MATURATIONAL CORRELATES OF AIRWAY CONTRACTION

建议继续研究呼吸道的个体发育。 高反应性。这项建议的中心目标是研究 粒细胞炎症在呼吸道上皮细胞调节中的作用 成熟期的伸缩性。初步研究旨在 确定粒细胞诱导呼吸道的作用和机制 新生和3月龄豚鼠的高反应性。其他内容 有研究建议在体外检测炎症对心脏的影响 成熟过程中气道平滑肌缩短的指标。 初步研究表明，呼吸道炎症诱导 嗜酸性粒细胞活化或外源性引起的高反应性 内皮素-1在成熟过程中因以下原因而减少 上皮细胞代谢功能的成熟改变。使用 在前一批赠款期间开发的“活体外植体”原位准备， 建议进行研究以考察1)的成熟发展 上皮屏障功能，2)炎症刺激的转导 (3)成熟上皮对ET-1反应的调节。 在之前的赠款期间，开发了免疫磁学的方法 分离人嗜酸性粒细胞和中性粒细胞(PMN)，使&gt；98% 嗜酸性粒细胞的纯化。建议进行进一步的研究，以研究 中性粒细胞或中性粒细胞对炎症转导的贡献及机制 成熟呼吸道体外激活后的嗜酸性粒细胞。在……里面 在前一批赠款期间的初步研究中，开发了一个模型来 评估高呼吸暂停诱导的支气管收缩的转导。 豚鼠的上皮性c纤维。建议进行进一步研究，以 研究这种神经反应在上皮细胞中的成熟情况。决赛 建议进行一系列实验来检验上皮细胞的作用 等张气道平滑肌缩短的成熟度。试点研究 都是使用专门开发的计算机化的 允许测量折射率的电磁液位系统 肌动球蛋白交联和最大缩短量。研究是 建议检查切除的呼吸道平滑的生物物理特性 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，而且炎症 下调这种酶的活性。提出了进一步的研究方向。 研究炎性刺激对副交感神经的作用 成熟气道对电场刺激的体外反应 平滑的肌肉。这些研究将奠定内在的基础 基础反应性的变化可能与细胞没有直接关系- 细胞间的相互作用。从这些研究中得出的数据将定义 炎症过程中上皮-平滑肌功能的变化 说明并确定激活的粒细胞的潜在作用。 进一步的研究将阐明这些成熟的机制。 改变和建议潜在的治疗策略，与 呼吸道的个体发生状态。

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.