The objective of this proposal is to define the role of certain biologically active lipids in the lung as mediators of pulmonary vascular and airway responses in experimental models of acute lung injury. These lipids, namely prostaglandins, thromboxanes, prostacyclin, leukotrienes and platelet-activating factor (PAF), are normally present or may be released in the lung in response to pathophysiologic stimuli. They have potent biological actions, including pulmonary vasoconstriction or vasolidation, airway constriction or relaxation, pulmonary edema and systemic hypotension. Our specific goals are to: 1) determine the full biological activities of the recently identified leukotrienes (C4, D4 and B4) and PAF, on pulmonary vessels, micro-vessels and airways; 2) investigate the release of arachidonic acid metabolites and PAF in experimental models of acute lung injury; 3) evaluate the relative contribution of these lipids as mediators of pulmonary vascular and airway responses in acute lung injury; and 4) investigate the possible protective effect of newly introduced selective inhibitors and antagonists of thromboxane and leukotrienes. Acute lung injury will be induced in awake sheep and in anesthetized dogs by i.v. infusion of E. coli endotoxin, intra-tracheal instillation of HCl or i.v. infusion of phorbol myristate acetate. Samples of arterial and mixed-venous blood, pulmonary lymph, and broncho-alveolar fluid will be assayed for active lipids. Assessment of altered pulmonary microvascular permeability and other responses will be based on bio-, immunochemical and chemical assays of the lipids, and on measurements of pulmonary vascular hemodynamics, mechanics, and pulmonary lymph flow and protein content. The modification of these responses by selective pharmacologic blockers and inhibitors will be examined. The proposed project, continuing research begun over 12 years ago, is a coordinated approach to some fundamental questions relating to the pathogenesis of acute lung injury: which biologically active lipids mediate the pulmonary vascular, microvascular and airway responses of acute lung injury? how do these mediators interact in producing their effects? can lung injury be modulated or prevented by selective inhibition of these compounds?
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| Sata, T; Linden, J; Liu, L W et al. (1988) Vasoactive intestinal peptide evokes endothelium-dependent relaxation and cyclic AMP accumulation in rat aorta. Peptides 9:853-8 |
