Our previous studies have shown by physiologic and morphometric methods that new alveolar and acinar airway growth occurs in the remaining lung after pneumonectomy (PNX) in adult dogs. Regenerative lung growth did not occur after left PNX (45% resection); physiologic compensation was by recruitment of existing capillary reserves functionally significant growth occurred after right PNX (55% resection) but was incomplete, so that abnormalities in exercise capacity, gas exchange and mechanical function persisted. Regenerative lung growth still occurred when mediastinal shift was prevented by an inflatable prosthesis after right PNX, proving that lung stretch was not the only growth signal. In rats after induction of emphysema, retinoic acid can also augment lung growth in the absence of applied stretch; however, somatic growth persists in rats throughout life. The structural response to retinoic acid has not been correlated with function, nor measured in large mature animals that stop growing as adults. We will explore in vivo effects and mechanisms of action of retinoic acid on post-PNX lung growth using our adult dog model. Hypotheses are: 1) After 45% lung resection where lung growth failed to occur, retinoic acid will induce alveolar and acinar airway growth. 2) After 55% lung resection where incomplete regenerative growth occurred, retinoic acid will significantly augment growth. 3) Growth induced retinoic acid will improve gas exchange and mechanical function. 4) One mechanism of action by retinoic acid will be induction of epidermal growth factor (EGF) and/or its receptor (EGFR) and/or its receptor (EGFR) after PNX, enhancing lung growth. All-trans retinoic acid or its diluent will be administered 5 days/week for 3 months after left PNX, right PNX or SHAM surgery (6 experimental groups). At intervals,. Lung mechanics, lung diffusing capacity, membrane diffusing capacity, capillary blood volume and lung tissue volume will be measured and high resolution CT scan obtained to asess in vivo lung tissue volume and airway dimensions. Lungs are harvested at 3 or 6 months for morphometric quantification of structural changes in alveolar septa, dimensions and number of acinar airways, alveolar and capillary surface areas, and morphometric diffusing capacity. Anatomic distribution and in vivo expression of EGF and EGFR will be determined by immunohistochemistry, immunogold labeling, immunoblots and RNA blots. Results will define both structural and physiological effects of retinoic acid on regenerative growth in the mature lung of a large fully grown mammal, and determine the in vivo effect of retinoic acid on EGF and EGFR.
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