NEGATIVE REGULATORS OF LUNG INFLAMMATION

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DESCRIPTION (provided by applicant): Prematurely born infants are at increased risk of dying from chronic lung disease (CLD). Inflammation is a key initiating and contributing factor to CLD and also to acute respiratory distress syndrome (ARDS). Together, these account for a significant number of deaths each year. In addition, inhalation anthrax is emerging as a potential public health threat. Although processes that initiate and promote inflammation through the innate immune system are intensely studied, the active down regulation of the same processes in the adult and developing lung has gone virtually unexplored. Bcr and Abr are two related proteins that are closely conserved between man and mouse. In phagocytic cells, they negatively regulate the activity of the small GTPase Rac, which stimulates phagocytosis, adhesion, motility and reactive oxygen species production in these cells. Abr x bcr null mutant mice, but not single knockouts or wild types develop acute lung inflammation subsequent to a single IV injection of LPS and possess remarkably hyper-reactive phagocytic cells. Based on our preliminary data, we hypothesize that Bcr and Abr are negative regulators of inflammation through their action on Rac, and that a further definition of their activity in vivo and on a molecular level will lead to the identification of new avenues of treatment for chronic and acute pulmonary inflammation and sepsis. To investigate this, we propose to 1) define which specific proinflammatory signals are subjected to regulation through Abr and Bcr in phagocytic cells using primary null mutant macrophages 2) elucidate how lung inflammation is negatively regulated by Bcr and Abr in vivo in null mutant mouse models 3) investigate rational therapeutic intervention of pulmonary inflammation, based on the amplified response to LPS in the abr x bcr double null mutants and the signal transduction pathways that cause this excessive response. An in-depth study of Abr and Bcr function will provide not only significant insight into the normal active down regulation of inflammation in the lung, but also new possibilities of treatment for CLD, ARDS and inhalation anthrax.