LUNG GROWTH AT HIGH ALTITUDE AND MAXIMAL O2 TRANSPORT

描述(申请人摘要)：人类在高海拔地区(HA)发展 肺容量和弥散能力的增加与肺泡的增强一致 生长，并增加血液容量，促进02的运输。然而，其他 对HA(肺小动脉肌化、呼吸紊乱)的适应 生长和胸部发育迟缓)可能会损害氧气的运输。这个 这些因素在不同海拔之间的相互作用尚不清楚。功能性 这些结构性变化的后果只有在以下情况下才能被隔离 当血容量发生可逆变化时重新适应海平面(SL) 肺血管反应性减弱。我们采用这种方法来 解决狗的HA成熟的长期结构-功能关系。 假设1)低氧刺激肺泡增生并增强 扩散性气体交换。2)HA的气道生长滞后于肺泡的生长， 导致通风分配不均，增加通风功。 3)HA时肺血管改变明显限制最大心输出量 在SL。4)HA的结构变化在重新适应SL和 对氧气运输产生相反的影响，即持续的血管和呼吸道 异常抵消了促进肺泡生长所带来的好处。5)增长 胸腔的高度依赖于高度而受损；在极端海拔， 胸围限制对肺生长和氧气运输设定了上限。 我们计划饲养未成熟的狗(2个月大)至体细胞成熟(12mo.)在3点 透明质酸水平(分别为3、100、3,800或4,500米)与 在SL处引发的控件。成年后，狗只将被送回SL，用于 休息和运动时的心肺测试，包括压力-容量曲线， 最大吸氧量、气体交换效率和肺弥散能力 (Dl)和肌肉、呼吸功、血流动力学和血量。尺寸 用螺旋CT对呼吸道、横隔膜、胸腔、肺和脾进行检查 扫描。DL的成分、间隔组织体积和肺血流量将 每隔一定时间测量一次，并与血容量相关。一年后。的 重新适应SL，将重复研究以确定回归 改变。最后，详细的结构分析将在 肺、呼吸肌、运动肌和心室肌，以及肋骨和 很长的骨头。腺泡、呼吸道、血管、胸腺的生长模式 结构和它们的功能相关性将在三个水平上进行比较 低氧以确定氧气运输中适应的海拔依赖性。

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.