Long-term post-pneumonectomy pulmonary adaptation following all-trans-retinoic acid supplementation

Abstract

In adult dogs following right pneumonectomy (PNX) and receiving all-trans-retinoic acid (RA) supplementation for 4 mo, we found modestly enhanced alveolar-capillary growth in the remaining lung without enhanced resting lung function (J Appl Physiol 96: 1080-1089 and 96: 1090-1096, 2004). Since alveolar remodeling progresses beyond this period and the lipid-soluble RA continues to be released from tissue stores, we hypothesized that RA supplementation may exert additional long-term effects. To examine this issue, adult male litter-matched foxhounds underwent right PNX followed by RA supplementation (2 mg/kg po 4 days/wk, n = 6) or placebo (n = 4) for 4 mo. Cardiopulmonary function was measured at rest and during exercise at 4 and 20 mo post-PNX. The remaining lung was fixed under a constant airway pressure for morphometric analysis. Comparing RA treatment to placebo controls, there were no differences in aerobic capacity, cardiopulmonary function, or lung volume at rest or exercise. Alveolar-capillary basal lamina thickness and mean harmonic thickness of air-blood diffusion barrier were 23-29% higher. The prevalence of double-capillary profiles remained 82% higher. Absolute volumes of septal interstitium, collagen fibers, cells, and matrix were 32% higher; the relative volumes of other septal components and alveolar-capillary surface areas expressed as ratios to control values were up to 24% higher. Thus RA supplementation following right PNX modestly and persistently enhanced long-term alveolar-capillary structural dimensions, especially the deposition of interstitial and connective tissue elements, in such a way that caused a net increase in barrier resistance to diffusion without improving lung mechanics or gas exchange.

Fig. 1.

Flow diagram of experiments. PNX, pneumonectomy; RA, all-trans retinoic acid.

Fig. 2.

Static pressure-volume relationships were not different between treatment groups at any time by repeated-measures ANOVA. Lung volume at a given transpulmonary pressure was lower 4 mo post-PNX in the RA group (†P ≤ 0.05 vs. Pre-PNX) but not in the Placebo group. By 16 mo post-PNX, the curves in both treatment groups were not significantly different from that pre-PNX or at 4 mo post-PNX.

Fig. 3.

Physiological Dl_CO measured during exercise, expressed at a constant hemoglobin concentration of 14.6 g/dl and an alveolar O₂ tension of 120 mmHg was interpolated to the same pulmonary blood flow. No significant difference was noted between RA and placebo groups by repeated-measures ANOVA (P > 0.05).

Fig. 4.

Representative light and electron micrographs show the smaller acinar air spaces (A, bar = 100 μm), prominent septal interstitial components (B, bar = 2 μm), and thickened alveolar-capillary basal lamina (C, bar = 500 nm) in RA-treated lungs compared with placebo-treated control lungs and an example of double septal capillaries (D, bar = 2 μm).

Fig. 5.

Frequency distribution of harmonic thickness of the blood-gas diffusion barrier, obtained from ∼350 measurements per animal of the intercept lengths from epithelial surface to the nearest red cell membrane, shifted toward higher values. Data are from the left lower lobe classified in bins of different size ranges. Mean ± SD. *P ≤ 0.05 vs. placebo.

Fig. 6.

Morphometric results in RA-treated animals expressed as ratios to the respective mean control values in placebo-treated group. Mean ± SD. *P < 0.05 vs. placebo (1.0).