Endothelial Cpt1a Inhibits Neonatal Hyperoxia‐Induced Pulmonary Vascular Remodeling by Repressing Endothelial‐Mesenchymal Transition
Xiaoyun LiKaty HegartyFanjie LinJason ChangAmro AbdallaKarthik DhanabalanSergey O. SolomevichWenliang SongKarim RoderChenrui YaoWenju LuPeter CarmelietGaurav ChoudharyPhyllis A. DenneryHongwei Yao
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Abstract Pulmonary hypertension (PH) increases the mortality of preterm infants with bronchopulmonary dysplasia (BPD). There are no curative therapies for this disease. Lung endothelial carnitine palmitoyltransferase 1a (Cpt1a), the rate‐limiting enzyme of the carnitine shuttle system, is reduced in a rodent model of BPD. It is unknown whether endothelial Cpt1a reduction causes pulmonary vascular (PV) remodeling. The latter can be the result of endothelial‐mesenchymal transition (EndoMT). Here, endothelial cell (EC)‐specific Cpt1a KO and WT mice (<12 h old) are exposed to hyperoxia (70% O 2 ) for 14 days and allow them to recover in normoxia until postnatal day 28. Hyperoxia causes PH, which is aggravated in EC‐specific Cpt1a KO mice. Upregulating endothelial Cpt1a expression inhibits hyperoxia‐induced PV remodeling. Hyperoxia causes lung EndoMT, detected by immunofluorescence, scRNA‐sequencing, and EC lineage tracing, which is further increased in EC‐specific Cpt1a KO mice. Blocking EndoMT inhibits hyperoxia‐induced PV remodeling. Male mice under the same high oxygen conditions develop a higher degree of PH than females, which is associated with reduced endothelial Cpt1a expression. Conclusively, neonatal hyperoxia causes PH by decreasing endothelial Cpt1a expression and upregulating EndoMT. This provides a valuable strategy for developing targeted therapies by upregulating endothelial Cpt1a levels or inhibiting EndoMT to treat BPD‐associated PH.Keywords:
Hyperoxia
Hypoxia
Bronchopulmonary Dysplasia
Bronchopulmonary dysplasia (BPD) is characterised by impaired alveolarisation, inflammation and aberrant vascular development. Phosphodiesterase (PDE) inhibitors can influence cell proliferation, antagonise inflammation and restore vascular development and homeostasis, suggesting a therapeutic potential in BPD. The aim of the present study was to investigate PDE expression in the lung of hyperoxia-exposed mice, and to assess the viability of PDE4 as a therapeutic target in BPD. Newborn C57BL/6N mice were exposed to normoxia or 85% oxygen for 28 days. Animal growth and dynamic respiratory compliance were reduced in animals exposed to hyperoxia, paralleled by decreased septation, airspace enlargement and increased septal wall thickness. Changes were evident after 14 days and were more pronounced after 28 days of hyperoxic exposure. At the mRNA level, PDE1A and PDE4A were upregulated while PDE5A was downregulated under hyperoxia. Immunoblotting confirmed these trends in PDE4A and PDE5A at the protein expression level. Treatment with cilomilast (PDE4 inhibitor, 5 mg·kg −1 ·day −1 ) between days 14 and 28 significantly decreased the mean intra-alveolar distance, septal wall thickness and total airspace area and improved dynamic lung compliance. Pharmacological inhibition of phosphodiesterase improved lung alveolarisation in hyperoxia-induced bronchopulmonary dysplasia, and thus may offer a new therapeutic modality in the clinical management of bronchopulmonary dysplasia.
Hyperoxia
Bronchopulmonary Dysplasia
Pulmonary compliance
Oxygen toxicity
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Objective:To study the effect and injuries of moderate hyperoxia exposure(60% O2) on a neonatal mouse development to observe the effect of TGF-β1 on the lung injuries of the neonatal mouse bronchopulmonary dysplasia.Methods: Thirty neonatal female KM mice were randomly divided into an experiment group and a control group(n=15).The control group was put in the air(FiO2 0.21) and the experiment group was put in the sealed oxygen box(FiO2 0.6) to prepare the model of the neonatal female mouse bronchopulmonary dysplasia induced by moderate hyperoxia,record the mouse body weight at the 2nd,7th,14th,21st,28th days after inhaling oxygen and observe the changes of pulmonary histopathology of different time points by HE staining and the expression levels of TGF-β1 protein by immunohistochemistry.Results: The body weight of the mouse in the experiment group was significantly reduced after 7 days of inhaling oxygen and the structure of normal alveolar disappeared,alveolar was fused and the alveolar intervals were thickened under the HE staining.The expression of TGF-β1 increased after 72 hours of hyperoxia exposure and the expression of TGF-β1 would continuously increase with the prolongation of inhaling oxygen.Conclusion:Oxygen inhalation of sustainable higher concentration may result in growth failure and pulmonary alveolarization block and appear pulmonary changes that is similarities to human bronchopulmonary dysplasia.TGF-β1 plays an important roles in development and sustainment of the pulmonary fibrosis(PF).
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Bronchopulmonary Dysplasia
Room air distribution
Histopathology
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Exogenous induction of hypercapnia is shown to improve pulmonary function during ventilator and endotoxin‐induced lung injury. These injuries, likewise hyperoxia‐induced lung injury, are partly mediated by neutrophils sequestration and production of reactive oxygen species. Therefore, we tested the hypothesis that hypercapnia may improve the morphological manifestations of prolonged hyperoxia in neonatal rats. One day‐old rats were randomly assigned for 96 hours of exposure to normoxia (21% O 2 ), hyperoxia (>98% O 2 ) and hypercapnic hyperoxia (95% O 2 plus 5% CO 2 ), (n=5/group). Pups were then euthanized, lungs cardiac lobe was dissected for histological preparations, and changes in the alveolar size (μ 2 ) were measured, using a computerized image analyzer. The results showed characteristic manifestations of pulmonary oxygen toxicity, such as substantial hypercellularity in both hyperoxic groups, as compared to normoxia. Although the alveolar density (number of alveoli/mm 2 ) was reduced, the alveolar size was increased by 21% (p>0.05) during hyperoxia, and by 60% during hypercapnic hyperoxia, as compared to normoxia (p<0.05; ANOVA followed by Tukey‐Kramer multiple comparisons test). These data suggest that exogenously induced hypercapnia does not improve the morphological manifestations of pulmonary oxygen toxicity.
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Oxygen toxicity
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Objectives To explore the effect of hyperoxia on expression of surfactant protein C(SP-C)in newborn rats.Methods The 72 newborn SD rats were randomly divided into air group and hyperoxia group.Each group has 36 rats.The rats in every group were randomly into the 3rd,7th,14th day subgroups respectively.The sub-groups of 3rd,7th and 14th were cut lung tissue in the corresponding of time,expression of SP-C protein was detected by immunohistochemistry.Results The expression of SP-C in hyperoxia group was stronger than air group in 3rd day,P0.05;The expression of SP-C showed no significant difference between hyperoxia group and air group in 7th day,(P0.05),Significant difference was noticed between hyperoxia group and air group in 14th day,(P0.01).Conclusion Hyperoxia exposure lead to a down regulation or functional impairment of the SP-C expression,this may be an important factor for hyperoxia lung injury.
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Surfactant protein C
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<i>Background:</i> Bronchopulmonary dysplasia (BPD) is thought to be one form of developmental arrest of the lung. Hepatocyte growth factor (HGF) participates in normal lung growth and in lung regeneration. <i>Objectives:</i> The purpose of this study is to investigate whether HGF can improve alveolarization and attenuates functional abnormalities of a murine model of BPD induced by hyperoxia. <i>Methods:</i> Three-day-old CD-1 mice were exposed to 90% of oxygen or room air (control group) for 7 days. These animals were then kept in room air for the next 7 days. Recombinant human (rh) HGF (100 μg/g b.w., divided 3 times, rhHGF group) or vehicle (vehicle group) was administered intraperitoneally during hyperoxia. On day 17, the pulmonary function test and bronchial hyperresponsiveness (BHR) were examined. Mean linear intercepts (MLI) were measured as parameters of alveolarization. Cell renewal (on day 10) and vascularization of the lung were also evaluated. <i>Results:</i> Exposure to hyperoxia induced increased airway resistance and BHR. These animals showed a severely simplified alveolar structure, increased MLI, decreased cell renewal (16.1 ± 2.4 vs. 29.6 ± 2.4%, p < 0.05), and decreased vascularization (15.1 ± 0.3 vs. 18.4 ± 1.5 vessels/hpf, p < 0.05, vehicle vs. control group, respectively). rhHGF treatment during exposure to hyperoxia significantly reduced all of these changes (27.9 ± 1.7%, 18.2 ± 0.5 vessels/hpf for cell renewal and vascularization, respectively; all values are p < 0.05 against vehicle animals). <i>Conclusion:</i> HGF partially protects against the inhibition of alveolarization and improves functional abnormality in the hyperoxia-induced neonatal mice model of BPD.
Bronchopulmonary Dysplasia
Hyperoxia
Room air distribution
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Effects of hypoxia and hyperoxia on the ultrastructure of aortic endothelial cells were studied in rats. Rats were subjected to FIO2 0.05, 0.06 or 0.1 for various period times. Hypoxia was followed by nuclei protrusion, appearance of holes through the luminal membranes of individual cells. Some cells showed signs of partial of total disintegration. Hyperoxia (FIO2 = 1.0) were followed by slight morphological changes notable after 8 hours but most pronounced after 24 hours. The present study corroborated previous studies in that both hypoxia and hyperoxia can alter endothelial integrity.
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Supplemental oxygen is frequently used in the treatment of infants having pulmonary insufficiency, but prolonged hyperoxia may contribute to the development of bronchopulmonary dysplasia in these infants. Cytochrome P4501A enzymes have been implicated in hyperoxic lung injury. Retinoic acid (RA) plays a key role in lung development. Here, we tested the hypotheses that newborn rats exposed to a combination of RA and hyperoxia would be less susceptible to lung injury than those exposed to hyperoxia only and that modulation of CYP1A enzymes by RA contribute to the beneficial effects of RA against hyperoxic lung injury. Newborn rats exposed to hyperoxia for 7 days showed higher lung weight/body weight ratios compared with those exposed to RA + hyperoxia. Hyperoxia for 7 days also caused a significant increase in hepatic and pulmonary CYP1A1/1A2 expression compared with air-breathing controls. RA + hyperoxia treatment lowered the expression of these genes. Seven to 30 days after withdrawal of hyperoxia, the animals showed marked induction of hepatic and pulmonary CYP1A1/1A2 expression, but animals that had been given RA + hyperoxia displayed lower expression of these enzymes. On postnatal days 22 or 38, the hyperoxic animals displayed retarded lung alveolarization; however, the RA + hyperoxia-exposed animals showed improved alveolarization. The improved alveolarization in animals given RA + hyperoxia, in conjunction with the attenuation of CYP1A1 and 1A2 expression in these animals, suggests that this phenomenon may play a role in the beneficial effects of RA.
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This study determines effects of oxygen levels on morphology and VEGF expression of developing chicken lungs following incubation in normoxia (21% O2), hypoxia (15% O2) or hyperoxia (30% O2), until developmental days 16 or 18. Lung morphology was assessed using light microscopy, while VEGF expression was determined with ELISA. In hypoxia, the proportion of parabronchial tissue and parabronchi including lumina increased from day 16 to 18 (61 to 68% and 74.2 to 82.2%, respectively). Non-parabronchial tissue was higher in hypoxia than in hyperoxia on day 16 (26 to 20%). However, by day 18, there were no differences between groups. VEGF expression was 33% higher in hypoxia than in hyperoxia on day 16 (736 vs. 492 pg/ml). On day 18, VEGF expression was 43% higher in hyperoxia than in normoxia (673 to 381pg/ml), and remained elevated by 40% in hypoxia over normoxia (631 pg/ml). VEGF may be a mechanism by which parabronchial tissue is stimulated from day 16 to 18 following exposure to chronic hypoxia.
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Hypoxia
Gallus gallus domesticus
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Bronchopulmonary dysplasia (BPD) is a severe complication of extreme prematurity that can be caused by hyperoxia inhalation. SP-B and TGF-β have been reported to be implicated in the development of lung. This study aimed to reveal the spatial and temporal expression patterns of these two factors in an animal model of BPD.Newborn Sprague-Dawley (SD) rats were subjected to hyperoxia conditions to establish an animal model of BPD. The levels of SP-B, TGF-β, MDA and TAOC, as well as the activations of MAPK and PI3K/AKT pathways in lung tissues were monitored during newborn rats prolonged exposure to hyperoxia.We found that hyperoxia exposure significantly induced body weight loss of SD rats. H&E staining for morphometric analyses revealed that hyperoxia arrested alveolar development or loss of alveoli, with fewer and dysmorphic capillaries. mRNA and protein levels of SP-B and TGF-β were high expressed in hyperoxic lung tissues. The concentrations of SP-B and TGF-β in bronchoalveolar lavage fluid were also increased. All these increases begin at the 3th day of hyperoxia exposure. MDA content was increased while TAOC content was decreased in response to hyperoxia. Furthermore, hyperoxia activated p38, and deactivated PI3K and AKT expression.Our research demonstrated that SP-B and TGF-β1 were highly expressed in three levels: mRNA and protein levels in lung tissues, and the release of SP-B and TGF-β1 in bronchoalveolar lavage fluid, beginning at the 3th day of hyperoxia exposure.
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