Starvation during the last trimester in the guinea pig causes high perinatal mortality, which is associated with pulmonary hypoplasia, reduced surfactant production and tissue elastic recoil, and decreased pulmonary diffusing capacity. Many of the starved neonates are cyanotic and hypothermic despite normoxic hyperventilation, and subsequently die of apparent respiratory failure. Because this animal model produces similar pathologies to those noted in human malnutrition as well as in premature and small-for-date infants, it can be further developed to advance understanding of these clinical conditions and their postnatal consequences. Research by others and preliminary studies have been synthesized to formulate four specific aims: 1) identification of the lung cell types most affected by starvation, and the time course of hypoplasia; 2) determination of the metabolic and ventilatory capacities of the starved neonates; 3) correlation of ventilatory abilities and respiratory failure with the development of oxidative potential and resistance to fatigue in the diaphragm during starvation; and 4) clarification of the mechanisms by which the glucocorticoid analog dexamethasone improves neonatal survival when given during prenatal starvation. The first objective will be approached by intensifying the ultrastructural morphometry and biochemical assessment of earlier studies, to compute cell dimensions, population sizes, and constiuents of the interstitial matrix. The protocol to achieve the second objective employs plethysmography over a range of ambient temperatures and oxygen tensions to elicit minimal and maximal ventilatory volumes, critical oxygen tensions, ventilatory drive, and thermoregulatory ability. Development of the diaphragm will be assessed through the use of histochemical stains to quantify fiber types and capillarity, ultrastructural morphometry to measure mitochondrial and sarcoplasmic reticulum densities, and stimulation of isolated muscle to measure latency, duration and fatigueability of contraction. The fourth objective seeks to understand the manner in which dexamethasone improved survivorship in earlier work, by determining the optimal dosage and timing of drug delivery to promote lung and muscle maturation, tolerance to hypoxia, etc., while produc-the fewest longterm decrements in postnatal growth.
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