Chronic lung disease in preterm lambs: effect of daily vitamin A treatment on alveolarization.

Neonatal chronic lung disease is characterized by failed formation of alveoli and capillaries, and excessive deposition of matrix elastin, which are linked to lengthy mechanical ventilation (MV) with O(2)-rich gas. Vitamin A supplementation has improved respiratory outcome of premature infants, but there is little information about the structural and molecular manifestations in the lung that occur with vitamin A treatment. We hypothesized that vitamin A supplementation during prolonged MV, without confounding by antenatal steroid treatment, would improve alveolar secondary septation, decrease thickness of the mesenchymal tissue cores between distal air space walls, and increase alveolar capillary growth. We further hypothesized that these structural advancements would be associated with modulated expression of tropoelastin and deposition of matrix elastin, phosphorylated Smad2 (pSmad2), cleaved caspase 3, proliferating cell nuclear antigen (PCNA), VEGF, VEGF-R2, and midkine in the parenchyma of the immature lung. Eight preterm lambs (125 days' gestation, term approximately 150 days) were managed by MV for 3 wk: four were treated with daily intramuscular Aquasol A (vitamin A), 5,000 IU/kg, starting at birth; four received vehicle alone. Postmortem lung assays included quantitative RT-PCR and in situ hybridization, immunoblot and immunohistochemistry, and morphometry and stereology. Daily vitamin A supplementation increased alveolar secondary septation, decreased thickness of the mesenchymal tissue cores between the distal air space walls, and increased alveolar capillary growth. Associated molecular changes were less tropoelastin mRNA expression, matrix elastin deposition, pSmad2, and PCNA protein localization in the mesenchymal tissue core of the distal air space walls. On the other hand, mRNA expression and protein abundance of VEGF, VEGF-R2, midkine, and cleaved caspase 3 were increased. We conclude that vitamin A treatment partially improves lung development in chronically ventilated preterm neonates by modulating expression of tropoelastin, deposition of elastin, and expression of vascular growth factors.

Elastin stabilization for treatment of abdominal aortic aneurysms.

BACKGROUND: Maintaining the integrity of arterial elastin is vital for the prevention of abdominal aortic aneurysm (AAA) development. We hypothesized that in vivo stabilization of aortic elastin with pentagalloyl glucose (PGG), an elastin-binding polyphenol, would interfere with AAA development. METHODS AND RESULTS: Safety and efficacy of PGG treatment were first tested in vitro using cytotoxicity, elastin stability, and PGG-elastin interaction assays. For in vivo studies, the efficacy of PGG was evaluated within a well-established AAA model in rats on the basis of CaCl2-mediated aortic injury. With this model, PGG was delivered periadventitially at 2 separate time points during the course of AAA development; aortic diameter, elastin integrity, and other pathological aspects were monitored and evaluated in PGG-treated aortas compared with saline-treated control aortas. Our results show that a one-time periadventitial delivery of noncytotoxic levels of PGG inhibits elastin degeneration, attenuates aneurysmal expansion, and hinders AAA development in rats without interfering with the pathogenic mechanisms typical of this model, namely inflammation, calcification, and high metalloproteinase activities. PGG binds specifically to arterial elastin and, in doing so, preserves the integrity of elastic lamellae despite the presence of high levels of proteinases derived from inflammatory cells. CONCLUSIONS: Periadventitial administration of PGG hinders the development of AAA in a clinically relevant animal model. Stabilization of aortic elastin in aneurysm-prone arterial segments offers great potential toward the development of safe and effective therapies for AAAs.

Vitamin C prevents the effects of prenatal nicotine on pulmonary function in newborn monkeys.

Smoking during pregnancy leads to decreased pulmonary function and increased respiratory illness in offspring. Our laboratory has previously demonstrated that many effects of smoking during pregnancy are mediated by nicotine. We now report that vitamin C supplementation can prevent some of the effects of maternal nicotine exposure on pulmonary function of offspring. Timed-pregnant rhesus monkeys were treated with 2 mg/kg/day nicotine bitartrate from Gestation Days 26 to 160. On Gestation Day 160 (term, 165 days) fetuses were delivered by C-section and subjected to pulmonary function testing the following day. Nicotine exposure significantly reduced forced expiratory flows, but supplementation of mothers with 250 mg vitamin C per day prevented the effects of nicotine on expiratory flows. Vitamin C supplementation also prevented the nicotine-induced increases in surfactant apoprotein-B protein. Neither nicotine nor nicotine plus vitamin C significantly affected levels of cortisol or cytokines, which have been shown to affect lung development and surfactant expression. Prenatal nicotine exposure significantly decreased levels of elastin content in the lungs of offspring, and these effects were slightly attenuated by vitamin C. These findings suggest that vitamin C supplementation may potentially be clinically useful to limit the deleterious effects of maternal smoking during pregnancy on offspring's lung function.