Inhaled Brevetoxins: Health Effects and Mechanisms

该项目的主要重点是研究潜在的不良健康影响 长期吸入短尾藻毒素所致吸入毒性的复杂混合物的 短杆菌毒素和短杆菌毒素拮抗剂;在大鼠中检查了短叶薯蓣提取物，并且纯的短叶薯蓣提取物 在大鼠和小鼠中检测短尾孢毒素3。大鼠中的大量免疫抑制，如a所示。 对绵羊红细胞免疫的抗体应答的减少，始终是主要的免疫缺陷。 回应观察抗体形成反应的抑制发生在没有明显毒性的情况下， 脾脏、淋巴细胞群的变化或T细胞对抗原的反应。这种免疫抑制 重要的是，鉴于在赤潮期间肺炎急诊室就诊的报告增加， Fleming项目中发现的，以及Abraham项目中绵羊吸入短尾藻毒素后肺泡巨噬细胞功能的降低。这 该提案将针对以下具体目标：（1）定义暴露浓度-反应关系 短尾寒毒对大鼠体液免疫的影响，并检查巨噬细胞组织蛋白酶的作用 抑制介导这些作用;（2）检查吸入短尾寒毒对恢复的影响， 感染流感大鼠模型，包括年轻成年大鼠和老年大鼠;和（3）确定免疫毒性 吸入短尾丝虫毒素的母鼠的后代中短尾丝虫毒素的可能性。这些调查将扩大 对短杆菌毒素诱导的对抗原的抗体应答的影响的暴露浓度-应答关系的检查，提供了对所观察到的免疫抑制的潜在机制的了解， 检查短尾丝虫毒素诱导的免疫抑制对病毒感染反应的潜在后果; 并确定围产期暴露于短吻蝮蛇毒素可能导致的发育免疫毒性。

The major focus of this Project has been to examine the potential adverse health effects resulting from prolonged inhalation exposure to brevetoxins. The inhalation toxicities of a complex mixture of brevetoxins and brevetoxin antagonists in K. brevis extract was examined in rats, and the toxicity of pure brevetoxin 3 was examined in both rats and mice. Substantial immune suppression in rats, as indicated by a reduction in antibody response to immunization with sheep red blood cells, was consistently the primary response observed. Suppression of antibody forming responses occurred in the absence of frank toxicity to the spleen, changes in lymphocyte populations, or T cell responses to antigen. This immune suppression is important in light of reports in increased emergency room visits for pneumonia during Red Tide episodes identified by Fleming project and decreases in alveolar macrophage function in sheep inhaling brevetoxins in project by Abraham. This proposal will address the following specific aims: (1) To define exposure concentration-response relationships for brevetoxin-induced effects on humoral immunity in rats and to examine the role of macrophage cathepsin inhibition in mediating these effects; (2) To examine the effects of brevetoxin inhalation on recovery from infection in a rat model of influenza including young adult and aged rats; and (3) To determine the immunotoxic potential of brevetoxin in offspring of dams inhaling brevetoxins. These investigations will broaden examination of the exposure concentration-response relationship for brevetoxin-induced effects on antibody responses to antigen, provide insight into the underlying mechanism(s) for the observed immune suppression, examine potential consequences to brevetoxin-induced immune suppression on responses to viral infection; and determine the potential developmental immunotoxicity resulting from perinatal brevetoxin exposure.