INFLAMMATORY MODULATION OF BRONCHOMOTOR TONE

支气管运动张力的炎症调节

• 批准号: 6099633
• 负责人: ALAN Richard LEFF
• 金额: --
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-01 至 1998-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6099633
• 关键词: asthma; beta adrenergic receptor; bronchomotion; bronchus; cell adhesion; cell adhesion molecules; cooperative study; cytokine; eosinophil; fibronectins; flow cytometry; guinea pigs; human tissue; immunologic assay /test; immunomagnetic separation; inflammation; leukocyte activation /transformation; leukotrienes; muscle contraction; peroxidases; respiratory epithelium; respiratory muscles; secretion; selectins; superoxides; tissue /cell culture; vascular endothelium

Studies are proposed to examine mechanisms by which activated inflammatory cells convert normally responsive airways into hyperreactive tissues. Investigations are planned to examine the relationship between adhesion of peripheral blood and cultured eosinophils to intra- and extracellular matrix ligands and the effect of these reactions in upregulating secretion of bronchoactive granular proteins and eicosanoids. A central hypothesis of the first series of investigations is that adhesion of peripheral blood eosinophils to vascular endothelium causes augmented secretion upon stimulation. Using immunomagnetic separation techniques that isolate eosinophils in high purity from non-atopic humans developed in preliminary studies, experiments are proposed to determine the effect of preincubation of eosinophils with human umbilical vein endothelial cells (HUVEC) on the spontaneous and stimulated secretion of eosinophils peroxidase (EPO), leukotriene C4 (LTC4), and superoxide anion (O2-). Additional studies will l) examine the incremental effects on metabolic activation and secretion of eosinophil-adhesion to HUVEC pretreated with IL-1 or IL-4 and 2) determine the effect of blockade of eosinophil adhesion molecules LFA-1, Mac-1, VLA-4, and L-selectin on adhesion-mediated regulation of eosinophil secretory function. Additional experiments will address the role of exposure to matrix protein on upregulation of secretion of bioactive eosinophil proteins and eicasonoids. A second series of experiments will examine the functional correlates of endothelial adhesion and matrix protein interactions with eosinophils on airway responsiveness. Using preparations of cultured cord-derived eosinophils (CDB) developed in preliminary studies for this proposal, cell-cell interactions between CDE and excised human bronchi will be assessed in vitro and in a guinea pig "living explant" preparation in vivo. Studies are proposed to assess the effect of exogenous activation of eosinophils with formylated tripeptide and by adhesion to matrix proteins and vascular endothelium on isometric contraction and auxotonic narrowing of human airways. Using a specially developed superfusion preparation of human bronchus, the effect of epithelial activation and adhesion will be assessed in vitro by videomicrometry. In a final series of experiments, the regulation of eosinophil secretion of bronchoactive proteins and LTC4 by the beta-adrenoceptor and by endogenous phospholipase A will be related to inhibition of airway hyperresponsiveness caused by activated eosinophils. The proposed studies are designed to l) determine mechanisms causing eosinophil activation, 2) assess indices of cellular secretion corresponding to augmented airway smooth muscle contraction, and 3) model the corresponding inflammatory induction of airway hyperresponsiveness in vitro. Data derived from these investigation should provide a mechanistic basis for therapeutic intervention in the inflammatory hyperresponsiveness of human asthma.

提出了研究以检查激活的机制 炎症细胞正常反应式气道转换为 高回应组织。计划进行调查以检查 外周血的粘附与培养之间的关系 嗜酸性粒细胞到细胞内和细胞外基质配体以及 这些反应在上调的分泌中的影响 支气管活性颗粒状蛋白和类花生素。中央 第一个研究的假设是粘附 外周血嗜酸性粒细胞到血管内皮原因 刺激后增强分泌。使用免疫磁性 分离嗜酸性粒细胞的分离技术与高纯度的分离 在初步研究中开发的非原始人类，实验是 提议确定嗜酸性粒细胞预孵育的影响 在人类脐静脉内皮细胞（HUVEC）上 嗜酸性粒细胞过氧化物酶的自发和刺激分泌 （EPO），白三烯C4（LTC4）和超氧化阴离子（O2-）。 其他研究将l）检查对 嗜酸性粒细胞粘附为HUVEC的代谢激活和分泌 用IL-1或IL-4预处理和2）确定 嗜酸性粒细胞粘附分子LFA-1，MAC-1，VLA-4和 L-选择素在粘附介导的嗜酸性分泌的调节中 功能。其他实验将解决暴露的作用 在生物活性的分泌上上调基质蛋白 嗜酸性粒细胞蛋白和花生素。第二系列实验 将检查内皮粘附和 基质蛋白与气道上的嗜酸性粒细胞相互作用 响应能力。使用培养的绳索衍生的准备 嗜酸性粒细胞（CDB）在初步研究中开发了 提案，CDE和切除的人之间的细胞细胞相互作用 支气管将在体外和豚鼠中评估 epplant“在体内制备。提出了研究以评估 嗜酸性粒细胞外源激活的影响 三肽和对基质蛋白和血管的粘附 等距收缩和辅助狭窄的内皮 人类航空。使用专门开发的超级灌注准备 人支气管，上皮激活和粘附的作用 将通过视频计量法在体外进行评估。在最后一系列 实验，调节嗜酸性粒细胞分泌的调节 Beta-Adrenoceptor的支气管活性蛋白和LTC4，由 内源性磷脂酶A将与气道的抑制有关 激活的嗜酸性粒细胞引起的过度反应性。提议 研究旨在确定引起嗜酸性粒细胞的机制 激活，2）评估细胞分泌的指标相应 增强气道平滑肌收缩，3）建模 气道高反应性的相应炎症诱导 体外。这些调查得出的数据应提供 炎症治疗干预的机械基础 人类哮喘的反应性过高。