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Production of an allergic inflammation model using human lungs resected by a surgical operation and its application to drug discovery for the treatment of asthma

利用外科手术切除的人肺制作过敏性炎症模型及其在治疗哮喘的药物发现中的应用

基本信息

批准号：
17590478
负责人：
ABE Masayoshi
金额：
$ 1.98万
依托单位：
Fukuoka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

In order to resolve a problem concerning species differences in pharmacological science, we tried to make an inflammation model using human lung tissues obtained from patients with lung cancer after surgical resection. When the chopped lung fragments passively sensitized with human IgE were incubated with anti-human IgE antibody, a significant amount of cysteinyl-leukotrienes (cysLTs) was generated in comparison with the control (without anti-IgE). The addition of human C3a or C5a alone did not generate cysLTs. The co-addition, however, of C5a at doses of 1.0 ng/ml to the anti-IgE antibody further potentiated cysLT production. Consequently, an allergic inflammation model in which complement activation was involved as a pathophysiological mechanism was produced. Either a novel C5a receptor complementary peptide or a C5a receptor antagonist inhibited cysLT production in a dose-dependent manner by the human lung fragments following the anaphylactic reaction in the presence of 1 ng/ml C5a. … More Since there are consideable species differences in primary structure of anaphylatoxins and those receptors, this model using human lung tissues may be valuable to perform screening for a novel drug. In contrast, the shortage of suitable human tissues and lack of methods for stable preservation are hindering to produce an adequate model using human tissues. After lung tissues were obtained from patients with lung cancer, they were kept at -5℃ or 4℃ for as many as 5 days, and then they were histologically and biochemically examined. Although the tissues preserved at-5℃ had an almost normal morphology with intact cilia on bronchial epithelium and normal endothelium, the tissues stored at 4℃ showed degradation of these structures. Single-stranded DNA, a sign of DNA cleavage, was frequently noted in tissues stored at 4℃, but only rarely observed at -5℃. A significant amount of cysLTs was generated by anaphylactic reaction from tissues stored at 5℃ for 3 days, but there was no response to antibody stimulation from tissues at 4℃. Therefore, such the novel preservation of human tissues as super-cooling system may facilitate availability of human tissues in medical science. Less

为了解决药理学中的物种差异问题，我们尝试使用从手术切除后的肺癌患者获得的人肺组织制作炎症模型。当用人IgE被动致敏的切碎的肺碎片与抗人IgE抗体孵育时，与对照（无抗IgE）相比，产生了显著量的半胱氨酰-白三烯（cysLT）。单独添加人C3 a或C5 a不产生cysLT。然而，以1.0 ng/ml的剂量向抗IgE抗体中共添加C5 a进一步增强了cysLT的产生。因此，产生了其中补体激活作为病理生理机制参与的过敏性炎症模型。无论是一种新的C5 a受体互补肽或C5 a受体拮抗剂抑制cysLT生产的剂量依赖性方式由人肺碎片过敏反应后，在1 ng/ml C5 a的存在下。 ...更多信息由于过敏毒素及其受体的一级结构存在明显的种属差异，因此使用人肺组织的模型可能对筛选新药有价值。相反，缺乏合适的人体组织和缺乏稳定保存的方法阻碍了使用人体组织产生适当的模型。取肺癌患者的肺组织，在-5℃或4℃下保存5天，然后进行组织学和生化检查。尽管在-5 ℃保存的组织具有几乎正常的形态，支气管上皮上的纤毛完整，内皮正常，但在4℃保存的组织显示这些结构的降解。在4℃下储存的组织中经常观察到单链DNA，这是DNA裂解的标志，但在-5℃下很少观察到。在5℃下储存3天的组织中，过敏反应产生了大量的cysLT，但在4℃下，组织对抗体刺激无反应。因此，这种新型的人体组织保存系统，如过冷系统，可以促进人体组织在医学科学中的可用性。少