Project 3: Mechanisms of Brevetoxin Induced Bronchial and Nasal Response in Allergic and Non-Allergic Airways (Abraham) Description (Taken from the Investigator's Abstract) Inhalation of Florida """"""""red tide"""""""" toxins has been associated with both lower and upper airway symptoms in humans such as non-productive cough, shortness of breath, rhinorrhea, and sneezing, and it has been suggested that the toxin predisposes asthma patients to exacerbations of the disease. Although previous studies suggest that the respiratory effects of the toxin are neurally mediated, the investigators' recent (preliminary) studies indicate that these adverse events involve not only a neuronal component, but a non-neuronal (mas cell) mediated component. Therefore, in the proposed project, the investigators will test the hypotheses that: 1) inhaled toxin contracts airway smooth muscle and airway vascular smooth muscle by releasing acetylcholine from cholinergic and norepinephrine from adrenergic neurons thereby activating muscarinic and alpha-adrenergic receptors in the airway, and that toxin-induced mast cell secretion of mediators with smooth muscle effects contributes to the neurally mediated effects, and 2) toxin induced-airway (both upper and lower) responses are potentiated in animals (sheep) with allergic inflammation as """"""""models"""""""" of human asthma and allergic rhinitis. These hypothesis will be tested with the following specific aims: 1a) to compare the effect of inhaled of inhaled toxin on bronchial airway smooth muscle (bronchoconstriction and airway hyperreponsiveness), mucocilliary clearance (bronchoconstriction and airway hyperreponsiveness), mucocilliary clearance, and airway vascular smooth muscle tone (bronchial blood flow) in vivo, in sheep with and without allergic airway inflammation, 1b) to assess modification of the bronchoconstrictor, mucocilliary transport and vascular responses by model drugs that interfere with the proposed mechanisms of toxin action, and 1c) to evaluate the possibility that standard bronchodilators prevent or attenuate the responses to airborne toxin; 2) to compare the effect of nasally of nasally administered toxin on nasal airway resistance in allergic and non- allergic sheep, to assess modifications of the nasal responses by model drugs that interfere with the proposed mechanisms of toxin action and to evaluate the possibility that standard therapies prevent or attenuate the responses to toxin; 3) to determine the mechanism of toxin-induced mast cell activation using bronchoprovocation studies in sheep in vivo, rat mast cell activation using bronchoprovocation studies in sheep in vivo, rat mast cells in vitro, and to show that toxin-induced pulmonary abnormality are reduced in vitro, and to show that toxin-induced pulmonary abnormalities are reduced in mast cell deficient animals (mice) compared with their normal lifter mates. The investigators expect the results of these experiments to pharmacologically characterize the mechanisms responsible for the spasmogenic effects of airborne toxin in the airway and to identify therapeutic drug interventions.
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