Effects of inhaled brevetoxins in allergic airways: toxin-allergen interactions and pharmacologic intervention

Abstract

During a Florida red tide, brevetoxins produced by the dinoflagellate Karenia brevis become aerosolized and cause airway symptoms in humans, especially in those with pre-existing airway disease (e.g., asthma). To understand these toxin-induced airway effects, we used sheep with airway hypersensitivity to Ascaris suum antigen as a surrogate for asthmatic patients and studied changes in pulmonary airflow resistance (R(L) after inhalation challenge with lysed cultures of K. brevis (crude brevetoxins). Studies were done without and with clinically available drugs to determine which might prevent/reverse these effects. Crude brevetoxins (20 breaths at 100 pg/mL; n = 5) increased R(L) 128 +/- 6% (mean +/- SE) over baseline. This bronchoconstriction was significantly reduced (% inhibition) after pretreatment with the glucocorticosteroid budesonide (49%), the beta(2) adrenergic agent albuterol (71%), the anticholinergic agent atropine (58%), and the histamine H1-antagonist diphenhydramine (47%). The protection afforded by atropine and diphenhydramine suggests that both cholinergic (vagal) and H1-mediated pathways contribute to the bronchoconstriction. The response to cutaneous toxin injection was also histamine mediated. Thus, the airway and skin data support the hypothesis that toxin activates mast cells in vivo. Albuterol given immediately after toxin challenge rapidly reversed the bronchoconstriction. Toxin inhalation increased airway kinins, and the response to inhaled toxin was enhanced after allergen challenge. Both factors could contribute to the increased sensitivity of asthmatic patients to toxin exposure. We conclude that K. brevis aerosols are potent airway constrictors. Clinically available drugs may be used to prevent or provide therapeutic relief for affected individuals.

Figure 1. Effect of pharmacologic agents on breve-toxin-induced bronchoconstriction. Crude brevetoxins produced an immediate increase in R_L, which then returned to baseline values within 1 hr. Pretreatment with atropine, budesonide, albuterol, and diphenhydramine all reduced the toxin-induced response. Values are mean ± SE for five sheep. : *p < 0.05 versus all others; ^#p < 0.05 albuterol versus diphenhydramine.

Figure 2. Reversal of crude brevetoxin–induced bronchoconstriction with albuterol. Values are mean ± SE for five sheep. : *p < 0.05 versus untreated.

Figure 3. Effect of the bradykinin B₂ receptor antagonist HOE-140 on crude brevetoxin–induced bronchoconstriction. Animals treated with HOE-140 had a reduced response compared with that seen when the animals were untreated (Un). The response in the presence of HOE-140 was similar to that seen with diphenhydramine (Diphen) but less than that seen with atropine (Atr). Values are mean ± SE for five sheep. : *p < 0.05 versus untreated; ^#p < 0.05 versus HOE-140.

Figure 4. Effect of the histamine H₁-antagonist diphenhydramine (H1A) on the ICRs to crude brevetoxins (PbTx) and PbTx-3. Values are mean ± SE for nine sheep. : *p < 0.05 versus untreated.

Figure 5. (A) The effect of 3 consecutive days of PbTx-3 exposure on antigen-induced EAR (early increase in R_L, 0–4 hr) and LAR (late increase in R_L, 4–8 hr; and (B) AHR to carbachol (indicated by the decreased PC400 24 hr after challenge). PbTx-3 exposure (20 breaths of 100 pg/mL) had no effect on any parameter. Values are mean ± SE for three sheep. : *p < 0.05 versus baseline.

Figure 6. Effect of allergen challenge on the response to PbTx-3. Animals were more sensitive (indicated by the leftward shift in the concentration–response curve) to inhaled PbTx-3 one day after antigen challenge (postantigen) compared with before challenge (preantigen). The animals also demonstrated AHR to carbachol at this time, as indicated by a fall in the PC400, as described in the text. Values are mean ± SE for five sheep. : *p < 0.05 versus preantigen.