“…The overall lung histology of the Bcmo1 −/− control mice was however different from the other groups due to a general increase in the number of inflammatory cells in the lung and occasionally larger inflamed areas (Fig. 6d, e) resembling previously described lung histology upon vitamin A deficiency in rats [31]. Fig.…”
Beta-carotene 15,15′-monooxygenase 1 knockout (Bcmo1−/−) mice accumulate beta-carotene (BC) similarly to humans, whereas wild-type (Bcmo1+/+) mice efficiently cleave BC. Bcmo1−/− mice are therefore suitable to investigate BC-induced alterations in gene expression in lung, assessed by microarray analysis. Bcmo1−/− mice receiving control diet had increased expression of inflammatory genes as compared to BC-supplemented Bcmo1−/− mice and Bcmo1+/+ mice that received either control or BC-supplemented diets. Differential gene expression in Bcmo1−/− mice was confirmed by real-time quantitative PCR. Histochemical analysis indeed showed an increase in inflammatory cells in lungs of control Bcmo1−/− mice. Supported by metabolite and gene-expression data, we hypothesize that the increased inflammatory response is due to an altered BC metabolism, resulting in an increased vitamin A requirement in Bcmo1−/− mice. This suggests that effects of BC may depend on inter-individual variations in BC-metabolizing enzymes, such as the frequently occurring human polymorphisms in BCMO1.
“…The overall lung histology of the Bcmo1 −/− control mice was however different from the other groups due to a general increase in the number of inflammatory cells in the lung and occasionally larger inflamed areas (Fig. 6d, e) resembling previously described lung histology upon vitamin A deficiency in rats [31]. Fig.…”
Beta-carotene 15,15′-monooxygenase 1 knockout (Bcmo1−/−) mice accumulate beta-carotene (BC) similarly to humans, whereas wild-type (Bcmo1+/+) mice efficiently cleave BC. Bcmo1−/− mice are therefore suitable to investigate BC-induced alterations in gene expression in lung, assessed by microarray analysis. Bcmo1−/− mice receiving control diet had increased expression of inflammatory genes as compared to BC-supplemented Bcmo1−/− mice and Bcmo1+/+ mice that received either control or BC-supplemented diets. Differential gene expression in Bcmo1−/− mice was confirmed by real-time quantitative PCR. Histochemical analysis indeed showed an increase in inflammatory cells in lungs of control Bcmo1−/− mice. Supported by metabolite and gene-expression data, we hypothesize that the increased inflammatory response is due to an altered BC metabolism, resulting in an increased vitamin A requirement in Bcmo1−/− mice. This suggests that effects of BC may depend on inter-individual variations in BC-metabolizing enzymes, such as the frequently occurring human polymorphisms in BCMO1.
“…Retinoic acid treatment of the VAD animals restores the collagen content and the mechanical properties of the lung but not the parenchymal defects such as the reduction in alveolar surface area. This correlation between collagen content and mechanical properties evidences the strong influence of the ECM on the lung function [9]. As BMs play an important role in pneumocyte differentiation [20], regulate gap junction formation and intercellular communication between alveolar epithelial cells [21], contain apoptotic and survival signals for endothelial cells [22] and form a continuous structure throughout the entire lung, they can be involved in the functional consequences of VAD.…”
Section: Introductionmentioning
confidence: 78%
“…Similarly, studies of adult rats with elastase-induced emphysema, and rat pups exposed to hyperoxia, have shown that retinoids promote post hoc improvements in alveolar septation and lung architecture [3,6]. In humans, administration of vitamin A reduces the incidence of bronchopulmonary dysplasia in vitamin Adeficient premature infants [7]; laboratory evidence suggests it could have a protective effect on respiratory status in patients with cystic fibrosis [8], and its potential application in the prevention and treatment of emphysema, based on the results with animals, is an exciting area of research [9].…”
Section: Introductionmentioning
confidence: 99%
“…Consequently, a deficiency of vitamin A could induce changes in the composition and the structure of BMs resulting in alterations of organ function and protracted pathological consequences. In fact, VAD promotes bronchial hyperreactivity [17], leads to emphysematous lungs with areas of interstitial pneumonitis [9,18] and results in squamous cell metaplasia with a relative decrease in the proportion of mucous and ciliated cells in the tracheobronchial tree [1]. Moreover, surfactant synthesis and ornithine decarboxylase activity, the rate-limiting enzyme in the synthesis of polyamines, are significantly lower in type II pneumocytes isolated from VAD rats [18], indicating an impaired functional and proliferative capacity.…”
“…g ., liver, lung, adipose) [3]. Vitamin A and RA are essential for normal lung growth, differentiation, and maintenance of pulmonary epithelium [4, 5] and have critical functions in alveolar formation and post-injury respiratory lining regeneration [6–8]. RA, in particular, is a regulator of alveologenesis [9, 10].…”
β-carotene 15,15’-oxygenase (BCO1) catalyzes the first step in the conversion of dietary provitamin A carotenoids to vitamin A. This enzyme is expressed in a variety of developing and adult tissues, suggesting that its activity may regulate local retinoid synthesis. Vitamin A and related compounds (retinoids) are critical regulators of lung epithelial development, integrity, and injury repair. A balance between the actions of retinoids and glucocorticoids (GCs) promotes normal lung development and, in particular, alveolarization. Alterations in this balance, including vitamin A deficiency and GC excess, contribute to the development of chronic lung disorders. Consequently, we investigated if GCs counteract retinoid effects in alveolar epithelial cells by mechanisms involving BCO1-dependent local vitamin A metabolism. We demonstrate that BCO1 is expressed in human fetal lung tissue and human alveolar epithelial-like A549 cells. Our results indicate A549 cells metabolize β-carotene to retinal and retinoic acid (RA). GCs exposure using dexamethasone (DEX) decreases BCO1 mRNA and protein levels in A549 cells and reduces BCO1 promoter activity via inhibiting peroxisome proliferator-activated receptor γ (PPARγ) DNA binding. DEX also induces expression of PPARα, which in turn most likely causes a decrease in PPARγ/RXRα heterodimer binding to the bco1 gene promoter and consequent inhibition of bco1 gene expression. PPARα knockdown with siRNA abolishes DEX-induced suppression of BCO1 expression, confirming the requirement for PPARα in this DEX-mediated BCO1 mechanism. Taken together, these findings provide the first evidence that GCs regulate vitamin A (retinoid) signaling via inhibition of bco1 gene expression in a PPARα-dependent manner. These results explicate novel aspects of local GC:retinoid interactions that may contribute to alveolar tissue remodeling in chronic lung diseases that affect children and, possibly, adults.
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