SITES OF ACTION AND ROLE OF MEDIATORS IN ASTHMA

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Histamine and slow reacting substance of anaphylaxis (a mixture of leukotrienes C4, D4, and E4) are important mediators of reversible airways obstruction in asthma. The airways obstruction observed in asthma is caused in large part by a combination of bronchospasm in the large airways, and bronchospasm and mucus hypersecretion in the smaller airways. We hypothesize that histamine acts primarily in the large airways, or uniformly throughout the lungs, whereas the LT's act primarily in the smaller airways. Furthermore, we hypothesize that the contribution of mucus hypersecretion to airways obstruction in asthma arises from alterations of mucociliary transport in the smaller airways. To test these hypotheses we propose to: 1) compare the provocation doses of preferentially deposited histamine and LTD4 aerosol in the large and smaller airways of healthy and asthmatic subjects; and 2) compare the effects of provocation doses of histamine and LTD4 on mucociliary transport in healthy and asthmatic subjects. The experiments we propose to conduct will employ measurement techniques of aerosol deposition, lung mucociliary clearance, and tracheal mucociliary transport developed in our laboratory. The sites of action of the mediators will be assessed with four separate mediator challenges: two with centrally deposited histamine or LTD4, and two with peripherally deposited histamine or LTD4. The mediator aerosols, generated by an ultrasonic nebulizer, (6 MuM diameter), will be preferentially deposited using two different breathing patterns. To determine mediator dose to the lungs each subject will inhale a 6 Mum aqueous aerosol of Tc-99m-labelled Fe2O3 in the same manner as the mediator aerosol prior to challenge. Total and regional lung deposition will be determined using aerosol photometry, scintillation counting, and gamma camera imaging. Mediator effects on mucociliary transport will be determined using a 6 Mum Tc-99m-labelled Fe2O3 aerosol inhaled in a manner to effect peripheral deposition. Immediately after radioaerosol deposition, a predetermined challenge dose of either histamine or LTD4, or a saline aerosol will be administered. The subject will then be placed in front of a gamma camera and a multidetector probe placed in front of his neck for a 4.7 hour measurement of lung mucociliary clearance and tracheal mucociliary transport rate.