MATURATIONAL CORRELATES OF AIRWAY CONTRACTION

气道收缩的成熟相关性

• 批准号: 2217895
• 负责人: ALAN Richard LEFF
• 金额: $ 26.55万
• 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/2217895
• 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生 高反应性 这项建议的主要目的是审查 粒细胞炎症在气道上皮调节中的作用 成熟过程中的收缩力。 初步研究旨在 确定粒细胞诱导气道的作用和机制 新生豚鼠和3月龄豚鼠高反应性。 额外 提出了体外研究炎症对 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 内皮素-1在成熟过程中减少， 上皮细胞代谢功能的成熟改变。 使用 在前一个赠款期开发的原位“活体外植体”制备， 建议进行研究，以检查1）的成熟发展 上皮屏障功能，2）炎症刺激的转导 和3）通过成熟上皮调节对内皮素-1的反应。 在前一个资助期，开发了免疫磁性的方法， 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。 建议进行进一步研究， 中性粒细胞或巨噬细胞对炎症转导的贡献和机制 在成熟气道中体外活化后的嗜酸性粒细胞。 在 在前一个赠款期的初步研究中，开发了一个模型， 评估呼吸过度诱导的支气管收缩的转导 豚鼠上皮C纤维。 建议开展进一步研究， 研究这种上皮神经反应的成熟。 最终 一系列的实验，提出了检查上皮细胞的影响， 等张气道平滑肌缩短的成熟。 试点研究 已经完成了使用专门开发的计算机 电磁水平系统，允许测量的指数， 肌动球蛋白交联和最大缩短能力。 研究是 建议检查切除的气道光滑的生物物理特性， 用活化的粒细胞进行炎症刺激后的肌肉。 初步研究还表明，平滑肌乙酰胆碱酯酶 在未成熟的动物中不表达， 下调这种酶的活性。 提出了进一步的研究建议 研究副交感神经的炎症刺激的作用， 体外成熟气道对电场刺激的反应 平滑肌 这些研究将建立内在的基础 基础反应性的变化可能与细胞不直接相关， 细胞相互作用 从这些研究中获得的数据将定义 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，并提出潜在的治疗策略， 气道的个体发育状态。