MATURATION OF NONSPECIFIC AIRWAY REACTIVITY

描述：(根据申请者的抽象和具体目标改编。) 根据临床证据表明，年龄相关的差异在 急性炎症后呼吸道高反应性的获得 对肺部的侮辱，提出了两个相互关联的假设：1) 调控非特异性气道平滑肌的内在机制 反应性成熟变化；和2)急性肺炎性 炎症以一种年龄依赖的方式改变呼吸道的反应性。 在处理这些假说时，体内和体外药效学 激动剂诱导的呼吸道和外周肺组织缩窄剂的研究 将在不同出生年龄的兔子身上进行反应。 评估肺组织调节机制的成熟度 响应性，具体目标1A将检查个体发育 不同之处在于：a)体内分离的呼吸道和肺组织 对胆碱能、内皮素、组胺和二十烷类化合物的贡献- 诱导的肺力学改变；b)表达，特征， 受体鸟嘌呤核苷酸结合蛋白(G)的调节作用 与后一种激动剂偶联，由放射性配基结合确定；c) 激动剂对产物的特异性调节--细胞内受体 关键的第二信使肌醇1，4，5-的结合和代谢 三磷酸，通过放射受体和酶分析测定；以及d) 蛋白激酶C激活对后者的调节作用 流程。评估呼吸道调节机制的成熟度 β-肾上腺素能松弛药反应性，特定目标1B将检查 个体发育差异：A)表达、特性和G- β-肾上腺素能受体结合的蛋白偶联调节 在气道平滑肌和肺组织中的表达；b)β-受体的作用。 肾上腺素能刺激收缩激动剂的特异性积聚， 1，4，5-三磷酸肌醇的代谢和受体结合； 钙和三磷酸腺苷依赖性钾通道的作用 在调节β-肾上腺素能介导的呼吸道松弛方面。要评估 急性肺炎症对呼吸道的增龄性影响 反应性，特定目标2旨在评估：a)呼吸道 以及肺组织对抗原特异性和非过敏性反应- 内毒素和臭氧诱导的肺部炎症反应 成熟兔吸入；以及b)炎症机制- 所反映的成熟肺中呼吸道反应性的诱导变化 由于上述机械性过程的贡献的改变 调节肺收缩反应和β-肾上腺素能 放松一下。拟议的研究可能会为我们提供关于 成熟度、呼吸道反应性和 肺部发炎。

DESCRIPTION: (Adapted from the applicant's abstract and Specific Aims.) In light of clinical evidence implying age-related differences in the acquisition of airways hyperreactivity following an acute inflammatory insult to the lungs, two interrelated hypotheses are raised: 1) that intrinsic mechanisms regulating non-specific airway smooth muscle responsiveness vary maturationally; and 2) that acute pulmonary inflammation alters airways responsiveness in an age-dependent manner. In addressing these hypotheses, in vivo and in vitro pharmacodynamic studies on agonist-induced airway and peripheral lung tissue constrictor responsiveness will be conducted in rabbits of varying post-natal age. To assess the maturation of mechanisms regulating pulmonary responsiveness, Specific Aim 1A will examine whether ontogenetic differences exist in: a) the partitioned in vivo airway and lung tissue contributions to cholinergic-, endothelin-, histamine-, and eicosanoid- induced changes in lung mechanics; b) the expression, characteristics, and modulation by guanine nucleotide-binding (G) proteins of receptors coupled to the latter agonists, determined by radioligand binding; c) the agonist-specific regulation of production, intracellular receptor binding, and metabolism of the key second messenger, inositol 1,4,5- trisphosphate, determined by radioreceptor and enzyme assays; and d) the regulatory actions of protein kinase C activation on the latter processes. To assess the maturation of mechanisms regulating airway beta-adrenergic relaxant responsiveness, Specific Aim 1B will examine ontogenetic differences in:a) the expression, characteristics, and G- protein-coupled modulation of binding of the beta- adrenergic receptor in airway smooth muscle and lung tissue; b) the effects of beta- adrenergic stimulation on constrictor agonist-specific accumulation, metabolism, and receptor binding of inositol 1,4,5-trisphosphate; and c) the contributions of the calcium- and ATP-dependent potassium channels in modulating beta-adrenergic-mediated airway relaxation. To assess the age- related effects of acute pulmonary inflammation on airways responsiveness, Specific Aim 2 is designed to evaluate: a) the airway and lung tissue responses to antigen-specific- and non-allergically- mediated pulmonary inflammation induced by endotoxin and ozone inhalation in maturing rabbits; and b) mechanisms of inflammation- induced changes in airways reactivity in the maturing lung as reflected by alterations in the contributions of the above mechanistic processes regulating pulmonary constrictor responsiveness and beta-adrenergic relaxation. The proposed studies may provide new insights into the interrelationship between maturation, airways responsiveness, and pulmonary inflammation.