Rat Model Of Bronchopulmonary Dysplasia Research Articles

Mesenchymal stem cells protect against neonatal rat hyperoxic lung injury

Objectives: Bronchopulmonary dysplasia (BPD) is a significant global health problem and currently lacks effective therapy. We established a neonatal rat model of BPD to investigate therapeutic potential of bone marrow-derived mesenchymal stem cells (BMSCs) in neonatal hyperoxic lung injury.Methods: BMSCs were isolated, identified, and transfected by lentiviral vector carrying green fluorescent protein gene in vitro. Neonatal Sprague-Dawley rats were injected intravenously with either BMSCs or phosphate-buffered saline following 95% oxygen exposure, and assessed for the survival rate and alveolar injury during recovery.Results: Treatment with BMSCs after oxygen exposure for 7 days improved survival of neonatal rat during recovery. BMSCs protected against neonatal rat hyperoxic lung injury during recovery as demonstrated by enhanced expression of AQP5 and SP-C, likely due to the suppression of alveolar cell apoptosis and lung inflammation responses to oxygen with up-regulation of the expression of BCL-2 gene and down-regulation of the expression of BAX gene and stimulation of vascular endothelial growth factor and so on.Conclusions:BMSCs protect against O2-mediated injury partially through stimulation of potent mediators that participate in tissue repair.

128 Intraperitoneal Administration of Cytidine 5’-Diphosphocholine (CDP-Choline) Reduces Hyperoxic Lung Injury in a Neonatal Rat Model of Bronchopulmonary Dysplasia

PurposeThe purpose of this study was to evaluate the preventive effect of CDP-choline treatment on hyperoxic lung injury, inflammation and apoptosis in a neonatal rat model of bronchopulmonary dysplasia BPD.MethodsA...

594 A Neonatal Rat Model of Bronchopulmonary Dysplasia Induced by Pre- And Postnatal Inflammation without Exposure to Hyperoxia

PurposeWe tested if pre- or postnatal inflammation can develop BPD per se and if there are any interaction between prenatal and postnatal inflammation.MethodsTwo days before delivery (E20), 1 µg of...

Lipopolysaccharide disrupts the directional persistence of alveolar myofibroblast migration through EGF receptor

Bronchopulmonary dysplasia (BPD) is characterized by alveolar simplification with decreased alveolar number and increased airspace size. Formation of alveoli involves a process known as secondary septation triggered by myofibroblasts. This study investigated the underlying mechanisms of altered lung morphogenesis in a rat model of BPD induced by intra-amniotic injection of lipopolysaccharide (LPS). Results showed that LPS disrupted alveolar morphology and led to abnormal localization of myofibroblasts in the lung of newborn rats, mostly in primary septa with few in secondary septa. To identify potential mechanisms, in vitro experiments were carried out to observe the migration behavior of myofibroblasts. The migration speed of lung myofibroblasts increased with LPS treatment, whereas the directional persistence decreased. We found that LPS induced activation of EGFR and overexpression of its ligand, TGF-α in myofibroblasts. AG1478, an EGFR inhibitor, abrogated the enhanced locomotivity of myofibroblasts by LPS and also increased the directional persistence of myofibroblast migration. Myofibroblasts showed a high asymmetry of phospho-EGFR localization, which was absent after LPS treatment. Application of rhTGF-α to myofibroblasts decreased the directional persistence. Our findings indicated that asymmetry of phospho-EGFR localization in myofibroblasts was important for cell migration and its directional persistence. We speculate that LPS exposure disrupts the asymmetric localization of phospho-EGFR, leading to decreased stability of cell polarity and final abnormal location of myofibroblasts in vivo, which is critical to secondary septation and may contribute to the arrested alveolar development in BPD.

Effects of Postnatal Dexamethasone or Hydrocortisone in a Rat Model of Antenatal Lipopolysaccharide and Neonatal Hyperoxia Exposure

The aim of our study was to investigate the differential effects of dexamethasone (DXM) and hydrocortisone (HCS) on somatic growth and postnatal lung development in a rat model of bronchopulmonary dysplasia (BPD). A rat model of BPD was induced by administering intra-amniotic lipopolysaccharide (LPS) and postnatal hyperoxia. The rats were treated with a 6-day (D1-D6) tapering course of DXM (starting dose 0.5 mg/kg/day), HCS (starting dose 2 mg/kg/day), or an equivalent volume of normal saline. DXM treatment in a rat model of BPD induced by LPS and hyperoxia was also associated with a more profound weight loss compared to control and LPS + O2 groups not exposed to corticosteroid, whereas HCS treatment affected body weight only slightly. Examination of lung morphology showed worse mean cord length in both LPS + O2 + DXM and LPS + O2 + HCS groups as compared to the LPS + O2 alone group, and the LPS + O2 + DXM group had thicker alveolar walls than the LPS + O2 group at day 14. The HCS treatment was not significantly associated with aberrant alveolar wall thickening and retarded somatic growth. The use of postnatal DXM or HCS in a rat model of BPD induced by intra-amniotic LPS and postnatal hyperoxia appeared detrimental to lung growth, but there was less effect in the case of HCS. These findings suggest that effect of HCS on somatic growth and pulmonary outcome may be better tolerated in neonates for preventing and/or treating BPD.

Serial changes of lung morphology and biochemical profiles in a rat model of bronchopulmonary dysplasia induced by intra-amniotic lipopolysaccharide and postnatal hyperoxia

to investigate serial changes of lung morphology and biochemical profiles in a rat model of bronchopulmonary dysplasia (BPD) induced by intra-amniotic lipopolysaccharide (LPS) administration and postnatal hyperoxia (85%). we evaluated histological changes of the lungs and compared the levels of interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and protein carbonyl in lung tissue on days 1, 7, and 14 after birth in a rat model of BPD. the inhibition of alveolarization was sustained in the LPS plus hyperoxia group from day 7 to 14, whereas alveolarization resumed in the hyperoxia group after oxygen exposure was withdrawn at day 7. Administration of LPS alone did not adversely affect lung morphometry. IL-6 levels showed transient overexpression at day 1 in the LPS-treated groups, but decreased at days 7 and 14. VEGF protein levels were elevated in the LPS-treated groups, but not in the hyper-oxia and control groups at days 1, 7, and 14. Exposure to hyperoxia affected protein carbonyl levels in the hyperoxia group at days 7 and 14. lung injury induced by intra-amniotic inflammation and postnatal hyperoxia may be due to inhibition of alveolarization without recovery even after withdrawal of oxygen.

Association of Increased Pulmonary Interleukin-6 with the Priming Effect of Intra-Amniotic Lipopolysaccharide on Hyperoxic Lung Injury in a Rat Model of Bronchopulmonary Dysplasia

Background: The authors previously demonstrated the priming effect of intra-amniotic lipopolysaccharide (LPS) on hyperoxic lung injury in a rat model of bronchopulmonary dysplasia (BPD). Objectives: To investigate the mechanism underlying this priming effect by determining biochemical profiles in a rat model of BPD. Methods: The rat model involved intra-amniotic LPS administration and postnatal hyperoxia (85%). The mRNA expressions of interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2), basic fibroblast growth factor (bFGF), and transforming growth factor β₁ (TGF-β₁), as well as the protein levels of IL-6, VEGF, and protein carbonyl in lung tissue were compared between the LPS plus hyperoxia, the LPS only, the hyperoxia only, and the control groups. Results: Morphometric analysis of lung tissues demonstrated that alveolarization was significantly inhibited only in the LPS plus hyperoxia group. IL-6 protein levels and its mRNA expression in the lungs were significantly increased only in the LPS plus hyperoxia group. Neither LPS nor hyperoxia increased IL-6 in the lungs independently. bFGF mRNA expression was significantly decreased in the LPS-treated groups. VEGF protein levels were significantly reduced by hyperoxia, whereas protein carbonyl levels were increased by intra-amniotic LPS or hyperoxia. No additional significant change to VEGF or protein carbonyl levels was produced by intra-amniotic LPS or hyperoxia. There were no significant differences in the mRNA expressions of VEGF, VEGFR-2, and TGF-β₁. Conclusions: The priming effect of intra-amniotic LPS on hyperoxic lung injury may be associated with IL-6 elevation in the lungs.

Melatonin protects against oxidative damage in a neonatal rat model of bronchopulmonary dysplasia

Oxidative stress plays an important role in the pathogenesis of bronchopulmonary dysplasia (BPD). Melatonin (MT) has direct and indirect free radical detoxifying activity. The present study was to investigate whether treatment with MT would attenuate hyperoxia-induced lung injury and the effect of MT on imbalance of oxidants/antioxidants in the lung of neonatal rats. BPD was induced by exposure to hyperoxia in neonatal rats (n=90). The rats were divided randomly into three groups (n=30 each): air-exposed control group, hyperoxia-exposed group, and hyperoxia-exposed MT-treated group. Lung specimens were obtained respectively on day 3, day 7, and day 14 after exposure (n=10 each). Activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT), and levels of myeloperoxidase (MPO), nitrite/nitrate, and malondialdehyde (MDA) were assayed. Histopathologic changes were observed in the tissues stained with hematoxylin and eosin and Masson's trichrome stain. Increased levels of MPO, nitrite/nitrate, and MDA in the hyperoxia-exposed rats were significantly reduced by MT (P<0.05). Activities of GSH-Px, SOD, and CAT which did not change after exposure to hyperoxia were increased by MT (P<0.05). Furthermore, BPD associated histopathological alterations such as reduced total number of alveoli and interstitial fibrosis were obviously abated in the MT-treated group. MT can reverse oxidants/antioxidants imbalance in damaged lung tissue and thus exert a beneficial effect on hyperoxia-induced lung disease in neonatal rats. With regard to humans, there may be a protective effect of MT on BPD.

Opposing effects of 60% oxygen and neutrophil influx on alveologenesis in the neonatal rat.

The lungs of newborn rats exposed to 60% oxygen for 14 days develop an injury that shares morphologic similarities to human bronchopulmonary dysplasia (BPD). Neutrophil influx into the lung, as part of an inflammatory response, may play a pivotal role in the development of BPD. A neutrophil chemokine, cytokine-induced neutrophil chemoattractant-1, which signals through the neutrophil CXC chemokine receptor-2, is increased in the lung tissue of newborn rats exposed to 60% oxygen. The purpose of this study was to explore the role of neutrophils in the rat model of BPD by inhibiting neutrophil influx using SB265610, a selective CXC chemokine receptor-2 antagonist. SB265610, administered to 60% oxygen-exposed newborn rats from birth to 14 days, completely inhibited neutrophil influx. It also attenuated increased production of reactive oxygen species in newborn rat lung tissue after exposure to 60% oxygen for 4 days. Lung morphometric analysis revealed that 60% oxygen for 14 days, when accompanied by treatment with SB265610 to prevent neutrophil accumulation, increased alveolar formation over that seen in newborn rats exposed to air. These data suggest that exposure of the neonatal lung to moderate hyperoxia may enhance postnatal lung growth, provided postnatal pulmonary inflammation is suppressed.