Morphometric and functional studies demonstrate that airways of mammals are completely developed at birth whereas parenchyma and vessels continue to develop after birth. This proposal explores the effect of this differential pattern of growth on the mechanical interdependence of airways, parenchyma, and pulmonary vasculature during early development in anesthetized lambs. Four hypotheses will be tested. The first three hypothesis concern airway- parenchymal interdependence: 1) Developing airways are particularly susceptible to dimensional deformation because of their intrinsic plasticity and the high radial stresses arising from the lung parenchyma. 2) The intrinsic plasticity of the airways is the result of maturational changes in structural composition and muscle tone. 3) Regional differences in composition and muscle tone determine longitudinal differences in the dimensional response of the airways to radial stress. These regional differences are influenced by development and pathological state. To test these hypotheses, airway dimensions will be quantified directly in bronchial casts and estimated functionally from measurements of central and peripheral airway resistance at various lung volumes and after different volume histories. Intrinsic properties of the airways that may modulate airway interdependence will then be examined from a developmental point of view both in health and after lung growth has been altered by administration of bleomycin. These intrinsic properties include vagal control of bronchomotor tone, bronchial contractility, and structural (collagen/elastin) composition of the airway wall. The fourth hypothesis concerns vascular-parenchymal interdependence. According to this hypothesis, the underdeveloped vascular bed 1 of the fetal and newborn lung dilates in the presence of increased blood flow but is not capable of further vascular recruitment. The relaxation of perivascular stress produced by vascular dilatation may decrease the total elastic recoil of the lung when pulmonary blood flow is increased. To test this hypothesis, in vivo elastic recoil pressure, pulmonary blood flow, blood volume, capillary surface area (apparent Vmax for pulmonary angiotensin-converting enzyme), and extravascular lung water (double indicator dilution) will be measured after increasing pulmonary blood flow with a controlled arteriovenous fistula. The information gained from these studies will help to clarify the response of the developing airways and pulmonary vessels to mechanical and pharmacological interventions as well as to pathological insults. The proposed research therefore will provide rational basis for the prevention and recognition of airway damage in critically ill newborns, particularly those requiring mechanical ventilation.
