LUNG GROWTH AT HIGH ALTITUDE AND MAXIMAL O2 TRANSPORT

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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.