Experimental Studies on Mechanisms of Eosinophil Infiltration in Airways in Bronchial Asthma and on its Modulation by Drugs

现在有相当多的证据表明，嗜酸性粒细胞参与sathma过程作为促炎效应细胞，最近的注意力集中在气道嗜酸性粒细胞的积累在进行性疾病的机制。本研究旨在确定哪些介质实际上负责将嗜酸性粒细胞吸引到气道粘膜，并检查抑制气道嗜酸性粒细胞对哮喘病理生理学的影响。致敏豚鼠腹腔注射卵清蛋白（OA）响应单次暴露于雾化OA与双相浸润的嗜酸性粒细胞在气道中，一个惊人的早期阶段，在6小时达到峰值，并在24小时达到峰值的延迟阶段，并持续长达5天。早期应用PAF拮抗剂可抑制淋巴细胞的浸润，而晚期应用T淋巴细胞选择性免疫抑制剂环孢菌素A（CyA）或FK-506（FK）则可抑制淋巴细胞的浸润。日 ...更多信息 结果提示，PAF可能参与了气道嗜酸性粒细胞浸润的早期阶段，T细胞因子可能参与了气道嗜酸性粒细胞浸润的延迟阶段。为了观察抗原攻击后豚鼠肺中是否真的产生PAF，我们测定了支气管肺泡灌洗液（BAL）中的PAF活性，发现每公斤体重PAF的浓度为1 pmol。CyA和FK对气道嗜酸性粒细胞增多的抑制导致抗原诱导的晚期哮喘反应的消除和随后通过反复暴露于雾化OA免疫的豚鼠的支气管高反应性的增加，提高了预防嗜酸性粒细胞迁移到气道中的药物在治疗哮喘中有用的可能性。我们测试了PAF或淋巴因子样物质是否在抗原诱导的人类嗜酸性粒细胞浸润中也可能是重要的。从粉尘螨（Dermatophagoides farinae，DF）敏感的哮喘患者外周血中分离嗜碱性粒细胞和单个核细胞，在DF抗原存在下培养，并采用改良Boyden小室技术检测上清液中嗜酸性粒细胞趋化活性（Eosinophil chemotactic activity，ECA）。嗜碱性粒细胞产生ECA，其被特异性PAF拮抗剂阻断，而单核细胞产生热稳定的ECA，分子量为30，000，推测为淋巴因子，其在3-5天达到峰值。提示PAF样物质和淋巴因子样物质在哮喘患者气道嗜酸性粒细胞中起重要作用。少

There is now considerable evidence that eosinophils participate in the sathma process as proinflammatory effector cells, and recent attention has been focused on the mechanisms of airway eosinophil accumulation in ongoing disease. This study was dedigned to determine which mediators are actually responsible for attracting eosinophils to the airway mucosa and examine the effect of suppression of airway eosinophilia on the pathophysiology of asthma. Guinea pigs sensitized by intraperitoneal injection of ovalbumin (OA) responded to a single exposure to aerosolized OA with biphasic infiltration of eosinophils in the airways ; a striking early-phase which peaked at 6 hr and a delayed-phase which peaked at 24 hr and persisted for as long as 5 days. The early-phase infiltration was suppressed by the precious administration ofPAF antagonist, and the delayed-phase was inhibited when animals were treated with Cyclosporin A (CyA) or FK-506 (FK), T lymphocyte-selective immunosuppressive agents. Th … More ese results suggested that PAF may contribute to early-phase and T cell factor (s) may contribute to delayed-phase eosinophil infiltration of the airways. To look at whether PAF generation really occurs in the lungs of guinea pigs after antigen challenge, we determined PAF activity in bronchoalveolar lavage (BAL) fluids and found that there existedl pmol of PAF ler 1 kg body weight. Suppression of airway eosinophilia by CyA and FK resulted in the inhivition of antigen-induced late asthmatic response and a subsequent increase in bronchial hyperresponsiveness in guineapigs immunized by repeated exposure to aerosolized OA, raising the possibility that drugs precenting eosinophil migration into the airways would be useful in the treatment of asthma.Finally, we tested whether PAF- or lymphokine-like substance might be also important in the antigeninduced eosinophil infiltration in humans. Basophils and mononuclear cells were separated from the peripheral blood of Dermatophagoides farinae (DF) -sensitive asthmatic subjects, cultured in the presence of DF antigen and eosinophil chemotactic activity (ECA) in the supernatants was tested using a modified Boyden chamber technique. Basophils produced ECA which was blocked by a specific PAF antagonist, whereas mononuclear cells produced heat-stable ECA with a MW 30,000, presumably lymphokine, which peaked at 3-5 day. These results suggest that PAF- and lymphokine-like substance may play a key role in the airway eosinophils in asthmatic subjects. Less