MATURATIONAL CORRELATES OF AIRWAY CONTRACTION

建议进行调查，以确定对 呼吸道收缩的局部和成熟性变化 在之前的授权期中阐明的答复。那些研究 显示出一种异质性分布的支气管收缩 相关犬主要阻力气道的反应 由于1)呼吸道机械性能的内在差异， 原位，2)平滑肌收缩力差，3) 呼吸道的固有稳定性和拉普拉斯特性 在活体内。离体气道肌的体外研究揭示 不同代人之间在气道力上的显著差异 等长收缩，这不仅仅与 呼吸道受体的地形性分布。在预赛中 在之前的资助期间，已经制定了研究方法 用于对呼吸道肌肉进行计算机形态测量分析，允许 用于几何形状的定量测定和评估 气道缩窄力在体内的分布。技术是 为放射性配基分析而开发，允许评估 受体在各代呼吸道中的分布。一个 对以前工作的主要扩展是应用了 这些技术可用于研究儿童的成熟反应。 猪的呼吸道平滑肌。因为它的迅速成熟 这一物种，呼吸道肌肉功能的主要变化可能是 在很短的时间内演示了。一种原位等轴测制剂， 使得对气管的比较评估成为可能 婴幼儿(2周)和幼年的平滑肌收缩力 (8-12周)猪。机械和机械方面的重大改变 这种肌肉的药理特性似乎随着年龄的增长而发生。 来自相同动物的气管肌肉的体外研究表明 猪的收缩特性发生了实质性变化 随着呼吸道肌肉的成熟。我们建议扩大这些研究的范围 进一步1)描述呼吸道的原位分布 原位收缩反应(使用钽支气管造影术)，2) 随着成熟而发生的形态和生化变化，以及 3)各种呼吸道中发生的生物物理变化 成熟的世代(使用最近开发的技术 用于测定力-速度和等长收缩 在支气管呼吸道中的属性)。这些机制解释了 肌力的地形性和成熟性差异 进一步的收缩将通过体外研究阐明 1)特异性受体配体(放射自显影定位)。 2)肌球蛋白同工酶及含量；3)ATPase-肌球蛋白交配率 桥骑自行车这些调查将雇用一个 跨学科的方法来阐明形态计量学， 气道收缩性的生物物理和生化相关性 它们既在地形上发育，也在成熟过程中发育。 这些数据应该表明基本的生理和 在呼吸道中发生的病理生理差异 治疗的成熟度和可能的本质差异 成人和儿童反应性呼吸道疾病之间的途径。

Investigations are proposed to define mechanisms accounting for the topographical and maturational changes in airway contractile response elucidated in the prior grant period. Those studies demonstrated a heterogeneous distribution of bronchoconstrictor responses in the major resistance airways of dogs that were related to intrinsic differences in 1) mechanical properties of airways in situ, 2) differences in force of smooth muscle contraction, and 3) intrinsic stability and Laplacian characteristics of the airways in vivo. Studies of isolated airway muscle in vitro revealed substantial differences among airway generations in the force of isometric contraction, which was not related solely to topographical distribution of airway receptors. In preliminary studies during the prior grant period, methods have been developed for computerized morphometric analysis of airway muscle that allow for quantitative determination and assessment of the geometric distribution of airway constrictor forces in vivo. Techniques were developed for radioligand assays permitting assessment of the distribution of receptors in the various airway generations. A major extension of the previous work has been the application of these techniques to the study of the maturational responses of airway smooth muscle in swine. Because of the rapid maturation of this species, major alterations in airway muscle function may be demonstrated in brief time. An in situ isometric preparation was developed that permitted the comparative assessment of tracheal smooth muscle contractile forces of infant (2 week) and juvenile (8-12 week) swine. Substantial alterations in the mechanical and pharmacological properties of this muscle appear to occur with age. In vitro study of tracheal muscle from the same animals suggests substantial alterations in the contractile properties of porcine airway muscle with maturation. We propose to extend these studies further to 1) describe the in situ distribution of airway contractile response in situ (using tantalum bronchography), 2) the morphometric and biochemical changes occurring with maturation, and 3) the biophysical changes that occur in the various airway generations with maturation (using recently developed techniques for measurement of force-velocity and isometric contractile properties in bronchial airways). These mechanisms accounting for topographical and maturation differences in force of, smooth muscle contraction further will be elucidated through in vitro studies of 1) specific receptor ligands (with autoradiographic localization). 2) myosin isoenzymes and content, 3) rate of ATPase-myosin cross bridge cycling These investigations will employ an intradisciplinary approach to elucidate the morphometric, biophysical and biochemical correlates of airway contractility as they are developed both topographically and during maturation. These data should suggest basic physiological and pathophysiological differences that occur in airways during maturation and possible essential differences in therapeutic approaches between adult and pediatric reactive airway disease.