Retinoic acid-induced alveolar cellular growth does not improve function after right pneumonectomy

Abstract

To determine whether all-trans retinoic acid (RA) treatment enhances lung function during compensatory lung growth in fully mature animals, adult male dogs (n = 4) received 2 mg x kg(-1) x day(-1) po RA 4 days/wk beginning the day after right pneumonectomy (R-PNX, 55-58% resection). Litter-matched male R-PNX controls (n = 4) received placebo. After 3 mo, transpulmonary pressure (TPP)-lung volume relationship, diffusing capacities for carbon monoxide and nitric oxide, cardiac output, and septal volume (V(tiss-RB)) were measured under anesthesia by a rebreathing technique at two lung volumes. Lung air and tissue volumes (V(air-CT) and V(tiss-CT)) were also measured from high-resolution computerized tomographic (CT) scans at a constant TPP. In RA-treated dogs compared with controls, TPP-lung volume relationships were similar. Diffusing capacities for carbon monoxide and nitric oxide were significantly impaired at a lower lung volume but similar at a high lung volume. Whereas V(tiss-RB) was significantly lower at both lung volumes in RA-treated animals, V(air-CT) and V(tiss-CT) were not different between groups; results suggest uneven distribution of ventilation consistent with distortion of alveolar geometry and/or altered small airway function induced by RA. We conclude that RA does not improve resting pulmonary function during the early months after R-PNX despite histological evidence of its action in enhancing alveolar cellular growth in the remaining lung.

Quantitative morphology of compensatory lung growth

“…From the alveolar-capillary surface area, the harmonic mean thickness of tissue-plasma barrier and the capillary blood volume, a morphometric lung diffusing capacity can be estimated [38,52], which correlates reasonably with physiological diffusing capacity measured at peak exercise [53]. In retinoic acid-treated lungs, morphometric membrane and lung diffusing capacities are unchanged from those in placebo controls, while physiological diffusing capacities are either unchanged or reduced depending on the lung volume at which measurements are performed [54]. Therefore, retinoic acid administration fails to improve gas exchange despite selective enhancement of alveolar cellular growth.…”

All-trans retinoic acid results in irregular repair of septa and fails to inhibit proinflammatory macrophages

“…Quantitative electron microscopic analysis revealed that alveolar septal growth was non-uniform with a selective enhancement of capillary and endothelial growth resulting in a distorted septal architecture accompanied by a decrease in lung diffusion capacity [41]. Analysis of lung function indicated uneven distribution of ventilation consistent with distortion of alveolar geometry and/or altered small airway function induced by ATRA after right-sided pneumonectomy in the dog [42]. These data are supported by the findings of TEPPER et al [43] that 2 weeks of supplementation with ATRA had no effect on compliance, forced flows or diffusing capacity of the lung for carbon monoxide in the rat elastase-model of emphysema, although there was a slight, albeit insignificant increase in computed tomography scan lung tissue density.…”

Lack of response to all-transretinoic acid supplementation in adult dogs following left pneumonectomy

“…1. The study design was identical to that previously described for right PNX (7,45). Twelve litter-matched male foxhounds underwent left PNX at ϳ1 yr of age.…”

“…The area occupied by lung in each image was multiplied by slice thickness to obtain volume; total lung volume was summed from the volume from individual images. Because the average CT density of lung is directly proportional to the ratio of tissue to air, the CT density (in Houndsfield units) of tracheal air and muscle was used to partition total lung volume into air and tissue volumes by established methods (7).…”

“…RA supplementation during the early post-PNX period selectively enhances ongoing compensatory growth of alveolar endothelial cells and capillaries without enhancing the growth of other septal cell types (45). RA supplementation also causes distortion of septal ultrastructure and alveolar architecture, thereby preventing a net increase in the absolute alveolar surface area or lung diffusing capacity during the treatment period (7,45). These results illustrate the need for a balanced tissue response at all levels of organization if optimal physiological improvement is to be realized.…”