Inhaled Brevetoxins: Health Effects and Mechanisms

该项目的主要重点一直是检查潜在的有害健康影响 由于长期吸入短杆菌毒素所致。一种复杂的混合毒物的吸入毒性 以大鼠为实验对象，检测了短杆菌提取物中的短杆菌毒素及其拮抗剂，并对其毒性进行了研究。 在大鼠和小鼠身上都检测到了短杆菌毒素3。对大鼠的免疫抑制，如一种 减少绵羊红细胞免疫后的抗体反应一直是主要的 观察到反应。在没有直接毒性的情况下发生抗体形成反应的抑制 脾，淋巴细胞群的变化，或T细胞对抗原的反应。这种免疫抑制是 鉴于赤潮期间肺炎急诊室就诊人数增加的报道，这一点很重要 由弗莱明项目鉴定，并在亚伯拉罕项目中发现吸入短毒素的绵羊肺泡巨噬细胞功能降低。这 提案将涉及以下具体目标：(1)界定暴露浓度-反应关系 研究短杆菌毒素对大鼠体液免疫的影响及巨噬细胞组织蛋白酶的作用 抑制介导这些效应；(2)观察吸入短春花毒素对小鼠呼吸功能恢复的影响。 包括幼年和老年大鼠在内的流感大鼠模型的感染；以及(3)测定免疫毒性 短杆菌毒素在吸入短杆菌毒素的母鼠子代中的潜力。这些调查将扩大范围 研究短杆菌毒素对抗原抗体反应的暴露浓度-反应关系，为观察到的免疫抑制的潜在机制提供洞察(S)， 研究短杆菌毒素诱导的免疫抑制对病毒感染反应的潜在后果； 并确定围产期接触短杆菌毒素可能造成的发育免疫毒性。

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.