Carole A. Conn

THE USE OF KNOCKOUT MICE TO UNDERSTAND THE ROLE OF CYTOKINES IN FEVER

1. In most instances, data obtained using knockout mice to dissect the role of cytokines in fever are similar to data obtained by other, more traditional experimental techniques.

Response of F344 rats to inhalation of subclinical levels of sarin: exploring potential causes of Gulf War illness

Subclinical, repeated exposures of F344 rats to sarin resulted in brain alterations in densities of chlonergic receptor subtypes that may be associated with memory loss and cognitive dysfunction. The exposures also depressed the immune system. The rat appears to be a good model for studying the effects of subclinical exposure to a nerve gas.

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.

ANIMAL MODELS OF PULMONARY INFECTION IN THE COMPROMISED HOST: Potential Usefulness for Studying Health Effects of Inhaled Particles

Pulmonary infection leading to pneumonia is a significant cause of morbidity and mortality worldwide. Airborne particles have been associated with pneumonia through epidemiological research, but the mechanisms by which particles affect the incidence of pneumonia are not well established. The purpose of this review is to examine the potential of animal models to improve our understanding of the mechanisms by which inhaled particles might affect the incidence and resolution of pulmonary infection. The pathogenesis of pneumonia in most animal models differs from that in humans because humans frequently have underlying diseases that predispose them to infection with relatively low doses of pathogens. Normal, healthy animals lack the underlying pathology often found in humans and clear bacteria and viruses rapidly from their lungs. To overcome this, animals are administered large inocula of pathogens, are treated with agents that cause mucosal lesions, or are treated with immunosuppressive drugs. Alternatively, pathogenic bacteria are protected from phagocytosis by encasing them in agar. No one animal model will replicate a human disease in its entirety, and the choice of model depends upon how well the animal infection mimics the particular human response being examined. The advantages and disadvantages of animal models in current use for bacterial and viral infections important in the etiology of human pneumonia are reviewed in detail. Considerable data indicate that prior exposure to particles compromises the ability of experimental animals to resolve a subsequent infection. In addition, information is available on the effects of particle exposure on various portions of respiratory defense including phagocytic function, ciliary movement, inflammation, and antibody response in the absence of infection. In contrast, little research to date has examined the consequences of particle exposure on the host defense mechanisms of animals already infected or on their ability to resolve their infection.Pulmonary infection leading to pneumonia is a significant cause of morbidity and mortality worldwide. Airborne particles have been associated with pneumonia through epidemiological research, but the mechanisms by which particles affect the incidence of pneumonia are not well established. The purpose of this review is to examine the potential of animal models to improve our understanding of the mechanisms by which inhaled particles might affect the incidence and resolution of pulmonary infection. The pathogenesis of pneumonia in most animal models differs from that in humans because humans frequently have underlying diseases that predispose them to infection with relatively low doses of pathogens. Normal, healthy animals lack the underlying pathology often found in humans and clear bacteria and viruses rapidly from their lungs. To overcome this, animals are administered large inocula of pathogens, are treated with agents that cause mucosal lesions, or are treated with immunosuppressive drugs. Alternatively, pathogenic bacteria are protected from phagocytosis by encasing them in agar. No one animal model will replicate a human disease in its entirety, and the choice of model depends upon how well the animal infection mimics the particular human response being examined. The advantages and disadvantages of animal models in current use for bacterial and viral infections important in the etiology of human pneumonia are reviewed in detail. Considerable data indicate that prior exposure to particles compromises the ability of experimental animals to resolve a subsequent infection. In addition, information is available on the effects of particle exposure on various portions of respiratory defense including phagocytic function, ciliary movement, inflammation, and antibody response in the absence of infection. In contrast, little research to date has examined the consequences of particle exposure on the host defense mechanisms of animals already infected or on their ability to resolve their infection.

Hemorrhage Suppresses Fever, lnterleukin-6, and Tumor Necrosis Factor-αResponses to Lipopolysaccharide in Rats

The purpose of this study was to test the hypothesis that attenuation of the fever response to lipopolysaccharide (LPS) following hemorrhage is accompanied by changes in serum glucocorticoid levels and a decreased bioactivity of TNF-alpha and IL-6 in plasma. Hemorrhage was induced in rats by the withdrawal of 20% of estimated total blood volume. LPS (50 microg/kg) or saline were injected intraperitoneally immediately after the hemorrhage. Blood samples were taken 1.5 h for TNF-alpha bioactivity and corticosterone measurements and 5 h after treatment for IL-6 bioactivity. Body temperature (Tb) was measured by biotelemetry. The 20% hemorrhage led to a significant reduction in hematocrit measured at 1.5 and 5 h after treatment. Furthermore, 20% hemorrhage caused a substantial elevation in serum corticosterone measured by radioimmunoassay at 1.5 h after treatment. This high concentration of corticosterone was not further potentiated by injection of LPS. Hemorrhaged rats treated with LPS responded with a markedly attenuated fever. Both TNF-alpha and IL-6 rises in the circulation due to LPS injection were significantly smaller in hemorrhaged rats compared to nonhemorrhaged LPS-injected rats. However, this degree of hemorrhage did not alter the T(b) or plasma TNF-alpha and IL-6 activity in hemorrhaged rats injected with saline. These results show that the inhibitory effect of hemorrhage on LPS-induced fever may be related to the decreased TNF-alpha and IL-6 activity in plasma. Hemorrhage-induced high level of corticosterone might contribute to the attenuation of fever, perhaps via the suppression of pyrogenic cytokines.