Dariusz Soszynski

THE ADAPTIVE VALUE OF FEVER

There is overwhelming evidence in favor of fever being an adaptive host response to infection that has persisted throughout the animal kingdom for hundreds of millions of years. As such, it is probable that the use of antipyretic/anti-inflammatory/analgesic drugs, when they lead to suppression of fever, results in increased morbidity and mortality during most infections; this morbidity and mortality may not be apparent to most health care workers because fever is only one of dozens of host defense responses. Furthermore, most infections are not life-threatening and subtle changes in morbidity are not easily detected.

Effect of nicotine on the immune system: Possible regulation of immune responses by central and peripheral mechanisms

Nicotine (NT) treatment impairs T-cell receptor (TCR)-mediated signaling, leading to the arrest of T cells in the G1 phase of the cell cycle and inhibition of the antibody plaque-forming cell (AFC) response to sheep red blood cells (SRBC). This paper summarizes some of the previous findings related to cigarette smoke/NT and the immune response, and presents preliminary evidence suggesting that mice chronically treated with NT (0.5 mg/day/kg body weight) have a depressed inflammatory response in the turpentine-induced abscess model of inflammation. This ability of nicotine to attenuate an inflammatory response may also be the cause of reduced mortality of chronically nicotine-treated mice from acute influenza A pneumonitis. Moreover, in LEW rats, decreased anti-SRBC AFC responses were also observed after intracerebroventricular (i.c.v.) administration of relatively small concentrations of NT (28 micrograms/day/kg body weight) which, when given peripherally, did not affect the AFC response. In vitro the addition of NT to T cells increased protein tyrosine kinase (PTK) activity and intracellular Ca2+ concentration [Ca2+]i. These results support the hypothesis that NT alters immune responses by directly interacting with T cells, as well as indirectly through brain-immune interactions.

Cytokines and Fever

Fever is an excellent example of neuroimmunomodulation in that mediators of immunity initiate a pathway to raise the thermoregulatory set-point, resulting in behavioral and physiological responses that increase body temperature. This rise in temperature is thought to be adaptive, facilitating host defenses. Many cytokines are endogenous mediators of fever (i.e. endogenous pyrogens), including interleukin (IL)-, 1 beta, IL-6 and others. Tumor necrosis factor-alpha may be both an endogenous pyrogen and an endogenous antipyretic or cryogen, depending on the nature of the inflammatory stimuli. Although there is evidence that cytokines within the hypothalamus initiate fever, recent findings indicate that the signal to increase these brain cytokines may be neural (i.e. from peripheral nerves), rather than humoral (i.e. circulating endogenous pyrogen).

The inhibition of nitric oxide synthase suppresses LPS- and psychological-stress-induced fever in rats.

The purpose of this study was to assess the effects of a non-selective nitric oxide synthase (NOS) inhibitor on changes in fever response due to injection of lipopolysaccharide (LPS) or on stress fever caused by exposure to an open field in freely moving biotelemetered rats. N(omega)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of all NOS-isoforms, was injected intraperitoneally (ip) at a dose of 50 mg/kg just before intraperitoneal injection of LPS at a dose of 50 microg/kg or exposure to open field. L-NAME at a dose of 50 mg/kg had no effect on normal day-time body temperature (T(b)) and normal night-time T(b). The same dose of L-NAME administered intraperitoneally caused a significant attenuation of LPS-induced fever. The thermal index calculated for rats pretreated with L-NAME and injected with LPS was reduced by approximately 75% compared to that calculated for saline-pretreated and LPS-injected rats. To examine the effect of NOS inhibition on psychological-stress-induced elevation in T(b), rats were injected intraperitoneally with L-NAME and then immediately exposed to open field for 60 min. After exposure to the open field, rats not treated with NOS inhibitor responded with a rapid rise in T(b), and it was accompanied with an increase of motor activity. L-NAME significantly suppressed the stress fever without any effect on changes in motor activity. Presented data provide clear evidence that NO formation is involved in LPS- and psychological-stress-induced fevers in rats.

Inhibition of nitric oxide synthase delays the development of tolerance to LPS in rats.

The role of nitric oxide (NO) was investigated in endotoxin (lipopolysaccharide, LPS) tolerance in freely moving biotelemetered rats. We monitored changes in febrile response and feeding behavior (food intake, water intake) during the development of tolerance to repeated intraperitoneal injections of LPS (50 microg/kg) along with injections of N(omega)-nitro-L-arginine methyl ester (L-NAME; 50 mg/kg), an inhibitor of NO synthase. Rats were treated with LPS and L-NAME for three consecutive days. On the fourth day, all rats were injected with LPS alone. Control rats were injected with saline along with saline or with L-NAME for four consecutive days. Rats repeatedly injected with LPS became tolerant to pyrogenic and hypophagic/cachexic effects of LPS as early as on the second day of experiment. The treatment with L-NAME prevented the attenuation of febrile response following the second LPS injection. Moreover, the depressive effects of LPS on body weight as well as on water and food intake were prolonged in rats treated with a combination of L-NAME and LPS. Injection of LPS caused a 3.5-fold increase in plasma nitrite within 3 h and nitrite levels remained significantly elevated 6 and 24 h after LPS. Rats injected secondly with LPS did have still 2.5- to 3-fold increase in plasma nitrite levels 3 and 6 h, but not 24 h, after injection. Third injection of LPS did not elevate nitrite level in plasma. Taken together, presented data provide clear evidence that NO formation is involved in mechanisms responsible for development of early-stage tolerance to endotoxin.

Chapter 22 Fever and antipyresis

Publisher Summary This chapter reviews the role of endogenous pyrogens and endogenous cryogens in the regulation of body temperature during fever. Fevers are triggered by the release of endogenous pyrogens from a large number of different types of macrophage-like cells. These endogenous pyrogens include the cytokines interleukin-1 (IL- 1), IL-6, and others. In addition to the release of endogenous pyrogens, there are also endogenous antipyretics or cryogens, which act to modulate the febrile rise in body temperature, thus generally preventing the body temperature from rising to the dangerous levels. Over the past few years, investigators have shown that arginine vasopressin, α -melanocyte stimulating hormone, glucocorticoids, and, in some cases, tumor necrosis factor (TNF α ) may act as endogenous antipyretics. This highly regulated nature of fever, containing factors that raise body temperature and others that prevent this rise in body temperature from becoming too high, supports the hypothesis that fever has evolved as a beneficial host defence response. There are considerable data supporting the hypothesis that cytokines are responsible for the fever associated with infection and cancer.

Endotoxin Tolerance Does Not Alter Open Field-Induced Fever in Rats

Exposure to an open field has been shown to cause a rise in the body temperature of rats. In many respects, this rise in body temperature is similar to fevers caused by endotoxin and other inflammatory stimuli. Rats repeatedly injected with endotoxin develop tolerance to the fever-inducing action of endotoxin. We hypothesized that repeated pretreatment with endotoxin would modify the fever caused by exposure to psychological stress. To test this hypothesis, we compared open field-induced fevers in rats made endotoxin tolerant to those rats not endotoxin tolerant. We found that endotoxin tolerance had no effect on open field fevers.

β-Adrenergic Receptor Subtype Effects on Stress Fever and Thermoregulation

Exposure to psychological stress increases body temperature (Tb). This stress fever may be immunologically beneficial in some patient populations but detrimental in others (e.g., HIV-infected individuals). For this reason, it is desirable to determine pharmacological methods of preventing stress fever. In rats, stress fever is modeled by exposure to a novel environment or ‘open field.’ The β-adrenergic antagonists, nadolol and propranolol, block this stress fever. Neither of these β-antagonists discriminates between subtypes of β-receptors. The purpose of this study was to determine the relative contribution of the different β-receptor types to stress fever using β1-, β2-, and β3-receptor subtype selective antagonists (atenolol [β1], ICI-118551 [β2], and SR 59230A [β3]) and agonists (dobutamine [β1], salbutamol [β2], and BRL 37344 [β3]) on the Tb of rats. Tb was measured with a biotelemetry system. Our data suggest that central nervous system β-receptor blockade with subtype-selective antagonists prevents the stress-induced rise in Tb; however, the β3-antagonist was effective only at doses that produced hypothermia in a non-stressed control group. The stress-induced fever was mimicked by central nervous system administration of the selective β2-agonist, salbutamol, and the β3-agonist, BRL 37344. We hypothesize that the blockade of stress-induced fever by β-blockers may be due to the sedative actions of these drugs.

Open Field-Induced Rise in Body Temperature and Plasma IL-6 Is Mediated by β-Adrenoceptors in the Braina

Exposure of rats to an open field, a mild psychological stressor, elevates body temperature and increases circulating interleukin-6 (IL-6). ‘3’ However, the pathway by which psychological stress triggers both responses is poorly recognized. Over the past few years, investigators increasingly have focused their attention on clarifying the possible involvement of the sympathetic nervous system in the psychological stress-induced rise in body temperature and plasma IL-6.3,4 Recently, we reported that pretreatment with L-propranolol, a nonselective /3-adrenoceptor antagonist, prevents the open field rise of body temperature and circulating 1L-6.5 The inhibitory effect of L-propranolol was observed after either peripheral (ip) or central (icv) injection of this blocking drug. Since L-propranolol can cross the blood-brain barrier by simple diffusion,6*’ we hypothesize that L-propranolol may prevent the effect of stress on body temperature and cytokine levels by competing for P-adrenoceptor sites inside the central nervous system. In addition, L-propranolol also has “local anesthetic” activity.8 This raises the possibility that its inhibitory effect may result not only from drug-receptor interactions but also from a tranquilizing effect due to the drug’s “local anesthetic” activity. The major hypothesis we have tested in this study is that P-adrenoceptors inside the blood-brain barrier are responsible for open field-induced elevation of body temperature and plasma IL-6 activity. To test our hypothesis, we used the unique properties of nadolol, a nonselective P-adrenoceptor antagonist. Nadolol has equivalent p-blocking properties to L-propranolol but is devoid of “local anesethetic” a ~ t i v i t y . ~ Moreover, because of its low lipophilicity, nadolol is unable to penetrate the blood-brain barrier.6

Blockade of Nitric Oxide Formation Enhances Thermal and Behavioral Responses in Rats during Turpentine Abscess

Objective: The purpose of this study was to investigate the role of nitric oxide (NO) during the development of fever and other symptoms of sickness behavior (i.e. anorexia, cachexia) in response to localized tissue inflammation caused by injection of turpentine in freely moving biotelemetered rats. Methods: To determine the role of NO in turpentine-induced fever, we injected the NO synthase (NOS) inhibitor Nω-nitro-L-arginine methyl ester (L-NAME) intraperitoneally simultaneously or 5 h after turpentine injection. Results: Rats responded with fever to intramuscular injection of 20 µl of turpentine that commenced 6 h after injection and reached peak values 11 h after injection. Although turpentine did not significantly alter food and water intake, it caused a drop in body weight. Rats injected with turpentine and treated with L-NAME responded with a substantial rise in fever, independently of the time of L-NAME injection. The rise in body temperature (Tb) due to turpentine injection began slightly sooner and reached the maximal Tb value faster in rats treated with L-NAME than in the ones treated with saline (control for L-NAME). The enhanced decrease in food and water intake in rats treated with a combination of L-NAME and turpentine was also observed. As a result, L-NAME-injected rats responded with a profound drop in body mass due to turpentine, independently of the time of L-NAME injection. L-NAME alone did not affect food and water intake, but slightly suppressed the gain of body mass. Conclusion: These results indirectly indicate that NO is involved in pyrogenic and behavioral responses in rats during turpentine abscess.