We hypothesize that endogenous substance P is released in the course of certain bronchoconstrictor responses and that the substance P released enhances the airway narrowing resulting from such stimuli. Further, and of major importance, we hypothesize that the physiological expression of the contractile potential of substance P is limited by its degradation by specific endopeptidases. Thus under conditions when the endopeptidases responsible for substance P degradation are rendered inactive a state of airway hyper-responsiveness could ensue. To test this hypothesis we propose a series of experiments using guinea pigs as a test species. We will use specific protease inhibitors to delineate the role of substance P degradation in the expression of its contractile activity and to tentatively identify the specific class of protease(s) responsible for substance P inactivation. We will use the inhibitors so identified to determine if the action of certain bronchoactive mediators can be enhanced by pharmacologic manipulation of substance P degradation, thus implicating endogenous release of substance P as contributing to the observed bronchoconstrictor response. We will purify the endopeptidase(s) responsible for substance P inactivation and use these as immunogens to produce both monoclonal and polyclonal antibodies. The antibodies obtained will be used to demonstrate the specificity of the pharmacologic effect observed using protease inhibitors. These antibodies and antibodies against substance P will also be used in immunohistochemical studies to determine the anatomic relationships between substance P and its degradative enzyme(s) in the lung. Finally we will evaluate the hypothesis that ozone induced airway hyper-responsiveness in the guinea pig is associated with a loss of substance P degradative activity.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL039827-04
Application #
3356745
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1988-03-01
Project End
1993-02-28
Budget Start
1991-03-08
Budget End
1992-02-29
Support Year
4
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215
Lilly, C M; Chapman, R W; Sehring, S J et al. (1996) Effects of interleukin 5-induced pulmonary eosinophilia on airway reactivity in the guinea pig. Am J Physiol 270:L368-75
Lilly, C M; Hall, A E; Rodger, I W et al. (1995) Substance P-induced histamine release in tracheally perfused guinea pig lungs. J Appl Physiol 78:1234-41
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
Lilly, C M; Martins, M A; Drazen, J M (1993) Peptidase modulation of vasoactive intestinal peptide pulmonary relaxation in tracheal superfused guinea pig lungs. J Clin Invest 91:235-43
Lilly, C M; Drazen, J M; Shore, S A (1993) Peptidase modulation of airway effects of neuropeptides. Proc Soc Exp Biol Med 203:388-404
Shore, S A; Martins, M A; Drazen, J M (1993) Pulmonary mechanical responses to intravenously administered capsaicin in guinea-pigs: effect of peptidase inhibitors. Pulm Pharmacol 6:193-9
Shore, S A; Sharpless, C; Drazen, J M (1993) Bronchoconstrictor activities of NP gamma and NPK in anaesthetized guinea-pigs: effect on NEP inhibition. Pulm Pharmacol 6:143-7
Shore, S A; Martins, M A; Drazen, J M (1992) Effect of the NEP inhibitor SCH32615 on airway responses to intravenous substance P in guinea pigs. J Appl Physiol 73:1847-53
Shore, S A; Drazen, J M (1991) Relative bronchoconstrictor activity of neurokinin A and neurokinin A fragments in guinea pigs. J Appl Physiol 71:452-7
Martins, M A; Shore, S A; Drazen, J M (1991) Release of tachykinins by histamine, methacholine, PAF, LTD4, and substance P from guinea pig lungs. Am J Physiol 261:L449-55

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