -/-) were injected with lipopolysaccharide (LPS). Changes in body temperature as well as plasma levels of IL-1beta, IL-6, and TNF-alpha and hepatic TNF-alpha mRNA level during fever in alpha(2)M -/- mice were compared with those in wild-type control mice. The alpha(2)M -/- mice developed a short-term markedly attenuated (ANOVA, P < 0.05) fever in response to LPS (2.5 mg/kg ip) compared with the wild-type mice. At 1.5 h after injection of LPS, the plasma concentration of TNF-alpha, but not IL-1beta or IL-6, was significantly lower (by 58%) in the alpha(2)M -/- mice compared with their wild-type controls (ANOVA, P < 0.05). There was no difference in hepatic TNF-alpha mRNA levels between alpha(2)M -/- and wild-type mice 1.5 h after injection of LPS. These data support the hypotheses that 1) alpha(2)M is important for the normal development of LPS-induced fever and 2) a putative mechanism of alpha(2)M involvement in fever is through the inhibition of TNF-alpha clearance. These findings indicate a novel physiological role for alpha(2)M.

IL-6 and IL-1 beta in fever. Studies using cytokine-deficient (knockout) mice.

Previous data support the hypothesis that during inflammation, interleukin (IL)-1 beta and IL-6 are involved in fever, in activation of the hypothalamic-pituitary-adrenal (HPA) axis, and in the induction of eicosanoids. Most of the pathophysiologic effects of IL-1 beta and Il-6 are mediated by prostaglandins (PGs), modulated by other cytokines, and antagonized by glucocorticoids (GC), a final product of the HPA axis. To further test these relationships, we measured changes in body temperature using biotelemetry in mice deficient in genes for IL-1 beta and/or IL-6 (IL-1 beta knockout [KO] and IL-6 KO) following injection with lipopolysaccharide (LPS) to induce systemic inflammation or turpentine to induce local abscess. Circulating IL-6, tumor necrosis factor alpha (TNF-alpha), GC, and PGE2 were measured in these mice after treatment. IL-1 beta KO mice responded with reduced fever and IL-6 KO mice with normal fever to a high dose of LPS. In contrast, neither type of KO mice produced fever to turpentine. PGE2 levels (measured in the circulation) were suppressed in both types of KO mice injected with turpentine. IL-1 beta KO mice showed deficiency in IL-6 following turpentine, but not LPS, injection. LPS-induced increases in TNF-alpha did not differ between IL-1 beta KO mice and their wild-type counterparts, whereas IL-6 KO mice showed exacerbated LPS-induced circulating TNF-alpha. No differences were noted in plasma elevations of GC between KO and wild-type mice following injection of LPS or turpentine, indicating that IL-1 beta and IL-6 are not required for activation of the HPA axis during inflammation. Our data demonstrate that in the mouse, IL-1 beta and IL-6 are critical for the induction of fever during local inflammation, whereas in systemic inflammation they appear only to contribute to fever.

Role of IL-10 in inflammation. Studies using cytokine knockout mice.

Interleukin-10 (IL-10) inhibits the synthesis of proinflammatory cytokines known to be involved in fever, including IL-1, IL-6, and tumor necrosis factor-alpha. We hypothesized that IL-10 modulates lipopolysaccharide (LPS)-induced fever in mice. Body temperature was measured by biotelemetry. Swiss Webster mice injected with recombinant murine IL-10 (rmuIL-10) were resistant to fever induced by a low dose of LPS (100 micrograms/kg, i.p.) and to the hypothermic and febrile effects of a high (septic-like) dose of LPS (2.5 mg/kg, i.p.). Injection of rmuIL-10 alone had no effect on afebrile body temperature of Swiss Webster mice. IL-10 knockout mice showed an exacerbated and prolonged fever in response to a low dose of LPS (50 micrograms/kg, i.p.) compared to their wild-type counterparts. These data support the hypothesis that IL-10 acts as an endogenous cryogen during LPS-induced fever in mice.

Role of fever in disease.

Infection, trauma, and injury result in a stereotypical response that includes loss of food appetite, increased sleepiness, muscle aches, and fever. For thousands of years fever was considered a protective response, and fevers were induced by physicians to combat certain infections. But with the advent of antipyretic drugs, physicians started to reduce fevers, and fever therapy was virtually abandoned. As a result of (1) studies on the evolution of fever, (2) further understanding of just how tightly the process of fever is regulated, and (3) detailed studies on how fever affects host morbidity and mortality, the view of fever as a host defense response has reemerged. However, data indicate that not all fevers are protective and that high fevers are maladaptive. These issues are discussed in the context of the evolution of host defense responses versus modern medical technology. In short, we speculate that patients who would not have survived severe sepsis in the past are now being kept alive and that the occasionally high fevers seen in these patients may be maladaptive.