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，嗜酸性粒细胞作为促炎效应细胞参与炎症过程，最近的注意力集中在正在进行的疾病中气道嗜酸性粒细胞积累的机制上。本研究旨在确定哪些介质实际上负责吸引嗜酸性粒细胞到气道粘膜，并检查气道嗜酸性粒细胞抑制对哮喘病理生理的影响。腹腔注射卵清蛋白（OA）致敏的豚鼠对雾化OA的单次暴露有反应，气道内嗜酸性粒细胞双期浸润；一个显著的早期阶段，在6小时达到高峰，一个延迟阶段，在24小时达到高峰，持续长达5天。paf拮抗剂可抑制早期浸润，而T淋巴细胞选择性免疫抑制剂环孢素A （CyA）或FK-506 （FK）可抑制晚期浸润。更多的结果表明，PAF可能参与气道的早期和T细胞因子(s)可能参与气道的延迟期嗜酸性粒细胞浸润。为了观察抗原激发后豚鼠肺部是否真的产生PAF，我们测定了支气管肺泡灌洗液（BAL）中PAF的活性，发现在1公斤体重时存在1 pmol PAF。在反复暴露于雾化OA的豚鼠中，CyA和FK对气道嗜酸性粒细胞的抑制导致抗原诱导的晚期哮喘反应的抑制和随后支气管高反应性的增加，这提高了防止嗜酸性粒细胞迁移到气道的药物可能有助于治疗哮喘的可能性。最后，我们测试了PAF-或淋巴因子样物质在抗原诱导的人类嗜酸性粒细胞浸润中是否也很重要。采用改良的Boyden室技术检测嗜酸性粒细胞趋化活性（ECA），并在DF抗原存在下对哮喘患者外周血嗜碱性粒细胞和单个核细胞进行培养。嗜碱性细胞产生的ECA被特定的PAF拮抗剂阻断，而单核细胞产生的ECA的分子量为30,000，可能是淋巴因子，在3-5天达到峰值。这些结果提示PAF-和淋巴因子样物质可能在哮喘患者气道嗜酸性粒细胞中起关键作用。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