Post-pneumonectomy (PNX) compensatory lung growth in adult dogs is biphasic: In the Ist phase, cell proliferation and/or hypertrophy increases septal tissue volume and thickness without increasing surface areas or improving gas exchange. In the 2nd phase, septal remodeling restores normal architecture with increasing surface areas and functional compensation. Exogenous retinoic acid (RA) selectively enhanced alveolar endothelial growth in the 1st phase after right PNX but did not enhance gas exchange at rest. The structure-function dichotomy is similar to the dichotomy seen in RA-treated emphysematous rats. Our objective is to define the time course, mechanisms and physiologic consequences of RA-enhanced lung growth. Hypotheses are: a) IRA in the 1st phase of a biphasic response selectively augments post-PNX endothelial growth relative to the epithelium (dysanaptic septal growth), thereby distorting septal architecture. Distortion limits compensation in 02 exchange in spite of enhanced cell growth but is corrected in the 2nd remodeling phase, b) RA impairs airway adaptation by restricting airway dilatation and aggravating the usual post-PNX airway-parenchyma dissociation (dysanaptic lung growth). Impaired airway adaptation reduces ventilatory compensation in spite of enhanced septal cell growth, c) Enhanced endothelial cell growth by RA out of proportion to the epithelium corresponds to selective activation of the vascular endothelial growth factor (VEGF) axis relative to the epidermal growth factor (EGF) axis. Matched adult dogs will receive RA or placebo for 4 mo after right PNX with follow-up for another 8 mo after cessation of treatment. Detailed studies include lung function at rest and exercise, thoracic CT scan and morphometric analysis of acinar and airway structure. Separate cohorts will be studied at different time points during and after RA treatment; lung tissue will be assayed for elastin and collagen content as well as protein and mRNA expression of EGF, VEGF, their receptors, cell proliferation markers, and surfactant proteins. This proposal integrates structure-function principles to define the determinants of compensatory lung growth beyond the immediate goal of clarifying the therapeutic utility of RA. Results provide a model for understanding a general phenomenon, i.e., the consequences when a natural compensatory response is distorted by pharmacological manipulation that selectively alters some but not all aspects of the natural response.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL062873-05
Application #
6688218
Study Section
Special Emphasis Panel (ZRG1-SSS-3 (03))
Program Officer
Berberich, Mary Anne
Project Start
1999-08-16
Project End
2007-06-30
Budget Start
2003-08-01
Budget End
2004-06-30
Support Year
5
Fiscal Year
2003
Total Cost
$338,680
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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