The objective is to define the role of VIP and other newly identified peptides in the lung as mediators of pulmonary vascular and airway responses. These peptides, acting mainly as neurotransmitters, are normally present or released in the lung, have potent biological actions, and are capable of influencing pulmonary vascular and airway smooth muscle tone, bronchial water, ion & macromolecular secretion, pulmonary microvascular permeability and systemic hemodynamics. Our specific goals are to: 1) elucidate the mechanism of the pulmonary vasodilator action of VIP; 2) characterize its receptors in the lung, including pulmonary endothelium; 3) determine its physiological role as a transmitter of nonadrenergic relaxation of airways and pulmonary vessels; 4) purify the spasmogenic lung peptide to homogeneity, determine its structure, and investigate its release in experimental conditions associated with bronchoconstriction and pulmonary vasoconstriction; 5) characterize the biological effects of Atrial Natriuretic Peptide (ANP) on airways and pulmonary vessels in in vitro and in vivo preparations, to help understand its physiological and pathophysiological significance in the lungs; and 6) measure the effects of Peptide Histidine Isoleucine (PHI) on airways and pulmonary vessels, especially in combination with VIP, since the two peptides coexist in the same neurons and are usually coreleased. Methods will include biochemicals, physiologic and pharmacologic techniques. Experiments will be performed on anesthetized dogs, unanesthetized sheep, isolated perfused lungs, and lung tissue in vitro. Data will be based on bioassay, radioimmunoassays, receptor-binding assays, and measurements of pulmonary vascular pressures, blood flow, pulmonary lymph flow and protein content, as indicators of pulmonary hemodynamics and microvascular permeability.
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