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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

基本信息

批准号：
3339814
负责人：
JEAN F. REGAL
金额：
$ 10.14万
依托单位：
UNIVERSITY OF MINNESOTA DULUTH
依托单位国家：
美国
项目类别：
财政年份：
1981
资助国家：
美国
起止时间：
1981-07-01 至 1991-06-30
项目状态：
已结题

项目摘要

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.

补体蛋白C3和C5的裂解通过激活补体系统产生低分子量片段C3a和C5a(过敏毒素)。杰出的生物学 C_(3a)和C_(5a)的活动是离体气道管的收缩肌肉。此外，C5a在体内是一种有效的支气管收缩因子那只小白鼠。我们最近的研究表明眼镜蛇毒因子激活血管内补体显著增强了后续抗原诱导的 IgE致敏豚鼠的支气管收缩作用。因此，拟议研究的目的有两个：1)评估补体C3a和C5a作为支气管收缩药本身的直接作用 2)检测补体激活的间接效应和C3a/C5a的产生增强抗原诱导支气管收缩。C3a和C5a将静脉注射。或通过气溶胶与组胺和花生四烯酸代谢产物在过敏性曲霉毒素引起的支气管收缩将使用药理拮抗剂及其放射免疫测定被释放的调解人。粒细胞和血小板将会使用特定的抗血清进行耗尽以确定过敏性黄曲霉毒素引起的支气管收缩依赖于这些细胞。抗原诱导的免疫增强机制 IgE-1患者补体系统激活后的支气管收缩致敏的豚鼠也将接受检查。研究将会确定这种增强的过敏性支气管收缩是否是直接的补体激活和C3a/C5a生成的结果呼吸道对内源性介质的敏感性增加，取决于循环中粒细胞的存在或血小板，或内源性释放增加的结果支气管缩缩症。将对体内的支气管收缩进行评估麻醉豚鼠气管的测量空气流量和经肺压力测定肺阻力和动态肺顺应性。抗原通过静脉或呼吸道途径给药将是在被动致敏的豚鼠身上进行了研究。这些研究将提供有关以下机制的重要信息 C3a和C5a的支气管收缩作用，从而有助于确定它们作为支气管收缩药的潜在贡献的程度在阻塞性呼吸道疾病中。此外，这些研究将确定补体系统激活和C3a/C5a 世代可能是一个重要的决定因素的严重程度过敏反应。