Effects of All-Trans-Retinoic Acid in Promoting Alveolar Repair

Belloni, Paula; Garvin, L J; Mao, Cheng-Ping; Bailey-Healy, Irene; Leaffer, David

doi:10.1378/chest.117.5_suppl_1.235s

Cited by 111 publications

(98 citation statements)

References 41 publications

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“…This is, however, unlikely because it happened independently from changes in lung compliance. Other potential explanations relate to the properties of vitamin A promoting alveolar repair (22,4), protecting against hyperoxia-mediated cell-cycle arrest (23), or improving septation (4,24,25). However, the duration of our experiment would be too short to enable lung repair.…”

Section: Discussionmentioning

confidence: 98%

Vitamin A Is Systemically Bioavailable After Intratracheal Administration With Surfactant in an Animal Model of Newborn Respiratory Distress

et al. 2010

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Chronic lung disease (CLD) is a major cause of long-term morbidity in extremely LBW infants with respiratory distress syndrome. Parenteral vitamin A administration decreases the risk of CLD. We tested the hypothesis that intratracheal vitamin A administration with surfactant is systemically bioavailable without interfering with the functional properties of exogenous surfactant. Newborn piglets were ventilated with 100% FiO 2 and sequential saline lavage induced respiratory distress syndrome. During lung injury induction, ventilator changes were allowed, but none were made following treatment allocation. Animals were assigned by chance in a blinded control trial to three groups: I ϭ control; II ϭ surfactant; III ϭ surfactant ϩ vitamin A. Hemodynamics, lung mechanics, and blood gases were measured following instrumentation, pre-and posttreatment for 4 h, at which time the liver was sampled for retinol determination. All parameters improved in animals receiving surfactant. A significant interaction existed between time and group for PaO 2 and alveolar-arterial oxygen difference (A-aDO 2 ). Hepatic levels of retinol were higher (p Ͻ 0.001) in animals receiving retinyl acetate. Intratracheal administration of surfactant ϩ vitamin A did not alter the beneficial effects of surfactant on lung compliance and gas exchange. Intratracheal Vitamin A was associated with rapid hepatic uptake. Further studies are warranted. (Pediatr Res 67: 619-623, 2010) C hronic lung disease (CLD) of prematurity is the major cause of long-term disability of extremely LBW (ELBW) premature infants, and it is the most cost consumptive disease in Neonatal Intensive Care Unit graduates (1). CLD is characterized by poor lung growth, disruption of alveolarization, and impaired pulmonary vascular development (2). Histologic changes in the lungs of patients with CLD have been compared with the features observed in vitamin A deficient animal models (3). The consequences of vitamin A deficiency are reversible with restoration of normal vitamin A status (4,5). This liposoluble vitamin is involved in the regulation and promotion of cellular differentiation and growth (6). Retinol, the active form of vitamin A, protects against hyperoxia-mediated cell-cycle arrest, stimulates surfactant synthesis, and improves pulmonary vascularization promoting alveolar repair (7,8). Premature infants are prone to vitamin A deficiency because they fail to accumulate retinol in the later half of pregnancy (9,10). Moreover, premature infants start feeding late, their absorption of fat soluble vitamins is compromised, and the metabolic requirements for vitamin A are high (9).Evidence from randomized clinical trials supports the use of parenteral vitamin A supplementation in premature infants at risk of CLD (11). On the other hand, oral supplementation of vitamin A does not alter the incidence of CLD in ELBW infants (12). Intramuscular administration of 5000 IU vitamin A every second day for 4 wk reduced the incidence of CLD with a relative risk of 0.87-0.93 and the...

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Section: Discussionmentioning

confidence: 98%

Vitamin A Is Systemically Bioavailable After Intratracheal Administration With Surfactant in an Animal Model of Newborn Respiratory Distress

et al. 2010

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“…Since the publication of the original study of Massaro and Massaro, other groups have shown that RA is able to fully or partially rescue emphysema-like lesions in different models (42)(43)(44). However, there are also studies that failed to show benefits of RA in emphysema (45)(46)(47)(48)(49).…”

Section: Retinoic Acid From Buds To Alveoli: a Role In Lung Repair Anmentioning

confidence: 99%

Mechanisms of Lung Development: Contribution to Adult Lung Disease and Relevance to Chronic Obstructive Pulmonary Disease

Shi¹,

Chen²,

Cardoso³

2009

Proceedings of the American Thoracic Society

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“…RA and other retinoids have been shown to enhance alveolar septation in neonatal rats and mice (as reviewed in Refs. 2,3,6,7 ) and in some cases to improve lung repair after injury in adults ( 3,8,9 ). Most of the VA present in the lungs is in the form of RE ( 10-12 ).…”

mentioning

confidence: 99%

Acidic retinoids synergize with vitamin A to enhance retinol uptake and STRA6, LRAT, and CYP26B1 expression in neonatal lung

Ross

2010

Journal of Lipid Research

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This article is available online at http://www.jlr.org but unlike VA, which is stored in tissues as retinyl ester (RE) and mobilized to produce RA ( 4 ), no signifi cant amount of RA is stored and the pool of RA turns over rapidly ( 5 ). RA and other retinoids have been shown to enhance alveolar septation in neonatal rats and mice (as reviewed in Refs. 2,3,6,7 ) and in some cases to improve lung repair after injury in adults ( 3,8,9 ). Most of the VA present in the lungs is in the form of RE ( 10-12 ). In fullterm infants, a process of signifi cant RE accumulation in the lungs has begun from the third trimester of fetal life, after which the stored RE becomes quickly depleted during late gestation and early postnatal life ( 10 ). By contrast, preterm infants often have low VA status at birth ( 13-15 ), which may contribute to poor lung maturation and increased susceptibility to respiratory diseases ( 16 ). Therefore, ways to improve RE storage in the lungs in the postnatal period could be useful clinically for supporting retinoid-requiring metabolic functions and aiding postnatal lung development.Previously, we tested a combination of VA (retinol) and RA, referred to as VARA (10:1 molar mixture of VA and RA) as an oral supplement for promoting lung RE formation ( 12 ). Lung RE increased synergistically, at least 4-fold more than for an equal amount of VA alone ( 17 ). As RA is not reduced to retinol in vivo and thus is not a substrate for tissue RE synthesis, the increase in RE in the lungs implies that RA plays a regulatory role in this organ, in some manner facilitating RE formation. The synergistic effect of VARA was selective for the lungs, as RE formation in the liver did not differ between VARA and an equal dose of VA only ( 12,17 ). In a metabolic study using [ 3 H]retinol to trace the uptake of newly absorbed retinol, we found that RA served to direct more of the [ 3 H]retinol tracer and, thus, the oral VA supplement, into the neonatal lung ( 12 ).Abstract Vitamin A (VA) is essential for fetal lung development and postnatal lung maturation. VA is stored mainly as retinyl esters (REs), which may be mobilized for production of retinoic acid (RA). This study was designed 1 ) to evaluate several acidic retinoids for their potential to increase RE in the lungs of VA-supplemented neonatal rats, and 2 ) to determine the expression of retinoid homeostatic genes related to retinol uptake, esterifi cation, and catabolism as possible mechanisms. When neonatal rats were treated with VA combined with any one of several acidic retinoids (RA, 9-cis -RA, or Am580, a stable analog of RA), lung RE increased ‫ف‬ 5-7 times more than after an equal amount of VA alone. Retinol uptake and esterifi cation during the period of absorption correlated with increased expression of both STRA6 (retinol-binding protein receptor) and LRAT (retinol esterifi cation), while a reduction in RE after 12 h in Am580-treated, VA-supplemented rats correlated with a strong and persistent increase in CYP26B1 (RA hydroxylase). We conclude that neona...

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Effects of All-Trans-Retinoic Acid in Promoting Alveolar Repair

Cited by 111 publications

References 41 publications

Vitamin A Is Systemically Bioavailable After Intratracheal Administration With Surfactant in an Animal Model of Newborn Respiratory Distress

Vitamin A Is Systemically Bioavailable After Intratracheal Administration With Surfactant in an Animal Model of Newborn Respiratory Distress

Mechanisms of Lung Development: Contribution to Adult Lung Disease and Relevance to Chronic Obstructive Pulmonary Disease

Acidic retinoids synergize with vitamin A to enhance retinol uptake and STRA6, LRAT, and CYP26B1 expression in neonatal lung

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