Repeated exposure to aerosolized brevetoxin-3 induces prolonged airway hyperresponsiveness and lung inflammation in sheep

Context: During a Florida red tide, brevetoxins (PbTxs) produced by Karenia brevis become aerosolized and can cause both immediate and prolonged airway symptoms in humans, especially in those with preexisting airway disease (e. g., asthma). Although environmental monitoring indicates that toxins remain airborne for up to 4 consecutive days, there is little information on airway responses after multiple-day exposures. Objectives: To delineate putative mechanisms leading to pulmonary dysfunction after PbTx exposure, we studied airway responses before and after multiple exposures to aerosol PbTx-3, the most potent PbTx produced, in nonallergic (healthy) and in allergic sheep, which serve as a surrogate for patients with compromised airways. Methods: Both groups were exposed to 20 breaths of increasing concentrations of PbTx-3 (30-300 pg/mL) for 4 consecutive days. Airway responsiveness to carbachol (1 and 8 days after) and airway inflammation as assessed by bronchoalveolar lavage (0 and 7 days after) were measured. Results: Both groups developed airway hyperresponsiveness (AHR) 1 day after challenge; the severity was concentration dependent and more severe in the allergic group. AHR remained after 8 days, but the difference in the severity between the groups was lost. Both groups developed an inflammatory response after exposure to 300 pg/-mL PbTx-3. Immediately after exposure, lung neutrophilia was prominent. This neutrophilia persisted for 7 days in addition to increases in total cells and macrophages. Conclusion: Repeated exposures to PbTx-3 result in prolonged AHR and lung inflammation. These pathophysiologic responses could be underlying contributors to the prolonged respiratory symptoms in humans after red tides.