During red tide events aerosolized polyether brevetoxins (PbTxs) have been linked to upper andlower airway symptoms in both normal individuals and in 'susceptible populations', i.e. those individuals withpre-existing airway disease. During the first grant cycle we showed that sheep inhaling PbTxs environmentallyrelevant concentrations of PbTx developed adverse pulmonary events including acute bronchoconstriction,airway hyperresponsiveness (AHR), airway inflammation and decreased mucociliary clearance. Both normaland allergic sheep, which serve as a surrogate for a 'susceptible population', responded to toxin challenge, butthe severity of the response was, in part, dependent on the underlying inflammatory status of the airways. Themost striking findings, however, were that the airway effects of the inhaled PbTxs differed in their physiologicalactions and their response to pharmacologic intervention. The differences in responses were related tochanges in the chemical structure of the PbTx tested. To further complicate the problem, we found that anatural congener of PbTx and chemically modified PbTxs not only could block the adverse pulmonary effectsof PbTx, but in some instances, improve pulmonary function on their own. These findings suggest thatsynthetic and/or natural modifications of the PbTx molecules can result in the generation of compounds thathave increased toxicity, or depending on the structural modification, beneficial effects in the airway. Therefore,in this proposal we will test the hypothesis that the severity of the airway effects of inhaled toxins, i.e.effects on bronchial tone, airway responsiveness, mucociliary clearance, inflammatory cell recruitmentand airway cell function are dependent on the chemical structure(s) of the individual PbTxs that areaerosolized. Furthermore, we postulate that the PbTx congeners and analogs can stimulate differentpulmonary cells/receptors and that the PbTx-induced effects (whether beneficial or harmful) will be dependenton cells/receptors on various pulmonary cells stimulated by the toxins.
Three Specific Aims will be used totest this hypothesis.
Specific Aim 1 : A) To compare the effects of selected PbTxs (both natural and synthetictoxins), PbTx congeners and toxin complexes identified in field studies on measures of bronchial tone(pulmonary airflow resistance, RL) and mucociliary clearance (tracheal mucus velocity, TMV and whole lungmucociliary clearance, MCC) to identify the chemical structure(s) responsible for the observed effects whetherbeneficial or harmful. And B) To use in vivo pharmacology to identify airway cells/receptors responsible fortoxin-induced effects.
Specific Aim 2 : To determine the mechanisms responsible for the airway inflammationand airway hyperresponsiveness (AHR) that result from 4-day PbTx exposure, including the regulation ofnuclear factor kappa beta (NFkB) activation, subsequent cytokine release and the role of adhesion moleculeactivation.
Specific Aim 3 : To determine if the immunosuppressive effects of PbTx on macrophages and thePbTx-induced depressions in TMV seen after toxin exposures affect bacterial clearance in vivo. We willcontinue to utilize the sheep model for these studies because this model responds to inhaled concentrations oftoxin that are present in the environment and cause respiratory symptoms in humans and comparisonsbetween normal and allergic sheep allow us to model airway effects in 'normal' and 'susceptible populations'.Furthermore, as demonstrated in the Progress Report / Preliminary Studies, the physiologic endpointsmeasured in this model have adequate sensitivity to differentiate amongst the PbTx congeners that differ by asingle atom or functional group, thereby providing confidence that the proposed Specific Aims can beaccomplished. The data generated in this proposal are novel in that they provide an approach to understandinghow structure and composition of aerosolized toxin affects the airways. The experiments are being conductedat environmentally relevant concentrations. Because of our extensive experience with delineating inflammatorycascades in this model, we are well positioned to understand mechanisms involved in toxin-inducedinflammation in the airways and the potential of toxin exposure to impair host defense mechanisms. With thecurrent paucity of data addressing these issues, the proposed studies should provide needed information onthe pathophysiological consequences of PbTx exposure.
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