Vasoconstriction of lung vessels with hypoxia is important for the defense of arterial oxygenation in the fetus, newborn, and adult, but is also a contributor to the pathogenesis of cor pulmonale in chronic lung disease. Although hypoxic pulmonary vasoconstriction is important in health and disease, its mechanism remains unknown. One possible mechanism is that some cells within the lung sense hypoxia and release one or more chemical mediators which induce the vasoconstriction. We hypothesized that lipoxygenase products of arachidonic acid metabolism could be involved in the sequence of events transducing alveolar hypoxia to pulmonary vascular constriction. The goal of this project is to determine if sulfidopeptide leukotrienes are involved in the mediation of acute and chronic hypoxic pulmonary vasoconstriction. Specifically, I will examine in isolated perfused rat lungs, vascular rings, cell systems, and intact animals whether sulfidopeptide leukotrienes possess the attributes necessary to function as mediators of hypoxic pulmonary vasoconstriction. The isolated perfused rat lung will be used extensively since in this model both the integrated vascular response to hypoxia and leukotriene production can be measured in the same system. Whether leukotrienes are mediators of hypoxic vasoconstriction or more general modulators of vascular reactivity will be examined. In addition, the site of lung leukotriene production in response to alveolar hypoxia as well as other stimuli will be investigated. Lastly, the ability of leukotriene inhibitors to prevent or reverse pulmonary hypertension due to chronic hypoxia will be determined in the intact rat. The overall goal of this study is to better understand the regulation of the pulmonary vasculature, which could lead to therapeutic interventions in humans with acute or chronic pulmonary hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL001595-04
Application #
3081982
Study Section
Research Manpower Review Committee (MR)
Project Start
1985-08-01
Project End
1990-07-31
Budget Start
1988-08-01
Budget End
1989-07-31
Support Year
4
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109