INFLAMMATORY EVENTS INITIATING AND PERPETUATING ASTHMA

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Asthma is a complex disorder characterized by intermittent reversible airway obstruction, airway hyper-responsiveness and airway inflammation. Although the cause(s) of asthma remain unknown, we now appreciate that asthma is a chronic inflammatory syndrome whose common pathobiological expression is inflammation leading to airway hyperresponsiveness and airway obstruction. In fact it is the presence of these common features which has led to the current NAEP definition of asthma which emphasizes that asthma is characterized by reversible obstruction and hyper-responsiveness of the airways with both of these physiological abnormalities occurring on the background of airway inflammation. Based on the known presence of airway inflammation, our response to the SCOR competition in asthma has been designed to address what we believe are the major unanswered questions in human asthma. In specific we believe that we must: Define the molecular and cellular events responsible for the initiation and perpetuation of asthmatic airway inflammation. However, beyond this definition we must clarify the links between asthmatic inflammation and the physiological phenotype that characterizes asthma. To address these questions we have assembled a SCOR consisting of 5 projects and 2 core units; each project addresses a specific aspect o this biology initiating asthma, perpetuating asthma or linking inflammation to the clinical asthma phenotype. Our core units will provide patient accrual, administrative and statistical services. Project #1 will address the role of nitric oxide as both an indicator and mediator of airway obstruction in asthma. Project #2 will examine the effects of cytokines on the contractile responsiveness of isolated human airway smooth muscle cells in culture. In Project #3 we will undertake the structural definition of novel lipid derived down-regulatory substances followed by a definition of their metabolism, ascertainment of their biological actions and determination of their expression in asthma. Project #4 is designed to test critically the hypothesis that must cells produce cytokines which play an important role in initiating and perpetuating airway inflammation in asthma. This project will also test the hypothesis that the mast cells ability to express and release cytokines may itself reflect other micro- environmental factors in the asthmatic airway. In Project #5 we will examine the expression of the high affinity receptor for IgE on nononuclear phagocytes isolated from patients with asthma as well as signal transduction initiated by receptor aggregation. Taken together the scientific insights gathered from these SCOR projects should enhance our understanding of the biology of asthma.