LUNG GROWTH AT HIGH ALTITUDE AND MAXIMAL O2 TRANSPORT

描述（申请人摘要）：高海拔地区（HA）的人类原住民发育 肺容量和弥散能力增加，与肺泡 生长，并增加促进O2运输的血量。但其他 对HA的适应（肺小动脉肌化，呼吸道适应不良 生长和胸部生长迟缓）可能损害O2运输。的 这些因素在不同海拔高度的相互作用尚不清楚。功能 这些结构变化的后果只能在 当血容量发生可逆变化时，重新适应海平面（SL） 肺血管反应性也减弱了我们采用这种方法， 解决犬HA成熟的长期结构-功能关系。 假设：1）缺氧刺激肺泡增生， 扩散气体交换2)在HA，气道生长落后于肺泡生长， 导致通风的不均匀分布和增加的净化工作。 3)HA时的肺血管变化显著限制了最大心输出量 在SL。4)HA的结构变化在重新适应SL后持续存在， 对O2运输产生相反的影响，即，持续性血管和气道 异常抵消了来自增强的肺泡生长的益处。5)增长 胸部的损伤是在一个高度依赖的方式;在极端的高度， 限制的胸廓尺寸设定了肺生长和O2运输的上限。 我们计划饲养未成熟的狗（2个月大）。至体细胞成熟（12 mo.）3时 HA水平（3，100米，3，800米或4，500米）与 控制在SL。狗将在成年后返回SL， 休息和运动时的心肺测试，包括压力-容积曲线， 肺的最大O2摄取、气体交换效率和弥散能力 (DL)以及肌肉、消化功、血液动力学和血容量。尺寸 将通过螺旋CT评估气道、横膈、胸腔、肺和脾 扫描. DL的组成部分、间隔组织体积和肺血流量将被 定期测量并与血容量相关。1年后的 重新适应SL，将重复研究以确定 变化最后，将对 肺，呼吸，运动和心室肌肉，以及肋骨和 长长的骨头腺泡、气道、脉管系统、胸廓的生长模式 结构及其功能相关物将在以下3个水平进行比较： 缺氧，以确定在O2运输的适应高度依赖性。

DESCRIPTION (Applicant's abstract): Human natives of high altitude (HA) develop increased lung volume and diffusing capacity consistent with enhanced alveolar growth, and increase blood volumes that facilitate 02 transport. However, other adaptation to HA (muscularization of pulmonary arterioles, dysanaptic airway growth and retardation of thoracic growth) may impair O2 transport. The interplay among these factors at different altitudes is not known. Functional consequences of these structural changes can be isolated only after re-acclimatization to sea level (SL) when reversible changes in blood volume and pulmonary vascular reactivity have subsided. We employ this approach to address long-term structure-function relationships of maturation at HA in dogs. Hypotheses are 1) Hypoxia stimulates alveolar hyperplasia and enhances diffusive gas exchange. 2) Airway growth lags behind alveolar growth at HA, leading to uneven distribution of ventilation and increased ventilatory work. 3) Pulmonary vascular changes at HA significantly limits maximal cardiac output at SL. 4) Structural changes at HA persist after reacclimatization to SL and exert opposing effects on O2 transport, i.e., persistent vascular and airway abnormalities offset benefits derived from enhanced alveolar growth. 5) Growth of thorax is impaired in an altitude-dependent way; at extreme altitude, the restricted thoracic size sets an upper limit to lung growth and O2 transport. We plan to raise immature dogs (age 2 mo.) to somatic maturity (12 mo.) at 3 levels of HA (3, 100m, 3,800m or 4,500m in separate groups) compared with controls raised at SL. Dogs will be returned to SL at maturity for cardiopulmonary testing at rest and exercise, including pressure-volume curves, maximal 02 uptake, efficiency of gas exchange and diffusing capacity of lungs (DL) and muscles, ventilatory work, hemodynamics and blood volume. Dimensions of airways, diaphragm, rib cage, lungs and spleen will be assessed by spiral CT scan. Components of DL, septal tissue volume and pulmonary blood flow will be measured at regular intervals and correlated with blood volume. After 1 yr. of re-acclimatization to SL, studies will be repeated to determine regression of changes. Terminally, detailed structural analysis will be performed on the lungs, respiratory, locomotive and ventricular muscles, as well as ribs and long bones. Growth patterns of the acini, airways, vasculature, thoracic structures and their functional correlates will be compared at the 3 levels of hypoxia to determine the altitude-dependence of adaptation in O2 transport.