AIRWAY PHARMACOLOGY DURING ONTOGENESIS

本建议的长期目标是确定这些因素 其负责降低体内气道反应性， 个体发育的特定时间。 这种减少在以下方面更为明显： 雌性比雄性动物多，并显示出明显的家族趋势。 我们 假设是成熟和家族因素（a）改变结合 和/或体液剂的功效（B）改变膜电位， 产电泵活性和（c）改变钙的移位。 将在已知年龄的动物中进行气道反应性的测量， 各种生理状态下的性行为，例如未成熟、成熟、年老、发情 还怀孕了 借助计算机的全身体积描记法将 用于确定肺力学，并结合 气道直径和平滑肌的形态测量，将 与成熟过程中的气道反应性有关。 性别的确定 激素和甲状腺功能的放射免疫测定将用于 监测成熟度。 这些分析也将用于验证我们的成功 通过手术或药物来控制激素水平 干预措施。 体外气道反应也显示出与年龄相关的变化。 将在已知的动物中评估这些变化的机制。 年龄、性别和生理状况。 对（a）部分激动剂的剂量反应 或（B）在受体拮抗剂或功能性激动剂之前和之后， 拮抗作用将允许评估受体亲和力和药物 亲和力 这些结果将与受体特性相关 由气道膜组分的配体结合测定确定 平滑肌 膜性能也将通过测定 膜电位和产电泵的贡献， 在各种生理状态下的动物组织中的潜力。 这些 将使用标准电生理学方法确定参数 技术. 钙的膜转运将使用 放射性标记的钙 我们的气道反应性的纵向研究， 豚鼠具有许多儿童支气管哮喘的特征， 缓解在青春期，并提供了这一建议的基础。

The long-term objective of this proposal is to determine those factors which are responsible for the reduction of in vivo airway reactivity at a specific time during ontogenesis. This reduction is more pronounced in female than in male animals and shows obvious familial trends. Our hypothesis is that maturation and familial factors (a) alter the binding and/or efficacy of humoral agents (b) alter membrane potential and electrogenic pump activity and (c) alter the translocation of calcium. Measurements of airway reactivity will be made in animals of known age and sex in various physiological states e.g. immature, mature, old, in estrus and pregnant. Whole body plethysmography with the aid of a computer will be used to determine pulmonary mechanics and, in conjunction with morphometric measurements of airway diameter and smooth muscle, will be related to airway reactivity during maturation. Determination of sex hormones and thyroid function using radioimmunoassays will be used to monitor maturation. These assays will also be used to verify our success in manipulating hormone levels by surgical or pharmacological interventions. In vitro airway responses also show age related changes. The mechanism(s) for these changes will be assessed in animals of known age, sex and physiological status. Dose response to (a) partial agonists or (b) to full agonists before and after receptor antagonism or functional antagonism will allow an assessment of receptor affinities and drug affinities. These results will be correlated with receptor properties determined from ligand binding assays of membrane fractions of airway smooth muscle. Membrane properties will also be assessed by determining membrane potentials and the contribution of the electrogenic pump to potential in tissues from animals in various physiological states. These parameters will be determined using standard electrophysiological techniques. The membrane transport of calcium will be determined using radiolabeled calcium. Our longitudinal study of airway reactivity in guinea pigs has many characteristics of childhood bronchial asthma and its remission at puberty and has provided the basis of this proposal.