MATURATIONAL CORRELATES OF AIRWAY CONTRACTION

气道收缩的成熟相关性

• 批准号: 3349906
• 负责人: ALAN Richard LEFF
• 金额: $ 23.26万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-30 至 1996-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3349906
• 关键词: acetylcholinesterase; autoradiography; bronchomotion; bronchospasm; endothelin; eosinophil; granulocyte; growth /development; guinea pigs; human tissue; infant animal; inflammation; leukocyte activation /transformation; lipoxygenase; mature animal; muscle contraction; neural information processing; online computer; respiratory airway pressure; respiratory epithelium; respiratory hypersensitivity; respiratory muscles; smooth muscle; vagotomy

Studies are proposed to continue investigation of the ontogeny of airway hyperresponsiveness. The central aim of this proposal is to examine the role of granulocytic inflammation on epithelial modulation of airway contractility during maturation. Initial studies are directed to determine the role and mechanism by which granulocytes induce airway hyperresponsiveness in neonatal and 3 month old guinea pigs. Additional studies are proposed to examine in vitro the effect of inflammation on indices of airway smooth muscle shortening during maturation. Preliminary studies suggest that inflammatory induction of airway hyperresponsiveness caused by activated eosinophils or exogenous endothelin-1 diminishes during maturation as a consequence of maturational alterations in metabolic function of epithelium. Using an in situ "living explant" preparation developed in the prior grant period, studies are proposed to examine the maturational development of 1) epithelial barrier function, 2) transduction of inflammatory stimulation and 3) modulation of the response to endothelin-1 by maturing epithelium. In the prior grant period, methods were developed for immunomagnetic separation of human eosinophils and neutrophils (PMN), enabling > 98% purification of eosinophils. Further studies are proposed to examine the contribution and mechanism of inflammatory transduction by either PMN or eosinophils after in vitro activation in maturing airways. In preliminary studies in the prior grant period, a model was developed to assess transduction of hyperpnea-induced bronchoconstriction mediated by epithelial c-fibers int he guinea pig. Further studies are proposed to study the maturation of this neural response in the epithelium. A final series of experiments is proposed to examine the effect of epithelial maturation on isotonic airway smooth muscle shortening. Pilot studies have been completed using a specially developed computerized electromagnetic level system that permits measurement of indices of actomyosin cross linkage and maximal shortening capacity. Studies are proposed to examine the biophysical properties of excised airway smooth muscle after inflammatory stimulation with activated granulocytes. Preliminary studies also indicate that smooth muscle acetylcholinesterase is not expressed phenotypically in immature animals and that inflammation downregulates the activity of this enzyme. Further studies are proposed to examine the role of inflammatory stimulation of the parasympathetic response to electrical field stimulation in vitro in maturing airway smooth muscle. These studies will establish the basis for intrinsic changes in basal responsiveness that may not be related directly to cell- cell interactions. Data derived from these studies will define alterations in epithelial-smooth muscle functions during inflammatory states and determine the potential role of activated granulocytes. Further studies will elucidate the mechanism of these maturational changes and suggest potential therapeutic strategies related to the ontogenic state of the airway.

建议继续研究气道的个体发育 过度反应。 该提案的中心目的是审查 粒细胞炎症对气道上皮调节的作用 成熟过程中的收缩性。 初步研究针对 确定粒细胞诱导气道的作用和机制 新生儿和 3 个月大豚鼠的高反应性。 额外的 建议进行体外研究以检查炎症对 成熟过程中气道平滑肌缩短的指标。 初步研究表明，气道炎症诱导 由活化的嗜酸性粒细胞或外源性物质引起的高反应性 由于以下原因，内皮素-1 在成熟过程中减少 上皮代谢功能的成熟改变。 使用 在上一个资助期间开发的原位“活外植体”制剂， 建议进行研究以检验 1) 的成熟发展 上皮屏障功能，2）炎症刺激的转导 3) 通过成熟上皮调节内皮素-1 的反应。 在之前的资助期内，开发了免疫磁性方法 分离人嗜酸性粒细胞和中性粒细胞 (PMN)，使 > 98% 嗜酸性粒细胞的纯化。 建议进一步研究以检验 PMN或PMN对炎症转导的贡献和机制 成熟气道中体外激活后的嗜酸性粒细胞。 在 在之前的资助期间进行了初步研究，开发了一个模型 评估呼吸过度引起的支气管收缩的转导 豚鼠上皮c纤维。 建议进一步研究 研究上皮细胞中这种神经反应的成熟。 决赛 提出了一系列实验来检查上皮细胞的影响 等渗气道平滑肌缩短的成熟。 试点研究 已使用专门开发的计算机化完成 电磁水平系统，允许测量指数 肌动球蛋白交联和最大缩短能力。 研究是 提议检查切除的气道光滑的生物物理特性 激活粒细胞炎症刺激后的肌肉。 初步研究还表明平滑肌乙酰胆碱酯酶 在未成熟动物中不表达表型，并且炎症 下调该酶的活性。 建议进一步研究 检查副交感神经炎症刺激的作用 成熟气道对体外电场刺激的反应 平滑肌。 这些研究将为内在的 基础反应性的变化可能与细胞不直接相关 细胞相互作用。 从这些研究中得出的数据将定义 炎症过程中上皮平滑肌功能的改变 状态并确定活化粒细胞的潜在作用。 进一步的研究将阐明这些成熟的机制 变化并提出与相关的潜在治疗策略 气道的本体状态。