CYTOCHROME P450 EICOSANOIDS AND PULMONARY HEMODYNAMICS

Saint Louis University, Saint Louis MO

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Abstract

Unlike other vascular beds, the lung must accept the entire cardiac output. Despite large variations in blood flow, pulmonary vascular resistance is maintained relatively constant and intrapulmonary distribution of blood flow is regulated by selectively increasing vascular resistance to alveoli with reduced oxygen tension (hypoxic pulmonary vasoconstriction, HPV). It was suggested that endogenous vasodilator substances act to moderate vasoconstrictor influences in the lung and participate in the maintenance of low pulmonary vascular resistance. Vasodilator influences may, however, oppose hypoxic vasoconstriction and permit perfusion to hypoxic alveoli resulting, thereby, in decreased oxygenation of the blood. A long-term objective of this laboratory is to define the role of products of arachidonic acid (AA) metabolism, in the regulation of the pulmonary circulation under physiological as well as pathophysiological conditions. Cytochrome P450 products of AA metabolism, epoxyeicosatrienoic acids (EET), and in particular, 5,6-EET, relax pulmonary blood vessels. 5,6-EET reduces agonist- mediated increases in pulmonary vascular resistance in the intact canine lung. Therefore, we propose that cytochrome P-450 monooxygenase metabolites of AA are local participants in the control of the pulmonary circulation. The goal of this study is to test the hypothesis that the mechanism by which pulmonary cytochrome P450 products of AA metabolism, and in particular 5,6- EET, support blood flow to hypoxic lung units is via their ability to reduce pulmonary vascular resistance. This hypothesis will be tested using chemical, biochemical, and pharmacological approaches in tissues, organs, and whole animals. We will determine the ability of these cytochrome P450 metabolites of AA to support blood flow to hypoxic lung units during unilateral alveolar hypoxia and in a model of acute lung injury (ALI). Using pharmacological tools that increase or decrease the expression or activity of phospholipase, cytochrome P450 monooxygenase, and cyclooxygenase enzymes, we will investigate the mechanism(s) by which pulmonary cytochrome P-450-mediated AA metabolites express vasodilator activity in the lung. Comprehension of the pulmonary vasodilator mechanism(s) of these endogenous compounds which maintain blood flow to hypoxic alveoli, will permit more rational therapeutic approaches to conditions such as the adult respiratory distress syndrome.