There are 5 lines of evidence indicating that the cysteinyl leukotrienes may be involved in the asthmatic response: 1) they are produced by constitutive (mast cells/macrophages) and infiltrating (eosinophils) cells implicated in the asthmatic response, 2) they are potent bronchoconstrictors, 3) asthma is somewhat ameliorated by agents capable of interfering with their synthesis or action, 4) LTC4 is metabolized in humans into LTD4 and LTE4, allowing LTE4 (which can be recovered in the urine) to serve as a marker for all three and 5) the formation of the cysteinyl leukotrienes may not only trigger bronchospasm, but LTE4 may also sensitize the airways to the effects of irritants and/or mediators, leading to bronchial hyperreactivity. Based on these data we tender the following hypothesis: Leukotriene E4 (LTE4), the biometabolic product derived from LTC4 and LTD4, is produced during asthmatic responses. The LTE4 so produced can cause both airway narrowing and hyperresponsiveness. Since a fraction of the LTE4 produced is excreted in the urine, the quantitative urinary excretion of LTE4 provides a possible chemical index of pulmonary obstruction and responsiveness which may be of diagnostic and therapeutic value. This hypothesis will be tested in two specific aims. In this first specific aim, urinary LTE4 excretion will be measured before and after induction of airway hyperresponsiveness by exposure to platelet activating factor (PAF) or ozone in normal subjects. If the transient induction of a hyperresponsive state is associated with the endogenous production of LTE4, then we expect the amounts of LTE4 in the urine to increase in relation to altered airway responsiveness. Three experiments, all in asthmatic subjects, are proposed in the second specific aim. First the relationship between urinary LTE4 excretion and airway responsiveness will be compared in asthmatic subjects with minimal and marked airway responsiveness. Second, the relationship between urinary LTE4 excretion and spontaneous alterations in airway responsiveness that occur during allergen season will be investigated in a group of asthmatic subjects with a documented allergic diathesis. Third the relationship between urinary LTE4 excretion and the variations in airway function that occur during treatment as an acute asthmatic attack resolves will be determined in a group of acutely ill patients.
Showing the most recent 10 out of 14 publications
