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)

Elevated level of oxygen (hyperoxia) is widely used in critical care units and in respiratory insufficiencies. In addition, hyperoxia has been implicated in many diseases such as bronchopulmonary dysplasia or acute respiratory distress syndrome. Although hyperoxia is known to cause DNA base modifications and strand breaks, the DNA damage response has not been adequately investigated. We have investigated the effect of hyperoxia on DNA damage signaling and show that hyperoxia is a unique stress that activates the ataxia telangiectasia mutant (ATM)- and Rad3-related protein kinase (ATR)-dependent p53 phosphorylations (Ser6, -15, -37, and -392), phosphorylation of histone H2AX (Ser139), and phosphorylation of checkpoint kinase 1 (Chk1). In addition, we show that phosphorylation of p53 (Ser6) and histone H2AX (Ser139) depend on both ATM and ATR. We demonstrate that ATR activation precedes ATM activation in hyperoxia. Finally, we show that ATR is required for ATM activation in hyperoxia. Taken together, we report that ATR is the major DNA damage signal transducer in hyperoxia that activates ATM.
Am J Physiol Lung Cell Mol Physiol 2008 May
PMID:Differential roles of ATR and ATM in p53, Chk1, and histone H2AX phosphorylation in response to hyperoxia: ATR-dependent ATM activation. 1834 16

Vascular endothelial growth factor (VEGF) is known to have a pivotal role in lung development and in a variety of pathologic conditions in the adult lung. Our earlier studies have shown that NO is a critical mediator of VEGF-induced vascular and extravascular effects in the adult murine lung. As significant differences have been reported in the cytokine responses in the adult versus the neonatal lung, we hypothesized that there may be significant differences in VEGF-induced alterations in the developing as opposed to the mature lung. Furthermore, nitric oxide (NO) mediation of these VEGF-induced effects may be developmentally regulated. Using a novel externally regulatable lung-targeted transgenic murine model, we found that VEGF-induced pulmonary hemorrhage was mediated by NO-dependent mechanisms in adults and newborns. VEGF enhanced surfactant production in adults as well as increased surfactant and lung development in newborns, via an NO-independent mechanism. While the enhanced survival in hyperoxia in the adult was partly NO-dependent, there was enhanced hyperoxia-induced lung injury in the newborn. In addition, human amniotic fluid VEGF levels correlated positively with surfactant phospholipids. Tracheal aspirate VEGF levels had an initial spike, followed by a decline, and then a subsequent rise, in human neonates with an outcome of bronchopulmonary dysplasia or death. Our data show that VEGF can have injurious as well as potentially beneficial developmental effects, of which some are NO dependent, others NO independent. This opens up the possibility of selective manipulation of any VEGF-based intervention using NO inhibitors for maximal potential clinical benefit.
Am J Respir Cell Mol Biol 2008 Oct
PMID:Developmental regulation of NO-mediated VEGF-induced effects in the lung. 1844 Dec 84

Endogenous and exogenous glucocorticoids influence fetal growth and development, and maternal administration of synthetic glucocorticoids may decrease the risk of perinatal morbidity including lung disease in preterm neonates. Because polymorphisms of the glucocorticoid receptor gene are known to influence the sensitivity to glucocorticoids, in the present study we examined whether any associations could exist among the BclI, N363S and ER22/23EK polymorphisms of the glucocorticoid receptor gene and gestational age, birth weight and/or perinatal morbidity of 125 preterm neonates born at 28-35 weeks' gestation with (n=57) or without maternal dexamethasone treatment (n=68). The prevalence of the three polymorphisms in the whole group of preterm infants was similar to that reported in healthy adult Hungarian population. However, we found that the BclI polymorphism significantly associated with higher birth weight adjusted for the gestational age (p=0.004, ANOVA analysis). None of the three polymorphisms showed an association with perinatal morbidities, including necrotizing enterocolitis, intraventricular hemorrhagia, patent ductus arteriosus, respiratory distress syndrome, bronchopulmonary dysplasia and sepsis in the two groups of preterm neonates with and without maternal dexamethasone treatment. These results suggest that the BclI polymorphism of the glucocorticoid receptor gene may have an impact on gestational age-adjusted birth weight, but it does not influence perinatal morbidities of preterm neonates.
J Steroid Biochem Mol Biol 2008 Jul
PMID:Association between birth weight in preterm neonates and the BclI polymorphism of the glucocorticoid receptor gene. 1859 87

Ventilatory treatment of neonatal respiratory distress often results in bronchopulmonary dysplasia from congenital surfactant deficiency due to mutants of transporter protein ABCA3. Association of this condition with other severe disorders in premature newborns has not heretofore been reported. A neonatal autopsy included an in vivo whole blood sample for genetic testing. Autopsy revealed severe interstitial pulmonary fibrosis at age 8 days with heterozygotic mutation p.E292V of ABCA3 and severe dystrophic retardation of cerebral cortex and cerebellum. Subsequently, 1300 archival neonatal autopsies, 1983-2006, were reviewed for comparable concurrent findings and bronchopulmonary dysplasia or retarded cerebral dystrophy lacking the other principal feature of this syndrome. Archival review revealed four similar cases and eight less so, without gene analysis. Further review for bronchopulmonary dysplasia revealed 59 cases, 1983-2006. Several other examples of similar retarded migration of germinal matrix and underdevelopment of cortical mantle, without pulmonary lesions of this type, were identified. The determination of an ABCA3 mutation in one case of severe pulmonary fibrosis with significant dystrophy of the brain and the identification of four highly similar archival cases and eight others with partial pathological findings supports the designation of an independent disorder, here referred to as the cerebropulmonary dysgenetic syndrome.
Exp Mol Pathol 2008 Oct
PMID:Cerebropulmonary dysgenetic syndrome. 1860 41

Matrix metalloprotease-9 (MMP-9) is increased in lung injury following hyperoxia exposure in neonatal mice, in association with impaired alveolar development. We studied the role of MMP-9 in the mechanism of hyperoxia-induced functional and histological changes in neonatal mouse lung. Reduced alveolarization with remodeling of ECM is a major morbidity component of oxidant injury in developing lung. MMP-9 mediates oxidant injury in developing lung causing altered lung remodeling. Five-day-old neonatal wild-type (WT) and MMP-9 (-/-) mice were exposed to hyperoxia for 8 days. The lungs were inflation fixed, and sections were examined for morphometry. The mean linear intercept and alveolar counts were evaluated. Immunohistochemistry for MMP-9 and elastin was performed. MMP-2, MMP-9, type I collagen, and tropoelastin were measured by Western blot analysis. Lung quasistatic compliance was studied in anaesthetized mice. MMP-2 and MMP-9 were significantly increased in lungs of WT mice exposed to hyperoxia compared with controls. Immunohistochemistry showed an increase in MMP-9 in mesenchyme and alveolar epithelium of hyperoxic lungs. The lungs of hyperoxia-exposed WT mice had less gas exchange surface area and were less compliant compared with room air-exposed WT and hyperoxia-exposed MMP-9 (-/-) mice. Type I collagen and tropoelastin were increased in hyperoxia-exposed WT with aberrant elastin staining. These changes were ameliorated in hyperoxia-exposed MMP-9 (-/-) mice. MMP-9 plays an important role in the structural changes consequent to oxygen-induced lung injury. Blocking MMP-9 activity may lead to novel therapeutic approaches in preventing bronchopulmonary dysplasia.
Am J Physiol Lung Cell Mol Physiol 2008 Oct
PMID:Role of matrix metalloprotease-9 in hyperoxic injury in developing lung. 1865 76

Increased activity of matrix metalloproteinase (MMP)-9 is associated with the development of bronchopulmonary dysplasia (BPD) in newborn infants, but the role of MMP-9 in the pathophysiology of BPD is unclear. We have shown that perinatal expression of interleukin-1 beta (IL-1 beta) in the lung is sufficient to cause a BPD-like illness in infant mice. To study the hypothesis that MMP-9 is an important downstream mediator in IL-1 beta-induced lung injury in the newborn, we compared the effects of IL-1 beta on fetal and postnatal lung inflammation and development in transgenic mice with regulatable pulmonary overexpression of human mature IL-1 beta with wild-type (IL-1 beta/MMP-9(+/+)) or null (IL-1 beta/MMP-9(-/-)) MMP-9 loci. IL-1 beta increased the expression of MMP-9 mRNA and amount of MMP-9 protein in the lungs of MMP-9(+/+) mice. IL-1 beta/MMP-9(-/-) mice had fewer neutrophils but more macrophages in the lungs than did IL-1 beta/MMP-9(+/+) mice. MMP-9 deficiency increased pulmonary cell death and macrophage clearance of dying cells in IL-1 beta-expressing mice. IL-1 beta/MMP-9(-/-) mice had more severe alveolar hypoplasia than IL-1 beta/MMP-9(+/+) mice, implying that IL-1 beta-induced lung disease was worsened in the absence of MMP-9. These results suggest that MMP-9 activity in the inflamed neonatal lung protects the lung against injury.
Am J Respir Cell Mol Biol 2009 Jul
PMID:Matrix metalloproteinase-9 deficiency worsens lung injury in a model of bronchopulmonary dysplasia. 1909 83

Chorioamnionitis, a risk factor for bronchopulmonary dysplasia in preterm infants, causes an influx of inflammatory cells into the fetal lung. Using a fetal sheep model, we evaluated the time course of activation, functional maturity, and apoptosis of the leukocytes recruited to the fetal air spaces by lipopolysaccharide (LPS). Time-mated sheep were given intra-amniotic injections with 10 mg of Escherichia coli LPS or saline 2 or 7 days before preterm delivery at 124 days of gestation (term is 150 days). Both neutrophils and monocytes in bronchoalveolar lavage fluid (BALF) had activated NF-kappaB after 2- and 7-day LPS exposures. These neutrophils and monocytes expressed the activation factor CD11b and the maturation factor PU.1 at 2 days, and increased PU.1 expression was detected in macrophages at 7 days. Leukocyte oxidative burst activity was greatest at 7 days. BALF lipid peroxidation increased fivefold at 2 days, while protein carbonyls increased eightfold at 7 days. Nitrative stress was not detected in the BALF, but leukocytes in the lung expressed nitric oxide synthase (NOS)II (inducible NOS). BALF leukocytes expressed the antioxidant peroxiredoxin V. Lung glutathione peroxidase was also increased with LPS exposure. There was minimal apoptosis of airway and lung leukocytes assessed by caspase-3 activation. Intra-amniotic LPS recruits leukocytes to the fetal air space that have a persistent activation. These results have implications for the pathogenesis of lung inflammatory disorders in the preterm.
Am J Physiol Lung Cell Mol Physiol 2009 Mar
PMID:Airway inflammatory cell responses to intra-amniotic lipopolysaccharide in a sheep model of chorioamnionitis. 1911 89

This study investigated whether mitochondrial dysfunction contributes to alveolar developmental arrest in a mouse model of bronchopulmonary dysplasia (BPD). To induce BPD, 3-day-old mice were exposed to 75% O2. Mice were studied at two time points of hyperoxia (72 h or 2 wk) and after 3 weeks of recovery in room air (RA). A separate cohort of mice was exposed to pyridaben, a complex-I (C-I) inhibitor, for 72 hours or 2 weeks. Alveolarization was quantified by radial alveolar count and mean linear intercept methods. Pulmonary mitochondrial function was defined by respiration rates, ATP-production rate, and C-I activity. At 72 hours, hyperoxic mice demonstrated significant inhibition of C-I activity, reduced respiration and ATP production rates, and significantly decreased radial alveolar count compared with controls. Exposure to pyridaben for 72 hours, as expected, caused significant inhibition of C-I and ADP-phosphorylating respiration. Similar to hyperoxic littermates, these pyridaben-exposed mice exhibited significantly delayed alveolarization compared with controls. At 2 weeks of exposure to hyperoxia or pyridaben, mitochondrial respiration was inhibited and associated with alveolar developmental arrest. However, after 3 weeks of recovery from hyperoxia or 2 weeks after 72 hours of exposure to pyridaben alveolarization significantly improved. In addition, there was marked normalization of C-I and mitochondrial respiration. The degree of hyperoxia-induced pulmonary simplification and recovery strongly (r(2) = 0.76) correlated with C-I activity in lung mitochondria. Thus, the arrest of alveolar development induced by either hyperoxia or direct inhibition of mitochondrial oxidative phosphorylation indicates that bioenergetic failure to maintain normal alveolar development is one of the fundamental mechanisms responsible for BPD.
Am J Respir Cell Mol Biol 2009 May
PMID:Mitochondrial dysfunction contributes to alveolar developmental arrest in hyperoxia-exposed mice. 1916 98

Alterations in vascular endothelial growth factor (VEGF) contribute to alveolar simplification seen in animal models of bronchopulmonary dysplasia, and VEGF expression is redox regulated by thioredoxin (Trx)-1 in other diseases. The present studies tested the hypothesis that exposure to 85% O2 negatively impacts the Trx1 system and VEGF expression in the lungs of newborn mice. There was no effect of fraction of inspired oxygen on lung Trx1 or Trx reductase-1 protein levels; however, lung Trx1 protein was predominantly oxidized in the lungs of newborn mice exposed to 85% O2 by 24 hours of exposure. In room air (RA), lung Trx interacting protein (Txnip) levels decreased developmentally through Day 7 (1.0 +/- 0.06 [Day 1] vs. 0.49 +/- 0.10 [Day 3] vs. 0.29 +/- 0.03 [Day 7]; P < 0.01), whereas VEGF expression increased (1.25 +/- 0.16 [Day 1] vs. 4.35 +/- 1.51 [Day 3] vs. 13.23 +/- 0.37 [Day 7]; P < 0.01). Newborn mice exposed to 85% O2 had no developmental decrease in Txnip protein levels and a delayed increase in VEGF protein levels. Lung Txnip and VEGF protein levels were different than in corresponding RA controls at Day 3, before the detection of lung morphologic abnormalities in our model. Txnip and VEGF protein levels were inversely correlated in both the RA and hyperoxia-exposed groups (n = 18; R = -0.66; P = 0.003). In conclusion, oxidation of Trx1 and sustained Txnip expression in the lungs of newborn mice exposed to 85% oxygen is likely to severely attenuate normal Trx1 function. The inverse correlation of Txnip with VEGF expression suggests that decreased Trx1 function contributes to the observed lung developmental abnormalities.
Am J Respir Cell Mol Biol 2009 Nov
PMID:Alterations of the thioredoxin system by hyperoxia: implications for alveolar development. 1924 2

Bronchopulmonary dysplasia of the premature neonate and emphysema of the adult lung are common diseases that are characterized by increased airspace size and respiratory insufficiency and that presently lack efficient treatment. Although the former leads to impaired alveolar development and the latter to alveolar destruction, they have striking similarities in their pathophysiology, including the precipitating effect of oxidative stress, sustained inflammation, enhanced apoptosis, protease-antiprotease imbalance, elastic fiber deterioration and altered microvascularization. This review aims to comparatively analyze their molecular mechanisms to try identify common therapeutic targets. The recent discovery that alveolar developmental and maintenance programs share the same signal molecules and pathways, together with considerable increase in their understanding, have facilitated the development of common innovative strategies that have started to be tested in experimental models and pilot clinical studies.
Trends Mol Med 2009 Apr
PMID:Bronchopulmonary dysplasia and emphysema: in search of common therapeutic targets. 1930 61


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