EXCEED THE SPACE PROVIDED. In response to bacteria deposited in the air spaces of the lung, precisely regulated gene expression is essential. Insufficient expression of chemokines and cytokines permits bacterial growth and infection, whereas excessive expression of the same genes causes inflammatory injury. This expression is regulated by transcription factors, including NF-KB. The p50 subunit of NF-KB can promote or repress gone expression. Preliminary studies indicate that, in response to E, coil in the lungs, p50 deficiency increased the expression of multiple chemokines and cytokines. Bacterial clearance was not affected, but lung injury was increased. These observations suggest the hypothesis that, in response to bacteria in the lungs, NF-KB p50 functions as agene repressor which is essential for preventing inflammatory injury. This central hypothesis will be tested by pursuing the following specific aims: (1) Determine whether p50 protects against inflammatory injury induced by E. coil in the lungs. (2) Determine whether protection from inflammatory injury induced by E. coil in the lungs is mediated by p50 in leukocytes. (3) Determine whether repression of TNF-a and/or IL-1 is the mechanism by which p50 prevents inflammatory injury induced by E. coil in the lungs. (4) Determine whether repression of IL-6 by p50 is differentially required for neutrophil emigration in the lungs elicited by E. coil and by E. coil LPS. (5) Determine whether p50 protects against inflammatory injury induced by S. pneumoniae in the lungs. Antibacterial host defenses will be measured by quantifying viable bacteria in the lungs and extrapulmonary tissues. Injury will be measured by assessing pulmonary edema, arterial hypoxemia, transit of alveolar contents to blood, and parenchymal destruction. Innate immune responses which contribute to both host defenses and injury will be quantified, including neutrophil emigration and production of chemokines and cytokines. Hypothesized mechanisms by which p50 regulates inflammatory injury and neutrophil recruitment will be investigated by interrupting TNF-a, IL-1, and IL-6 signaling, using both genetic and biochemical means. The roles of p50 in distinct cell-types will be investigated using in vivo analyses of hematopoietically reconstituted mice and using in vitro analyses of isolated alveolar macrophages. The results from these studies will provide new insights into how gene expression and innate immunity are limited in order to prevent inflammatory injury to the lung. PERFORMANCE SITE ========================================Section End===========================================
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