The broad, long-term goals are to improve our understanding of the mechanisms of the pathogenesis of bronchial asthma and to design more effective means of its prevention and management. The underlying general hypothesis is that neuropeptides and other neurotransmitters contribute to both the pathogenesis and modulation of the hyperreactivity, inflammation and smooth muscle proliferation of asthmatic airways. The proposal will test the following specific hypotheses regarding two transmitters, vasoactive intestinal peptide (VIP) and nitric oxide (NO): 1) As cotransmitters of non-adrenergic, non-cholinergic relaxation, VIP and NO modulate the bronchoconstriction and airway hyperreactivity of asthma; 2) VIP modulates the airway inflammation and smooth muscle proliferation of ronchial asthma; 3) Constitutive neuronal NO production may be deficient in asthma, predisposing to airway constriction and hyperreactivity, while inducible NO synthesis may be excessively stimulated in other sites, thereby promoting airway inflammation; and 4) The expression of VIP or its receptor may be deficient in asthmatic airways. To achieve these goals, experiments are designed to measure: 1) The co-expression of VIP and neuronal NO synthase in the same neurons, their co-release during electrical field stimulation of tracheal segment, and the possible interactions among VIP and NO, and their signal transduction pathways; 2) the stimulated production of VIP by the lung, and the increased expression of VIP and neuronal synthase in immunologic, neurogenic, and environmental models of airway inflammation induced in vivo and in guinea pig lung by antigen challenge, capsaicin, ozone and activation of NMDA receptors; 3) the attenuation by VIP and NO synthase inhibitors of airway inflammation and obstruction in these models, and the relationship of such attenuation to action at the tachykinin receptors; 4) the inhibition by VIP of the proliferation of human airway smooth muscle cells in culture; 5) the expression and distribution of neuronal and inducible NO synthases in biopsy samples from asthmatic airways, examined by immunocytochemical techniques (NO synthase antibody), by the NADPH-diaphorase reaction, and by molecular probes; and 6) the possible deficiency of VIP or its receptor in asthmatic airways, assessed by radioimmunoassay in bronchial tissue and BAL fluid from asthmatic and nonasthmatic subjects by immunofluorescence, molecular probes, and in situ hybridization.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG2-RAP (01))
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State University New York Stony Brook
Internal Medicine/Medicine
Schools of Medicine
Stony Brook
United States
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Hasaneen, Nadia A; Foda, Hussein D; Said, Sami I (2003) Nitric oxide and vasoactive intestinal peptide as co-transmitters of airway smooth-muscle relaxation: analysis in neuronal nitric oxide synthase knockout mice. Chest 124:1067-72
Berisha, H I; Bratut, M; Bangale, Yogesh et al. (2002) New evidence for transmitter role of VIP in the airways: impaired relaxation by a catalytic antibody. Pulm Pharmacol Ther 15:121-7
Said, S I; Dickman, K G (2000) Pathways of inflammation and cell death in the lung: modulation by vasoactive intestinal peptide. Regul Pept 93:21-9
Said, S I (1999) Glutamate receptors and asthmatic airway disease. Trends Pharmacol Sci 20:132-4
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