Adaptive lung growth following exposure to simulated high altitude
Creators: name: Sekhon, Harmanjatinder S.
Publisher: name: University of British Columbia
Year: 2008

description: Altered oxygen balance in the body at high altitude and in some physiological and pathological conditions may induce adaptive changes in the body which may be organ specific. Because gas exchange is the primary function of the lungs, they may undergo structural changes to adapt to the imbalance of oxygen. High altitude residents have large lungs and short body stature. Whether these adaptive changes are caused by hypobaric pressure or hypoxia (low oxygen) or hypobaric hypoxia is not known. In hypoxic conditions, somatic growth retardation occurs due to undernutrition, but the effect of undernutrition on growth of lung and other organs is not known. In this thesis, the influence of hypobaric normoxia (410 mm Hg, oxygen enriched to correspond the fraction of oxygen (Fo2) to0.21 at sea level), normobaric hypoxia (Fo2 0.11), hypobaric hypoxia (410 mm Hg, Fo2 equivalent to 0.11 at sea level) and diminished somatic growth (equivalent to that occurs in hypobaric hypoxia, food restriction) on lung growth (including biochemical, morphometric, cytokinetic and functional aspects) in rats from 4 to 7 weeks of age was studied. After 3 weeks of exposure, somatic growth was diminished in hypobaric hypoxic and normobarichypoxic animals, but lung growth was accelerated. All absolute biochemical and morphometric measurements in hypobaric hypoxic and normobaric hypoxic rats were higher than undernourished animals indicating that augmented lung growth occurred by hyperplastic and hypertrophic changes with increased accumulation of collagen and elastin. Lung weight, lung volume, DNA, RNA, protein and desmosine were also increased compared to general controls. Maximal tritiated thymidine uptake occurred on day 3 and declined thereafter suggesting that lung growth stimulation occurred during early exposure. With the exception of endothelial cells (alveolar wall, arterial), the maximum response in other cells (type II pneumonocytes, interstitial cells, unidentifiable cells) in the central alveoli wall cells lagged behind and was lower than in the peripheral alveoli. After 3 day recovery, lung DNA synthesis reached the control levels. Pulmonary function tests showed that hypobaric hypoxia caused a decrease in expiratory flow rates (FEF corrected for FVC) and an increase in specific upstream airway resistance while in normobaric hypoxia, FEV0.1/FVC%, expiratory flow rates (absolute and FEF corrected for FVC, and PEER) decreased but both absolute and specific upstream airway resistance increased. However, static compliance remained unchanged. In addition to above parameters, hypobaric hypoxia also caused an increase in collagen and alveolar surface area. These changes did not occur in normobaric hypoxia instead enlargement of airspaces occurred indicating over inflation of the lungs. The collagen concentration and elastic lung recoil at high lung volumes were also decreased in normobaric hypoxic animals. Hypobaric normoxia caused slight reduction in somatic growth which was associated with decreased lung volume, but biochemical and morphometric parameters did not change. Morphometric unit structures were smaller. Peak lung growth stimulation occurred on day 5 in all the main cell types, but not in endothelial cells. Undernutrition impaired both somatic and lung growth as lung weight and volume, cell number and size, accumulation of connective tissue proteins, alveolar number, and alveolar surface area were decreased compared to controls. DNA synthetic activity in all the main cell types diminished. However, body weight normalized lung weight, DNA, alveolar surface area and total alveolar number were higher in undernourished animals than general controls. These data suggest that lung growth stimulation occurs in normobaric hypoxia and hypobarichypoxia despite an inhibitory effect of undernutrition. Accelerated lung growth at high altitude is primarily induced by low oxygen tension. However, the differences in hypobaric hypoxia and normobaric hypoxia and changes in normobaric hypoxia indicate that hypobaric pressure per se may play a role in lung growth adaptation at high altitude. Geometrical location of the central alveoli may limit their adaptive response compared to the peripheral alveoli. Synchronous endothelial cell stimulation in each component of the lung suggests that endothelial cells may respond to hemodynamic changes while the other cells respond to functional demand of the lungs. Although lung growth was increased in normobaric hypoxic and hypobaric hypoxic animals, pulmonary function tests observations suggested that it may be dysanaptic. The response to hypoxic stress is organ specific as growth of lung, heart and spleen increased, but liver and kidney followed the growth patterns of undernourished animals. Increased specific parameters of lung growth in undernourished animals suggest that in conditions which compromise somatic growth, corrections made for body weight may lead to misinterpretation of true changes.