tretinoin and Bronchopulmonary-Dysplasia

The simplification of alveoli leads to various lung pathologies such as bronchopulmonary dysplasia and emphysema. Deep insight into the process of emergence of the secondary septa during development and regeneration after pneumonectomy, and into the contribution of the drivers of alveologenesis and neo-alveolarization is required in an efficient search for therapeutic approaches. In this review, we describe the formation of the gas exchange units of the lung as a multifactorial process, which includes changes in the actomyosin cytoskeleton of alveocytes and myofibroblasts, elastogenesis, retinoic acid signaling, and the contribution of alveolar mesenchymal cells in secondary septation. Knowledge of the mechanistic context of alveologenesis remains incomplete. The characterization of the mechanisms that govern the emergence and depletion of αSMA will allow for an understanding of how the niche of fibroblasts is changing. Taking into account the intense studies that have been performed on the pool of lung mesenchymal cells, we present data on the typing of interstitial fibroblasts and their role in the formation and maintenance of alveoli. On the whole, when identifying cell subpopulations in lung mesenchyme, one has to consider the developmental context, the changing cellular functions, and the lability of gene signatures.

Topics: Actomyosin; Bronchopulmonary Dysplasia; Cell Lineage; Cytoskeleton; Emphysema; Gases; Humans; Lung; Mesoderm; Myofibroblasts; Organogenesis; Pulmonary Alveoli; Tretinoin

Despite recent advances in perinatal medicine, bronchopulmonary dysplasia (BPD) remains the most common complication of preterm birth. Inflammation, the main cause for BPD, results in arrested alveolarization. All trans-retinoic acid (ATRA), the active metabolite of Vitamin A, facilitates recovery from hyperoxia induced cell damage. The mechanisms involved in this response, and the genes activated, however, are poorly understood. In this study, we investigated the mechanisms of action of ATRA in human lung epithelial cells exposed to hyperoxia. We hypothesized that ATRA reduces hyperoxia-induced inflammatory responses in A549 alveolar epithelial cells.. A549 cells were exposed to hyperoxia with or without treatment with ATRA, followed by RNA-seq analysis.. Transcriptomic analysis of A549 cells revealed ~2,000 differentially expressed genes with a higher than 2-fold change. Treatment of cells with ATRA alleviated some of the hyperoxia-induced changes, including Wnt signaling, cell adhesion and cytochrome P450 genes, partially through NF-κB signaling.. Our findings support the idea that ATRA supplementation may decrease hyperoxia-induced disruption of the neonatal respiratory epithelium and alleviate development of BPD.

Topics: Alveolar Epithelial Cells; Animals; Animals, Newborn; Bronchopulmonary Dysplasia; Female; Humans; Hyperoxia; Infant, Newborn; Lung; NF-kappa B; Pregnancy; Premature Birth; Tretinoin; Wnt Signaling Pathway

All-trans retinoic acid (RA) is a potent modulator of lung development. Chorioamnionitis, which is frequently associated with preterm birth, causes fetal lung inflammation and improves lung function but also results in alveolar simplification and microvascular injury. Endotoxin-mediated chorioamnionitis reduces RA concentration in the fetal lung to 16% of control values. We hypothesized that administration of RA to the fetus before induction of chorioamnionitis would preserve septation of the distal airspaces. Time-mated ewes with singletons were assigned to receive a fetal intramuscular treatment with 20,000 IU of RA in olive oil (or olive oil only) 3 hr prior to intra-amniotic injection of endotoxin (20 mg, E. coli 055:B5) or saline, at 124-day gestational age and 7 days after the fetal treatment. The right cranial lung lobe was processed for morphometric analysis. RA treatment did not affect chorioamnionitis-induced fetal and systemic inflammation or interleukin-8 concentrations in lung tissue. RA administration alone did not alter lung structure. Relative to control lungs (5 +/- 3 mL/kg), lung volume increased similarly with endotoxin (22 +/- 4 mL/kg) or RA plus endotoxin (20 +/- 3 mL/kg; P < 0.05). Alveolar wall thickness was 4.2 +/- 0.3 mum after endotoxin-induced chorioamnionitis, 6.0 +/- 0.4 mum in controls (P < 0.05 versus endotoxin) and 5.5 +/- 0.2 mum after RA and endotoxin (P < 0.05 versus control, n.s. versus endotoxin). The ratio of airspace versus tissue was 4.6 +/- 0.3 in endotoxin-induced chorioamnionitis, 2.1 +/- 0.3 in controls and 4.1 +/- 0.5 after RA and endotoxin. We conclude that fetal treatment with RA did not prevent inflammation-induced alveolar simplification.

Topics: Animals; Bronchopulmonary Dysplasia; Chorioamnionitis; Disease Models, Animal; Elastin; Endotoxins; Female; Fetus; Humans; Infant, Newborn; Interleukin-8; Lung; Pregnancy; Pulmonary Alveoli; Sheep; Tretinoin

Pulmonary inflammation, increased production of the inflammatory cytokine interleukin-1beta (IL-1beta), and vitamin A deficiency are risk factors for the development of bronchopulmonary dysplasia (BPD) in premature infants. To determine the mechanisms by which IL-1beta influences lung development, we have generated transgenic mice in which human IL-1beta is expressed in the lung epithelium with a doxycycline-inducible system controlled by the Clara cell secretory protein promoter. Perinatal IL-1beta production in these mice causes a phenotype that is strikingly similar to BPD. Pulmonary pathology in the mice shows inflammation, lack of alveolar septation, and impaired vascular development of the lung, similar to the histological characteristics of BPD. Retinoic acid (RA), one of the most biologically active derivatives of vitamin A, increases septation. Proteins involved in mediating the cellular responses to RA include the cellular retinoic acid binding proteins CRABP-I and CRABP-II and the nuclear retinoic acid receptors RAR-alpha, RAR-beta, and RAR-gamma.. To test the hypothesis that IL-1beta inhibits the expression of proteins involved in mediating the cellular response to RA.. The mRNA expression of CRABP-I, CRABP-II, RAR-alpha1, RAR-beta2, RAR-beta4, and RAR-gamma2 was studied with real-time RT-PCR on gestational day 18, and postnatal days 0, 1, 5, and 7 in IL-1beta-expressing mice and their control littermates. In addition, immunohistochemistry for CRABP-I was performed.. IL-1beta decreased the mRNA expression and protein production of CRABP-I as well as the mRNA expression of RAR-gamma2. In contrast, no differences between IL-1beta-expressing and control mice were detected in the expression of CRABP-II, RAR-alpha1, RAR-beta2, or RAR-beta4.. The present study demonstrates for the first time a link between inflammation and the retinoic acid pathway. Inhibition of CRABP-I and RAR-gamma2 expression may be one mechanism by which inflammation prevents alveolar septation. The therapeutic potential of RA in promoting septation in the setting of perinatal lung inflammation deserves further investigation.

Topics: Animals; Bronchopulmonary Dysplasia; Disease Models, Animal; Gene Expression Profiling; Gene Expression Regulation; Humans; Infant, Newborn; Infant, Premature; Interleukin-1; Mice; Mice, Transgenic; Pulmonary Alveoli; Respiratory Mucosa; Reverse Transcriptase Polymerase Chain Reaction; Tretinoin

Oxygen-induced lung injury is believed to lead to the development of bronchopulmonary dysplasia (BPD). To determine whether retinoic acid (RA) treatment prevents the development of BPD by minimizing lung injury, we investigated the effect of RA on the histopathologic characteristics of oxygen-induced lung injury in a newborn rat model. Eighteen rat pups were divided into three groups: room air-exposed control group (n=5), oxygen-exposed placebo group (n=7), and RA-treated oxygen-exposed group (n=6). Measurement of alveolar area, quantitation of secondary crest formation, microvessel count, evaluation of alveolar septal fibrosis, and smooth muscle actin (SMA) immunostaining were performed to assess oxygen-induced changes in lung morphology. Treatment of oxygen-exposed animals with RA resulted in a significant increase in mean alveolar area; however, it had no effect on the number of secondary crests and microvessel count. The degree of fibrosis and SMA expression showed a significant decrease in RA-treated animals. We conclude that RA treatment improves alveolar structure and decreases fibrosis in the newborn rat with oxygen-induced lung injury. Extrapolating these findings to humans, we speculate that similar treatment with RA may reduce lung injury in preterm infants at risk for BPD.

Topics: Animals; Animals, Newborn; Antioxidants; Bronchopulmonary Dysplasia; Disease Models, Animal; Humans; Infant, Newborn; Oxygen Inhalation Therapy; Pulmonary Alveoli; Rats; Rats, Wistar; Risk Factors; Tretinoin

Infants suffering from bronchopulmonary dysplasia (BPD) are known to have low levels of vitamin A, a factor which may be implicated in the pathogenesis of the condition. The ability of retinoic acid (RA) (one of the active forms of vitamin A) to influence the production of superoxide anion (02-) and hydrogen peroxide (H2O2) by stimulated human adult or cord blood neutrophils and macrophages has been studied. RA was found to inhibit the O2- and H2O2 production in a dose-dependent manner. The time required for maximal inhibition was 30 min for neutrophils and 24 h for macrophages. Although cord blood neutrophils produced larger quantities of O2- and H2O2 both with and without RA, the degree of inhibition was similar in both adult and neonatal cells (40-60%). The results suggest that retinoic acid may prevent neutrophil and macrophage mediated lung damage by inhibiting the production of toxic oxygen compounds, especially in BPD conditions.

Topics: Adult; Bronchopulmonary Dysplasia; Cells, Cultured; Female; Fetal Blood; Humans; Hydrogen Peroxide; In Vitro Techniques; Infant, Newborn; Macrophages; Male; Neutrophils; Superoxides; Tretinoin