Attenuation of Oxygen-Induced Abnormal Lung Maturation in Rats by Retinoic Acid: Possible Role of Cytochrome P4501A Enzymes

Couroucli, Xanthi I.; Liang, Yanhong; Jiang, Weiwu; Barrios, Roberto; Moorthy, Bhagavatula

doi:10.1124/jpet.105.100677

Cited by 20 publications

(28 citation statements)

References 36 publications

(60 reference statements)

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“…The data in the literature are conflicting. Peak expression levels either occur prior to weaning with a decrease to adult levels by puberty [29,34], or a gradual rise in protein content to achieve adult levels in puberty, similar to our data [28]. We cannot explain these conflicting data, but they do suggest a need to reexamine immunoblotting procedures and to consider the influence of strain, diet, and bedding on CYP enzyme ontogeny.…”

Section: Discussionsupporting

confidence: 76%

“…These findings are not consistent with other reports [23][24][25][26][27], but assay sensitivity likely is a limiting factor in these studies and our own. Consistent with the literature, CYP2E1 transcript levels rose dramatically in the early neonatal and neonatal period to reach maximum expression at PD14, although CYP1A2 mRNA levels remain low during the early neonatal period and reach maximum expression only at the end of weaning (PD28) [27][28][29]. In humans, fetal and early neonatal livers fail to express detectable CYP1A2 mRNA [30][31][32], and data beyond the early neonatal period is not available.…”

Section: Discussionsupporting

confidence: 57%

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Ontogeny of hepatic CYP1A2 and CYP2E1 expression in rat

Elbarbry

McNamara

Alcorn

2007

J Biochem & Molecular Tox

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We report a comprehensive examination of rat hepatic CYP1A2 and CYP2E1 ontogeny. We compare the data to human data to determine the rat's capacity as a model to identify CYP-mediated mechanisms underlying age-dependent differences in susceptibility to toxicity. We evaluated CYP expression using real-time RT-PCR, immunoblot and immunohistochemistry, and specific probe activity in male rat livers (n = 4) at critical developmental life stages. CYP2E1 mRNA expression was low at birth, then increased rapidly to peak prior to weaning. CYP1A2 transcript levels remained very low postnatally and then increased dramatically to reach peak expression during weaning. Immunoreactive CYP1A2 and CYP2E1 was first detected at postnatal day 3 (PD3), and reached 50% of adult levels after weaning, and adult levels by puberty. CYP1A2 and CYP2E1 probe activity (pmol/(min mg)) was detected at PD3 and peaked during weaning and late neonatal period, respectively. CYP activity fell to adult values by puberty, a pattern that closely mirrored the temporal changes in mRNA but not protein. An increasing preferential localization of CYP1A2 and CYP2E1 immunoreactivity in perivenous hepatocytes was observed with maturation to adulthood. Although differences in CYP1A2 and CYP2E1 ontogeny between rats and humans exist, knowledge of these differences will aid interspecies extrapolation of developmental toxicokinetic data.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionsupporting

confidence: 57%

Ontogeny of hepatic CYP1A2 and CYP2E1 expression in rat

Elbarbry

McNamara

Alcorn

2007

J Biochem & Molecular Tox

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“…However, our study has some limitations. We evaluated important mechanisms associated with abnormal alveolar development (oxidative stress, angiogenesis, cytokines, chemokines, growth factors, and extracellular matrix), but retinoids may affect multiple pathways simultaneously, including those that were not evaluated in this study (1,17,39,47). Experiments using whole lung homogenates do not permit the identification of changes in gene expression or protein synthesis in selected cell populations in vivo, such as airway epithelia, endothelial VARA, 10:1 molar combination of vitamin A (the nutrient) and all-trans retinoic acid (the metabolite); n ϭ 3 mice/group.…”

Section: Discussionmentioning

confidence: 99%

VARA attenuates hyperoxia-induced impaired alveolar development and lung function in newborn mice

James

Ross

Nicola

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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James ML, Ross AC, Nicola T, Steele C, Ambalavanan N. VARA attenuates hyperoxia-induced impaired alveolar development and lung function in newborn mice. Am J Physiol Lung Cell Mol Physiol 304: L803-L812, 2013. First published April 12, 2013 doi:10.1152/ajplung.00257.2012We have recently shown that a combination of vitamin A (VA) and retinoic acid (RA) in a 10:1 molar ratio (VARA) synergistically increases lung retinoid content in newborn rodents, more than either VA or RA alone in equimolar amounts. We hypothesized that the increase in lung retinoids would reduce oxidative stress and proinflammatory cytokines, resulting in attenuation of alveolar simplification and abnormal lung function in hyperoxia-exposed newborn mice. Newborn C57BL/6 mice were exposed to 85% O2 (hyperoxia) or air (normoxia) for 7 or 14 days from birth and given vehicle or VARA every other day. Lung retinol content was measured by HPLC, function was assessed by flexiVent, and development was evaluated by radial alveolar counts, mean linear intercept, and secondary septal crest density. Mediators of oxidative stress, inflammation, and alveolar development were evaluated in lung homogenates. We observed that VARA increased lung retinol stores and attenuated hyperoxia-induced alveolar simplification while increasing lung compliance and lowering resistance. VARA attenuated hyperoxiainduced increases in DNA damage and protein oxidation accompanied with a reduction in nuclear factor (erythroid-derived 2)-like 2 protein but did not alter malondialdehyde adducts, nitrotyrosine, or myeloperoxidase concentrations. Interferon-␥ and macrophage inflammatory protein-2␣ mRNA and protein increased with hyperoxia, and this increase was attenuated by VARA. Our study suggests that the VARA combination may be a potential therapeutic strategy in conditions characterized by VA deficiency and hyperoxia-induced lung injury during lung development, such as bronchopulmonary dysplasia in preterm infants. bronchopulmonary dysplasia; vitamin A; retinoic acid; 8-OH deoxyguanosine; nuclear factor (erythroid-derived 2)-like 2 protein; 10:1 molar combination of Vitamin A and all-trans retinoic acid BRONCHOPULMONARY DYSPLASIA (BPD) in preterm infants, a common cause of morbidity and mortality, is characterized by fewer and larger alveoli with loss of septation (alveolar simplification) and reduced microvascular development (2,8,15,27). The etiology of BPD is multifactorial and includes genetic predisposition, barotrauma, and volutrauma from mechanical ventilation, reactive oxygen species (ROS) production from prolonged oxygen use and high oxygen concentrations, and infections that lead to inflammation, damage, and attenuation of normal growth and repair of the developing neonatal lung (2).Extremely low birth weight (ELBW; birth wt Յ1,000 g) infants are at high risk for the development of BPD (3). Low plasma and tissue concentrations of vitamin A (VA; retinol) are often observed in ELBW infants and are associated with a higher incidence of BPD (43). Randomized controlled tri...

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“…The pathogenesis of BPD is multifactorial, and researchers believe pulmonary oxygen toxicity may play an important role in the lung injury process, which leads to the development of BPD (Welty, 2001). In previous studies, prolonged exposure of neonatal mice to hyperoxia resulted in decreased alveolar septation, increased terminal air space size, and increased lung fibrosis in a similar manner to human BPD (Manji et al, 2001;Couroucli et al, 2006;Chen et al, 2007). Currently no effective therapy is clinically available to prevent long-term pulmonary sequelae of BPD.…”

Section: Introductionmentioning

confidence: 98%

“…d, hyperoxia-exposed rats treated with losartan. injury in newborn rats exposed to prolonged hyperoxia (Couroucli et al, 2006;Chen et al, 2007). This study tested the hypothesis that an AT 1 R antagonist would attenuate hyperoxia-induced lung fibrosis in newborn rats.…”

Section: Tablementioning

confidence: 99%

Angiotensin II Type 1 Receptor Antagonist Attenuates Lung Fibrosis in Hyperoxia-Exposed Newborn Rats

Chou

Lang

Wang³

et al. 2011

J Pharmacol Exp Ther

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Bronchopulmonary dysplasia (BPD) remains a major cause of morbidity and mortality during the first year of life, and many infants have significant respiratory problems throughout childhood. Currently no effective therapy is clinically available to prevent the long-term pulmonary sequelae of BPD. Previous research has demonstrated that the renin-angiotensin system is up-regulated in human lung fibroblasts. Angiotensin II type 1 receptor (AT 1 R) antagonists and AT 1 R short interfering RNA diminished hyperoxia-increased collagen expression, whereas AT 2 R antagonists did not have any effects on these hyperoxiainduced changes. The in vivo therapeutic effects of AT 1 R antagonists on hyperoxia-induced lung fibrosis remain unknown. The present study assessed the effects of an AT 1 R antagonist (losartan) on preventing hyperoxia-induced lung fibrosis in newborn rats. Rat pups were exposed to 7 days of Ͼ95% O 2 and an additional 2 weeks of 60% O 2 . AT 1 R antagonist-treated pups were injected intraperitoneally with losartan at a dose of 10 mg/kg/day from postnatal days 1 to 7 and a dose of 5 mg/kg/day from postnatal days 8 to 21. Control group pups were injected with an equal volume of normal saline. AT 1 R antagonist treatment attenuated the hyperoxia-induced lung fibrosis on postnatal days 7 and 21 and also decreased the hyperoxia-induced expression of extracellular signal-regulated protein kinase and ␣-smooth muscle actin. AT 1 R antagonist treatment did not affect body weight or lung weight of the rats. These data suggest that AT 1 R antagonist may offer a novel therapeutic strategy for preventing hyperoxia-induced lung fibrosis.

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Attenuation of Oxygen-Induced Abnormal Lung Maturation in Rats by Retinoic Acid: Possible Role of Cytochrome P4501A Enzymes

Cited by 20 publications

References 36 publications

Ontogeny of hepatic CYP1A2 and CYP2E1 expression in rat

Ontogeny of hepatic CYP1A2 and CYP2E1 expression in rat

VARA attenuates hyperoxia-induced impaired alveolar development and lung function in newborn mice

Angiotensin II Type 1 Receptor Antagonist Attenuates Lung Fibrosis in Hyperoxia-Exposed Newborn Rats

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