Asthma is a chronic inflammatory syndrome that manifests through airway obstruction and airway hyper-responsiveness. Over the past 30 years evidence has accumulated that asthma has increased in prevalence and severity worldwide. Current data strongly implicate inflammation, as a major hallmark of the asthma phenotype. There are many factors that contribute to the initiation and propagation of airway inflammation of asthma including genetic and environmental factors. Recently, innate immunity has been increasingly recognized to play a significant role in airway inflammation of asthma. In this context, the overall objective of this Center proposal is to investigate the mechanisms of key factors of innate immunity to the allergic inflammation of asthma. The Center has a programmatic focus on translational research and utilizes a multidisciplinary approach. The strength of the Center lies in the unique yet complementary expertise of the founding investigators in several disciplines including human subject investigation, molecular cell biology, cytokine biology, cellular transduction, immunology, and physiology. Our program addresses three independent yet complementary factors of innate immunity that contribute to the allergic airway inflammation of asthma. These factors are nitric oxide, environmental proteases, and endogenous metalloproteinases. Project 1 will focus on elucidation of the mechanisms of overproduction of NO by iNOS in airway inflammation of asthma. It also evaluates the use of iNOS translational inhibitors in a mouse model of asthma. Project 2 will determine the earliest innate immune signaling pathway activated by allergens that conditions the lung for subsequent allergic lung disease. Further, it will determine the relationship between allergenic proteinases in home environments and the development of childhood asthma. Project 3 will define the role of key matrix proteinases and proteoglycans in coordinating the crosstalk between immune and non-immune cells in the lung and in orchestrating the progression of allergic inflammation and clearance of inflammatory cells from lung. All three projects study asthma patients as well as mouse models of asthma. Three cores support the Center. The Administrative Core (Core A) has the overall responsibility of managing all scientific and administrative aspects of the Center. Core B (Animal Core) assists investigators in all studies related to the development and testing of a mouse model of asthma. Core C handles primary cell culture, tissue processing and imaging needs of Center investigators. The results of the studies, in this highly interactive Center, will increase our understanding of the pathophysiology and potential therapy for asthma.