Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

TNF-alpha has been associated with chorioamnionitis and the subsequent development of bronchopulmonary dysplasia in preterm infants. We asked whether bioactive recombinant ovine TNF-alpha could induce chorioamnionitis, lung inflammation, lung maturation, and systemic effects in fetal sheep. We compared the responses to IL-1alpha, a cytokine known to induce these responses in preterm sheep. Intra-amniotic TNF-alpha caused no chorioamnionitis, no lung maturation, and a very small increase in inflammatory cells in the fetal lung after 5 h, 2 days (d), and 7 d. In contrast, IL-1alpha induced inflammation and lung maturation. TNF-alpha given into the airways at birth increased granulocytes in the bronchoalveolar lavage fluid of ventilated preterm lungs and decreased the mRNA for surfactant protein C but did not adversely effect postnatal lung function. An intravascular injection of IL-1alpha caused a systemic inflammatory response in fetal sheep, whereas there was no fetal response to intravascular TNF-alpha. Fetal and newborn preterm sheep are minimally responsive to TNF-alpha. Therefore, the presence of a mediator such as TNF-alpha in a developing animal does not necessarily mean that it is causing the responses anticipated from previous results in adult animals.
Am J Physiol Lung Cell Mol Physiol 2003 Jul
PMID:Minimal lung and systemic responses to TNF-alpha in preterm sheep. 1261 17

Parathyroid hormone-related protein (PTHrP) expression is necessary for differentiation of mesenchymal lipofibroblasts, which induce epithelial type II (TII) cell differentiation, both of which are necessary for alveolarization. PTHrP deficiency may be associated with bronchopulmonary dysplasia (BPD), characterized by truncation of alveolarization among preterm infants. This is supported by the baboon model of BPD (failure of alveolarization) that manifests PTHrP deficiency. We provide evidence that TII cell PTHrP expression is downregulated by alveolar overdistension, resulting in the transdifferentiation of lipofibroblasts to myofibroblasts, characterized by progressive loss of PTHrP receptor expression and triglyceride content, and sequential upregulation of alpha-smooth muscle actin (alphaSMA), typifying fibrosis. PTHrP reverses the downregulation of the PTHrP receptor and upregulation of alphaSMA, reverting myofibroblasts to a lipofibroblast genotype. When TII cells are co-cultured with lipofibroblasts, they proliferate and differentiate, expressing surfactant protein-B; in contrast, TII cells co-cultured with myofibroblasts fail to develop, mimicking the failed alveolarization associated with BPD. Treatment of myofibroblasts with 15-deoxy-Delta 12, 14 prostaglandinJ(2) (PGJ(2)) stimulates ADRP expression, reconstituting the lipofibroblast phenotype. PGJ(2)-treated myofibroblasts promote TII cell growth and surfactant protein-B expression, indicating that failed alveolarization due to transdifferentiation is reversible. We conclude that alveolar overdistension can cause fibroblast transdifferentiation, resulting in failed alveolarization.
Pediatr Pathol Mol Med
PMID:The role of fibroblast transdifferentiation in lung epithelial cell proliferation, differentiation, and repair in vitro. 1274 70

Ureaplasma urealyticum is a common inhabitant of mucosal surfaces but is also associated with a higher incidence of pneumonia and bronchopulmonary dysplasia in preterm infants. Culture and polymerase chain reaction demonstrate high isolation rates of ureaplasma in clinical specimens documenting their presence but do not associate the organism directly with the diseased tissue. In this study, lung tissue samples from newborn mice inoculated intranasally with U. urealyticum were used to develop an in situ hybridization (ISH) test for the organism. In situ hybridization allows the localization of gene expression for visualization within the context of tissue morphology. New techniques which use biotinyl-tyramide based signal amplification have been able to greatly enhance the sensitivity of ISH. Using the Dako GenPoint Catalyzed Signal Amplification system to detect a biotinylated DNA probe specific for an internal nucleotide sequence within the urease gene of U. urealyticum, the organism was detected within the infected murine lung tissues. Electron microscopy was used to verify the presence of the organisms in the positive ISH areas. The ISH procedure developed in this study can be used to analyze the presence of ureaplasma in human neonatal lung tissue with the corresponding histopathology.
Exp Mol Pathol 2003 Oct
PMID:Ureaplasma in lung. 1. Localization by in situ hybridization in a mouse model. 1451 80

Infants with Ureaplasma urealyticum in the lower respiratory tract are at risk for chronic lung disease (CLD) or bronchopulmonary dysplasia (BPD) but causality has been difficult to prove. The goal of this study was to identify ureaplasma in human neonatal lung tissue using the in situ hybridization (ISH) procedure described in Part 1 (Exp. Mol. Pathol., in press) of this report. By correlating their presence with the histopathologic findings, it may be possible to provide further evidence of the pathogenicity of ureaplasmas and their association with BPD. Lung autopsy tissue from seven infants with positive cultures and seven infants with negative cultures for ureaplasma were included in the study. All culture-positive infants were positive for ureaplasma on ISH and all had histopathologic evidence of BPD. Two of the seven infants with negative cultures were positive for ureaplasma with ISH. Of interest, these two infants were also found to have BPD at autopsy. The other five infants with negative cultures were also negative for ureaplasma on ISH and had no evidence of BPD. This study correlates the presence of U. urealyticum by ISH with the finding of BPD on histopathologic evaluation and provides evidence that it has a role in the development of CLD.
Exp Mol Pathol 2003 Oct
PMID:Ureaplasma in lung. 2. Association with bronchopulmonary dysplasia in premature newborns. 1451 81

Hyperoxia is an important factor in the development of bronchopulmonary dysplasia and is associated with growth arrest and impaired alveolar septal development in the neonatal lung. p21(Waf1/Cip1/Sdi1) (p21), a cyclin-dependent kinase inhibitor, acts as a checkpoint regulator in the cell cycle during periods of stress and is induced in neonatal lung during hyperoxia exposure. To determine if p21 protects against lung injury during neonatal lung development, we placed newborn p21 knockout (p21(-/-)) and p21 wild-type (p21(+/+)) mice in 85-90% O(2) for 4 d. We found that newborn p21(-/-) mice exposed to O(2) had decreased survival in hyperoxia compared with p21(+/+) mice (P < 0.01). At 2 and 6 wk after exposure to neonatal hyperoxia, p21(-/-) O(2) lung had significantly larger alveoli then p21(-/-) control lung, as assessed by mean alveolar size and mean linear intercept. Pulmonary function tests at 6 wk demonstrated increased lung volume in both p21(-/-) and p21(+/+) O(2) mice consistent with altered lung growth from neonatal exposure to hyperoxia. Antibodies to nitrotyrosine, a marker for oxidative stress revealed that at 2 and 6 wk of age, p21(-/-) O(2) lung had significantly more oxidative stress than p21(-/-) and p21(+/+) control and p21(+/+) O(2) lung. We therefore conclude that p21 confers some additional protection to the lung during exposure to neonatal hyperoxia. Furthermore, p21 may be important during recovery from lung injury because it is associated with lower levels of oxidative stress and increased oxidative stress may contribute to alveolar growth abnormalities in the p21(-/-) O(2) lung.
Am J Respir Cell Mol Biol 2004 May
PMID:The effect of neonatal hyperoxia on the lung of p21Waf1/Cip1/Sdi1-deficient mice. 1460 13

VEGF plays a critical role during lung development and is decreased in human infants with bronchopulmonary dysplasia. Inhibition of VEGF receptors in the newborn rat decreases vascular growth and alveolarization and causes pulmonary hypertension (PH). Nitric oxide (NO) is a downstream mediator of VEGF, but whether the effects of impaired VEGF signaling are due to decreased NO production is unknown. Therefore, we sought to determine whether impaired VEGF signaling downregulates endothelial NO synthase (eNOS) expression in the developing lung and whether inhaled NO (iNO) decreases PH and improves lung growth after VEGF inhibition. Newborn rats received a single dose of SU-5416 (a VEGF receptor inhibitor) or vehicle by subcutaneous injection and were killed up to 3 wk of age for assessments of right ventricular hypertrophy (RVH), radial alveolar counts (RAC), lung eNOS protein, and NOx production in isolated perfused lungs (IPL). Neonatal treatment with SU-5416 increased RVH in infant rats and reduced RAC. Compared with controls, SU-5416 reduced lung eNOS protein expression by 89% at 5 days (P < 0.01). IPL studies from day 14 rats demonstrated increased baseline pulmonary artery pressure and lower perfusate NOx concentration after SU-5416 treatment. Importantly, iNO treatment prevented the increase in RVH and improved RAC after SU-5416 treatment. We conclude that treatment of neonatal rats with SU-5416 downregulates lung eNOS expression and that iNO therapy decreases PH and improves lung growth after SU-5416 treatment. We speculate that decreased NO production contributes to PH and decreases distal lung growth caused by impaired VEGF signaling.
Am J Physiol Lung Cell Mol Physiol 2004 Aug
PMID:Inhaled nitric oxide attenuates pulmonary hypertension and improves lung growth in infant rats after neonatal treatment with a VEGF receptor inhibitor. 1506 25

Clinical studies have associated increased transforming growth factor (TGF)-alpha and EGF receptor with lung remodeling in diseases including bronchopulmonary dysplasia (BPD). BPD is characterized by disrupted alveolar and vascular morphogenesis, inflammation, and remodeling. To determine whether transient increases in TGF-alpha are sufficient to disrupt postnatal lung morphogenesis, we utilized neonatal transgenic mice conditionally expressing TGF-alpha. Expression of TGF-alpha from postnatal days 3 to 5 disrupted postnatal alveologenesis, causing permanent enlargement of distal air spaces in neonatal and adult mice. Lung volume-to-body weight ratios and lung compliance were increased in adult TGF-alpha transgenic mice, whereas tissue and airway elastance were reduced. Elastin fibers in the alveolar septae were fragmented and disorganized. Pulmonary vascular morphogenesis was abnormal in TGF-alpha mice, with attenuated and occasionally tortuous arterial branching. The ratios of right ventricle weight to left ventricle plus septal weight were increased in TGF-alpha mice, indicating pulmonary hypertension. Electron microscopy showed gaps in the capillary endothelium and extravasation of erythrocytes into the alveolar space of TGF-alpha mice. Hemorrhage and inflammatory cells were seen in distal air spaces at 1 mo of age. In adult TGF-alpha mice, alveolar remodeling, nodules, proteinaceous deposits, and inflammatory cells were seen. Immunostaining for pro-surfactant protein C showed that type II cells were abundant in the nodules, as well as neutrophils and macrophages. Trichrome staining showed that pulmonary fibrosis was minimal, apart from areas of nodular remodeling in adult TGF-alpha mice. Transient induction of TGF-alpha during early alveologenesis permanently disrupted lung structure and function and caused chronic lung disease.
Am J Physiol Lung Cell Mol Physiol 2004 Oct
PMID:Transient induction of TGF-alpha disrupts lung morphogenesis, causing pulmonary disease in adulthood. 1535 62

Bronchopulmonary dysplasia (BPD), the most common chronic lung disease in infancy, is influenced by a number of antenatal and postnatal risk factors and is mostly preceded by respiratory distress syndrome (RDS) in the newborn. Surfactant protein (SP-A, -B, -C and -D) gene variations may play a role in both BPD and RDS. An association study between these candidate genes and BPD was performed. A total of 365 preterm Finnish infants in a high-risk population with gestational age <or=32 weeks were genotyped for all SP genes. A multiparameter analysis was performed using Agrawal's algorithm based data mining and conventional methods of statistical allelic association. In singletons and presenting multiples, the frequency of SP-B intron 4 deletion variant allele was increased in BPD versus controls (P=0.008, OR=2.0, 95%CI 1.2-3.4). The presence of the SP-B intron 4 deletion variant was a risk factor for BPD even when essential external confounding factors were included in the analyses. No other SP polymorphisms associated with BPD, and the SP-B intron 4 variation did not associate with RDS. Transcription Element Search Software predicted allele-specific differences at several putative transcription factor binding sites that may be important in SP-B regulation. The present multiparameter analysis demonstrates the presumable direct involvement of the SP-B intron 4 deletion variant allele as a genetic risk factor to BPD. We propose that two separate SP-B gene polymorphisms have a phenotypic significance via separate molecular mechanisms: the intron 4 length variation affecting transcriptional regulation, and the exonic Ile131Thr variation affecting post-translationally.
Hum Mol Genet 2004 Jun 01
PMID:Data mining and multiparameter analysis of lung surfactant protein genes in bronchopulmonary dysplasia. 1510 13

Chorioamnionitis is associated with preterm delivery and bronchopulmonary dysplasia (BPD), characterized by impaired alveolar and pulmonary vascular development and vascular dysfunction. To study the vascular effects in a model of chorioamnionitis, preterm lambs were exposed to 20 mg of intra-amniotic endotoxin or saline for 1, 2, 4, or 7 days and delivered at 122 days gestational age (term = 150 days). This intra-amniotic endotoxin dose was previously shown to induce lung maturation. The effect of intra-amniotic endotoxin on expression of endothelial proteins was evaluated. Muscularization of the media and collagen deposition in adventitia of small pulmonary arteries was used to assess vascular remodeling. Compared with controls, bronchoalveolar lavage fluid protein content was increased 2 days after intra-amniotic endotoxin exposure. Vascular endothelial growth factor (VEGF) 165 isoform mRNA decreased 2-4 days after intra-amniotic endotoxin. VEGF, VEGF receptor-2, endothelial nitric oxide synthase (eNOS), platelet endothelial cell adhesion molecule-1, and Tie-2 protein expression in the lung coordinately decreased 1-7 days after intra-amniotic endotoxin. Intra-amniotic endotoxin appeared to selectively decrease eNOS expression in small pulmonary vessels compared with large vessels. Medial smooth muscle hypertrophy and increased adventitial fibrosis were observed 4 and 7 days after intra-amniotic endotoxin. These results demonstrate that, in the preterm lamb lung, antenatal inflammation inhibits endothelial cell protein expression followed by vascular remodeling changes in small pulmonary arteries. Exposure to antenatal inflammation may cause vascular remodeling and contribute to the development of BPD.
Am J Physiol Lung Cell Mol Physiol 2004 Dec
PMID:Vascular changes after intra-amniotic endotoxin in preterm lamb lungs. 1532 88

Research interest in bronchopulmonary dysplasia (BPD) has steadily increased, and numerous potential mediators have been implicated in the development of the disease. Among such mediators is transforming growth factor (TGF)-beta. Unfortunately, commonly utilized murine transgenic models are not optimal to investigate the effects of TGF-beta specifically during the 2-3 wk period of alveolar formation, the developmental stage that corresponds histologically to early alveolar development in humans, and the time frame during which BPD develops. In the current study, we utilized a triple-transgenic construct to overexpress bioactive TGF-beta1 in the neonatal mouse lung during the period of alveolar formation. Lungs were then examined by histologic, Western blot, and immunofluorescent methods. We found that overexpression of bioactive TGF-beta1 in neonatal mouse lungs resulted in structural changes that have been described in BPD. Included in those characteristics are abnormal alveolar structure, cellular composition, and vascular development. Our study indicates that TGF-beta1 overexpression in the neonatal mouse lung results in histologic alterations that have striking similarities to pathologic descriptions of BPD. We encourage the use of conditional transgenic models for the study of BPD, and hypothesize that the TGF-beta system is a central mediator for the histologic alterations described in association with the disease.
Am J Respir Cell Mol Biol 2004 Dec
PMID:Conditional overexpression of bioactive transforming growth factor-beta1 in neonatal mouse lung: a new model for bronchopulmonary dysplasia? 1533 28


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