Airway responses to aerosolized brevetoxins in an animal model of asthma
Airway responses to aerosolized brevetoxins in an animal model of asthma
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DOI：
10.1164/rccm.200406-735oc
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发表时间：
2005-01-01
影响因子：
24.7
通讯作者：
Baden, DG
中科院分区：
文献类型：
--
作者：
Abraham, WM;Bourdelais, AJ;Baden, DG
佛罗里达赤潮短毒素是由甲藻短卡伦藻产生的钠通道神经毒素。当雾化时，该毒素会导致正常人和患有气道疾病的患者出现气道症状，但缺乏系统暴露来确定肺部后果和推定机制。在此，我们报告了短卡伦菌（短短毒素粗品）、纯短毒素-2、短毒素-3和短毒素-tbm（短毒素-2减去侧链）裂解培养物对过敏性和非过敏性绵羊的肺阻力和气管粘液速度（粘液纤毛清除的标志物）的气道挑战的影响。皮克浓度的毒素引起两组绵羊的支气管收缩。 Brevetoxin-tbm 的效力最弱，表明侧链对于发挥最大效果的重要性。组胺 Hj 和胆碱能介导的途径均有助于支气管收缩。合成拮抗剂 β-萘甲酰基-brevetoxin-3 和天然拮抗剂 brevenal 可抑制支气管收缩。仅粗品短尾毒素和短尾毒素-3降低气管粘液流速；两个对手都阻止了这一点。更重要的是，皮摩尔浓度的拮抗剂单独改善气管粘液流速，达到毫摩尔浓度的钠通道阻滞剂阿米洛利所见的程度。因此，短卡伦菌除了产生对气道产生不利影响的毒素外，还可能是治疗粘液纤毛功能障碍的药物来源。
Florida red tide brevetoxins are sodium channel neurotoxins produced by the dinoflagellate Karenia brevis. When aerosolized, the toxin causes airway symptoms in normal individuals and patients with airway disease, but systematic exposures to define the pulmonary consequences and putative mechanisms are lacking. Here we report the effects of airway challenges with lysed cultures of Karenia brevis (crude brevetoxin), pure brevetoxin-2, brevetoxin-3, and brevetoxin-tbm (brevetoxin-2 minus the side chain) on pulmonary resistance and tracheal mucus velocity, a marker of mucociliary clearance, in allergic and nonallergic sheep. Picogram concentrations of toxin caused bronchoconstriction in both groups of sheep. Brevetoxin-tbm was the least potent, indicating the importance of the side chain for maximum effect. Both histamine Hj- and cholinergic-mediated pathways contributed to the bronchoconstriction. A synthetic antagonist, beta-naphthoyl-brevetoxin-3, and brevenal, a natural antagonist, inhibited the bronchoconstriction. Only crude brevetoxin and brevetoxin-3 decreased tracheal mucus velocity; both antagonists prevented this. More importantly, picomolar concentrations of the antagonists alone improved tracheal mucus velocity to the degree seen with mM concentrations of the sodium channel blocker amiloride. Thus, Karenia brevis, in addition to producing toxins that adversely affect the airways, may be a source of agents for treating mucociliary dysfunction.