Leukotriene (LT)C4 can be produced in the airways under stimulatory conditions and its presence can be responsible for a variety of pathophysiologic symptoms in the lung. The cells involved in LTC4 synthesis and also leukotriene uptake in the rat lung will be localized by autoradiographic techniques. Following synthesis, LTC4 is exported out of synthetic cells where it can then interact with cell receptors, be metabolized, or be transferred out of the airways. The mechanisms by which LTC4 is exported out of as well as transported into cells will be investigated. The metabolic pathway of LTC4 in the lung involves conversion of LTC4 to LTD4 catalyzed by the enzyme gamma-glutamyl transpeptidase followed by conversion to LTE by dipeptidases. In the rat lung, LTE4 can also be acetylated to N-acetyl-LTE4. The physiologic role of leukotriene metabolism in inactivation will be studied by administering leukotriene metabolizing enzymes or inhibitors of these enzymes to the rate airways and determining the resultant effects on the actions of exogenously added or endogenously synthesized leukotriene. The mechanism by which leukotrienes are transferred out of the airways, possibly involving passive diffusion or active transport, will also be studied in the rat. These studies will provide needed information on the mechanisms and physiologic role of leukotriene inactivation in the lung. It has been widely speculated that increased synthesis of leukotrienes may be responsible for symptoms observed with certain inflammatory lung diseases in humans. Since a small percentage (3-13%) of leukotrienes synthesized in the lung may be excreted in the urine as LTE4, an index of increased lung synthesis of leukotrienes could be an increased concentration of LTE4 in the urine. Urine LTE4 will be quantitated in patients with asthma and adult respiratory distress syndrome and comparisons made with lung function. Since inactivation of leukotrienes may also be altered in lung inflammatory diseases, the effect of asthma on leukotriene metabolism and transfer in the airways will be determined. In this study, exogenous instillation of radiolabelled LTC4 into the airways will also demonstrate whether differences in excretion of leukotrienes in the urine exist in asthmatics compared to nonasthmatics These studies should determine whether lung pathologic conditions are associated with increased production or altered metabolism of leukotrienes.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Pathology A Study Section (PTHA)
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University of Colorado Denver
Schools of Medicine
United States
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