MECHANISMS OF CAL CHELATOR INDUCED AIRWAY CONSTRICTION

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Asthmatic subjects manifest nonspecific airway hyperreactivity by exaggerated responses to nonantigenic stimuli. Although separate defects may be responsible for these exaggerated responses, there may be some common pathways. If so, a defect along a common pathway could be responsible for nonspecific airway hyperreactivity in response to agents which, superficially, appear to differ greatly. We propose to explore common mechanisms by which nonspecific stimuli induce bronchoconstriction. Two different agents that chelate calcium, Na2EDTA and citric acid, induce bronchoconstriction when inhaled by asthmatic humans and animals with airway hyperreactivity. The mechanism responsible for this phenomenon is not known, but may be due to an alteration of calcium homeostasis. hypocapnia, which induces bronchoconstriction in canine lung periphery, may share this response differs between mongrel dogs and Basenji-Greyhound (BG) dogs, which have nonspecific airway hyperreactivity. We will explore the mechanism of Na2EDTA-induced bronchoconstriction in canine lung periphery as a model of nonspecific airway reactivity. We hypothesize that calcium chelators act on the epithelium, increasing the production of constructing agents of decreasing the production of dilating agents. We will test the importance of calcium chelation and determine if calcium chelator aerosols and hypocapnia act via similar mechanisms by using pharmacologic interventions in the in vivo model. We will test the hypothesis that the airway epithelium is involved in the production of constricting and dilating agents by using two in vitro preparations that isolate the epithelial surface from the serosal surface. We will identify these agents by direct assay of bronchoalveolar lavage fluid. One of the in vitro preparations also allows measurements of bioelectric parameters of epithelium. Finally, we will use the information gained from in vivo and in vitro studies in mongrel dogs to probe the difference in the in vivo response in a dog model of airway hyperreactivity. This work will further clarify the importance of a disturbance of calcium homeostasis as a common mechanism of bronchial hyperreactivity, which will lead to a better understanding of the mechanisms underlying asthma.