ROLE OF C3A/C5A IN ANTIGEN-INDUCED BRONCHOCONSTRICTION

C3A/C5A 在抗原诱导的支气管收缩中的作用

• 批准号: 3339813
• 负责人: JEAN F. REGAL
• 金额: $ 9.91万
• 依托单位: UNIVERSITY OF MINNESOTA DULUTH
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-07-01 至 1990-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3339813
• 关键词: anaphylatoxins; anaphylaxis; antigens; antihistamines; arachidonate; atropine; bronchospasm; complement; complement pathway; dosage; drug administration routes; endotoxins; enzyme inhibitors; enzyme linked immunosorbent assay; granulocyte; guinea pigs; histamine; immunoglobulin E; immunoglobulin G; indomethacin; lipoxygenase; ovalbumin; platelets; prostaglandin endoperoxide synthase; prostaglandins; radioimmunoassay; respiratory airway pressure; respiratory pharmacology; thromboxanes

Cleavage of the complement proteins C3 and C5 by activation of the complement system yields the low molecular weight fragments C3a and C5a (anaphylatoxins). A prominent biological activity of C3a and C5a is contraction of isolated airway smooth muscle. In addition C5a is a potent bronchoconstrictor in vivo in the guinea pig. Our recent studies have demonstrated that intravascular complement activation with cobra venom factor markedly enhances a subsequent antigen-induced bronchoconstriction in IgE-sensitized guinea pigs. Thus, the purpose of the proposed research is two-fold: 1) to assess the direct action of C3a and C5a as bronchoconstrictors themselves and 2) to examine the indirect effect of complement activation and C3a/C5a generation in enhancing antigen-induced bronchoconstriction. C3a and C5a will be administered i.v. or by aerosol and the role of histamine and arachidonate metabolites in anaphylatoxin-induced bronchoconstriction will be assessed using pharmacological antagonists and radioimmunoassay measurements of released mediators. Granulocytes and platelets will be depleted using specific antisera in order to determine the dependence of anaphylatoxin-induced bronchoconstriction on these cells. The mechanism of enhancement of antigen-induced bronchoconstriction after complement system activation in IgE- sensitized guinea pigs will also be examined. Studies will determine if this enhanced allergic bronchoconstriction is a direct result of complement activation and C3a/C5a generation, a result of increased sensitivity of the airways to endogenous mediators, dependent on the presence of circulating granulocytes or platelets, or the result of increased release of endogenous bronchoconstrictors. Bronchoconstriction in vivo will be assessed in anesthetized guinea pigs using measurements of tracheal airflow and transpulmonary pressure for determination of pulmonary resistance and dynamic lung compliance. Antigen administration via the intravenous or respiratory route will be investigated in passively sensitized guinea pigs. These studies will provide important information regarding the mechanism of bronchoconstrictor action of C3a and C5a and thus help determine the extent of their potential contribution as bronchoconstrictors in obstructive airway disease. In addition, these studies will determine if complement system activation and C3a/C5a generation could be important determinants of the severity of an anaphylactic reaction.

通过激活补体蛋白C3和C5的切割 补体系统产生低分子量 片段C3 a和C5 a（过敏毒素）。 一位杰出的生物学家 C3 a和C5 a的活性是离体气道平滑肌的收缩 肌肉. 此外，C5 a在体内是一种有效的支气管收缩剂， 豚鼠 我们最近的研究表明， 用眼镜蛇毒因子激活血管内补体 显著增强随后的抗原诱导的 IgE致敏豚鼠的支气管收缩。 因此 拟议研究的目的有两个方面：1）评估 C3 a和C5 a本身作为支气管收缩剂的直接作用 和2）检查补体激活的间接作用 和C3 a/C5 a生成在增强抗原诱导的 支气管收缩 C3 a和C5 a将通过静脉注射或 气溶胶和组胺和花生四烯酸代谢物的作用 过敏毒素诱导的支气管收缩将使用 药理学拮抗剂和放射免疫测定 被释放的调解人。 粒细胞和血小板将 使用特异性抗血清耗尽，以确定 过敏毒素引起的支气管收缩对 这些细胞。 增强抗原诱导的免疫反应的机制 支气管收缩后补体系统激活IgE- 还将检查致敏豚鼠。 研究将 确定这种增强的过敏性支气管收缩是否是 补体激活和C3 a/C5 a生成的结果， 气道对内源性介质的敏感性增加， 取决于循环粒细胞的存在，或 血小板，或增加释放内源性 支气管收缩剂 将评估体内支气管收缩 在麻醉豚鼠中，使用测量气管 空气流量和透湿压力， 肺阻力和动态肺顺应性。 抗原 通过静脉内或呼吸途径给药将是优选的。 在被动致敏豚鼠中进行研究。 这些研究将 提供关于 C3 a和C5 a的支气管收缩作用，从而帮助确定 它们作为支气管收缩剂的潜在作用程度 阻塞性气道疾病 此外，这些研究将 确定补体系统激活和C3 a/C5 a 一代可能是严重的一个重要的决定因素， 过敏反应。