Major lung resection by pneumonectomy (PNX) has been utilized to study the sources and limits of adaptation in the lung. Previous studies in fully grown and immature dogs after PNX show that the nature, progression and extent of functional compensation depend on the developmental stage and the extent of resection, suggesting that different mechanisms of structural adaptation are elicited. Exact signals, mediators and anatomic sites of response are unknown. We ask these questions: a) What are the structural basis and functional consequence of compensatory alveolar growth in immature dogs and how do they differ from normal alveolar development? b) What are the structural changes in adult dogs after right PNX and how do they differ fron that in immature dogs? c) What are the structural changes in adult dogs afer left PNX in the absence of tissue growth? d) What are the structural changes in adult dogs after more extensive (68%) lung resection and how do they differ from that after simple right PNX? Hypotheses: 1) coompensatory growth in immature dogs is achieved via addition of acini or one generation of intra-acinar airways, associated with a decreased or slightly increased gas phase diffusion resistance (RG), respectively. Changes are complete by 8 weeks after PNX. 2) Compensatory growth in adult dogs after right PNX is achieved via longitudal growth of existing alveolar ducts, adding alveoli but causing a higher RG; changes are slowly progressive over 1 year. The final increase in alveolar number is less than in immature animals. 3) In the absence of alveolar tissue growth, compensation in adult dogs after left PNX is achieved via dilatation and elongation of intra-acinar airways without altering the number of acini; changes are slowly progessive over 1 year and net RG is decreased. 4) After 68% resecton, alveolar growth should be more vigorous but acinar airway dilatation may also occur if a limit of growth is reached. Structural changes are defined by morphometric analysis and 3-D video reconstruction of acinar airways and CT analysis of large airways at selected time points after PNX. A theoretical model is used to predict the effect of each type of growth on RG; predictions are customized to actual anatomical dimensions in each animal and compared to physiologic estimates of RG. Answers to these questions advance present understanding of the fundamental nature and limits of structural adaptation in the lung and its functional consequences. This project would identify the anatomical site(s) and structural basis of response to PNX, its relationship to maturity and to extent of lung resection, and help direct future investigation to the specific cellular components that might mediate compensatory lung growth.
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