In this proposal a combined didactic and practical research experience is outlined which will advance our understanding of the role of airway inflammation in the airway obstruction and hyper-responsiveness of asthma. Airway inflammation is now recognized as an important defining pathological feature of asthma. The objective of this proposal is to define possible links among airway inflammation, airway responsiveness, and abnormalities in lung neuropeptide sensitivity and metabolism with special focus on the role of neuropeptides in the process. Among the neuropeptides found in various nerves in the lung are the contractile agonists, substance P (SP) and neurokinin (NKA), and the inhibitory peptide, vasoactive intestinal peptide (VIP). There is reason to believe that these neuropeptides modulate bronchoconstrictor responses, with the excitatory physiological effects of SP and NKA counterbalanced by the inhibitory effects of VIP. Furthermore, it is now well established that the physiological effects of SP, NKA, and VIP are limited by their enzymatic degradation at or near the site of their release. Since the effects of these peptides are modulated by factors which alter their availability or processing in the microenvironment, it is possible that there are pathophysiologically important connections among airway inflammation, neuropeptide action, and airway constriction. On the basis of these findings we hypothesize that chronic airway inflammation results in an altered phlogistic potential of exogenous and endogenous neuropeptides by altering the enzymatic cleavage of these molecules in the pulmonary microenvironment. To test this hypothesis we will determine how antigen- and IL5-induced airway inflammation alters the enzymatic cleavage of neuropeptides in guinea pig lungs. The mechanism(s) responsible for altered activity of neuropeptide regulatory enzymes will be explored at a number of levels from transcription through stability of the mature protein product in inflamed lungs. In order to pursue these goals the first part of the award period will be used to complete specific projects related to neuropeptide processing in inflamed lungs.
|Lilly, C M; Bai, T R; Shore, S A et al. (1995) Neuropeptide content of lungs from asthmatic and nonasthmatic patients. Am J Respir Crit Care Med 151:548-53|