Role of Cytokines in the Developing Immune System

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It has been suggested that SIDS may be a patho-physiological response elicited by combinations of microbial products and/or other environmental factors such as environmental tobacco smoke (ETS) at a time when the developing immune system is more vulnerable to the effects of inflammatory mediators. We have developed an animal model to mimic dual infection, using a non-lethal strain of Influenza A virus and a sub-lethal dose of endotoxin. In this model inoculation with influenza at 10 days of age followed by endotoxin 0.2 mg/kg 2 days post influenza caused mortality with the lowest morbidity. These elements became the defining parameters of the model. Mortality only occurred when specific criteria such as timing between infectious insults and developmental age of the pup were met and age was a key risk factor in the model. We have defined similarities of SIDS pathology in human infants and that seen in this model and examined basic immune factors associated with dual challenge. These studies suggest that the developing immune system can be primed to respond in an exaggerated way to a second immune challenge resulting in unexpected death. To examine the mechanisms underlying this mortality, a series of experiments were conducted to evaluate immune parameters 2-8 hours following endotoxin administration. As the pathologic findings a suggested modulation of systemic immunity rather than lung-specific damage, we evaluated cytokine responses related to systemic shock and oxidative stress. Significant alterations in serum and spleen IFN gamma levels were observed in dually challenged pups, as well as changes in specific immune cell populations in the spleen and lung. Inflammatory cytokine gene expression peaked earlier in dually challenged animals in both the lung and liver. As nitric oxide is an important aspect of the immune response to both bacterial and viral infection, nitric oxide synthase mRNA expression was examined in the target tissues. Increased gene expression was observed in the liver (iNOS, eNOS and nNOS) and the lung (iNOS, eNOS) in dually challenged animals as compared to animal receiving only endotoxin. We also investigated whether intranasal administration of endotoxin, which would more closely mimic potential human exposure, would show similar patterns of immunologic changes. No mortality was observed in animals challenged in this fashion. We are collaborating with Dr. Blood-Siegfried at Duke University to examine the role of environmental tobacco smoke in the development of SIDS using this model. Nicotine exposure appears to prime the immune system in a manner similar to influenza exposure in that nicotine-exposed animals appear to be sensitive to the exposure to bacterial products during a specific developmental window.