Olfactory acuity is dependent upon the efficient processing and clearance of potentially toxic substances from the nasal cavity. A compromise in expression or activity of cytochrome P450 nasal detoxifying enzymes could result in disease or infection, leading to loss of function. The regulation of P450 2G1 expression in non-neuronal cells is poorly understood, however, P450 2G1 expression is suppressed during periods of neuronal trauma. Recent in vivo evidence from hepatic systems indicates that acute phase response or localized inflammatory reaction generates reactive oxygen species (ROS) that negatively affect the expression and activity of liver P450s. Inflammation in the nasal cavity is correlated with increases in nitric oxide synthase (NOS), superoxide dismutase (SOD) enzymatic activity and the formation of potentially toxic nitrotyrosines. We hypothesize that ROS mediate the suppression of P450 2G1 during olfactory trauma in the mouse. In support of this hypothesis, our preliminary data demonstrate that the acute phase response suppresses olfactory P450 enzyme activity, and decreases P450 2G1 expression. A correlate with this is an increase in SOD activity, suggesting that ROS production is associated with P450 suppression. Our objectives are: 1) to characterize the expression and activity of P450 2G1, NOS, and SOD enzymes in olfactory tissue during trauma and the acute phase response; 2) to measure nitrotyrosines during these stages; 3) to determine the ability of NOS inhibitors to attenuate the effects of immunomodulatory agents; and 4) determine the effect of acute phase response on olfactory signaling. In summary, this study will determine how cytokines and ROS affect gene expression and function, namely cytochromes P450, in sustentacular cells of the olfactory system. Decreased olfactory acuity has been noted following infection in the nasal cavity. Thus, determining how olfactory tissue adapts to immune response mechanisms is directly relevant to olfactory performance during systemic infection and conditions such as upper respiratory disease in humans.
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