Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242706 (hyperoxia)
 5,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interactions between extracellular matrix, proteins, metalloproteinases, and their inhibitors play a major role in determining the structure of the lung during in utero development and after birth. To better understand the molecular mechanisms underlying lung development and morphogenesis, expression of the tissue inhibitor of metalloproteinase (TIMP-1) gene was examined 1) through the course of late fetal development, 2) when normal fetal development was interrupted by premature birth and extrauterine survival, and 3) during exposure of prematurely delivered neonates to hyperoxia. Total RNA isolated from lung tissue of fetal baboons (Papio sp) at 140, 150, and 180 d of gestation (term gestation = 180 d); baboons prematurely delivered at 140 d of gestation, 1, 2, 6, and 10 d old; and premature baboons ventilated for 6 and 10 d with 100% oxygen was examined by Northern blot analysis. The results demonstrated that TIMP-1 mRNA, which is expressed at low levels during fetal development, undergoes a marked increase in abundance shortly after both premature and term birth. This parturition-induced pattern of gene expression appears to be tissue specific to the lung and, contrary to results reported for adult and neonatal animals, is not affected by ventilation of the premature lungs with 100% inspired oxygen. Although the physiologic consequences of TIMP-1 mRNA induction by birth are not yet known, these data suggest a possible role for TIMP-1 in postnatal adaptation of lung tissue.
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PMID:Tissue inhibitor of metalloproteinase-1 mRNA is specifically induced in lung tissue after birth. 810 84

Subacute hyperoxia may cause basement membrane disruption and subsequent fibrosis. To test the role of extracellular matrix degradation in hyperoxic damage, we analyzed the expression of gelatinases A and B and tissue inhibitors of metalloproteinases (TIMP)-1 and TIMP-2 in rats exposed to 85% O2. Oxygen-exposed rats were studied at 1, 3, 5, and 7 days, and compared with air-breathing rats. Lung mRNAs assayed by Northern and in situ hybridization showed an up-regulation of lung gelatinases A and B from the 3rd day on. Gelatinase A was localized in alveolar macrophages and in interstitial and alveolar epithelial cells. Gelatinase B mRNA and protein were localized in macrophages and bronchiolar and alveolar epithelial cells. Increased gelatinase A and B activities were demonstrated in bronchoalveolar lavage. TIMP-1 and TIMP-2 were constitutively expressed, and only TIMP-1 displayed a moderate increase with hyperoxia. To elucidate transcriptional mechanisms for increased gelatinase B expression after hyperoxia, nuclear transcription factor-kappabeta activation was explored. Oxidative stress significantly increased the lung expression of nuclear transcription factor-kappabeta (p65) protein, and nuclear transcription factor-kappabeta activation and increased levels of gelatinases A and B were found in isolated type II alveolar cells obtained from hyperoxic rats. Conceivably, subacute hyperoxia induces excessive gelatinase activity, which may contribute to lung damage.
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PMID:Gelatinases A and B are up-regulated in rat lungs by subacute hyperoxia: pathogenetic implications. 973 32

Peroxynitrite (ONOO-) is a strong oxidant derived from nitric oxide ('NO) and superoxide (O2.-), reactive nitrogen (RNS) and oxygen species (ROS) present in inflamed tissue. Other oxidant stresses, e.g., TNF-alpha and hyperoxia, induce mitochondrial, manganese-containing superoxide dismutase (MnSOD) gene expression. These experiments tested whether ONOO regulated MnSOD gene expression in human lung epithelial (A549) cells. 3-morpholinosydnonimine HCI (SIN-1) (10 or 1000 microM) increased MnSOD mRNA, but did not change hypoxanthine guanine phosphoribosyl transferase (HPRT) mRNA. Authentic peroxynitrite (ONOO ) (100-500 microM) also increased MnSOD mRNA but did not change constitutive HPRT mRNA expression. ONOO stimulated luciferase gene expression driven by a 2.5 kb fragment of the rat MnSOD gene 5' promoter region. MnSOD gene induction due to ONOO- was inhibited effectively by L-cysteine (10 mM) and partially inhibited by N-acetyl cysteine (50 mM) or pyrrole dithiocarbamate (10 mM). .NO from 1-propanamine, 3-(2-hydroxy-2-nitroso-1-propylhydrazine) (PAPA NONOate) (100 or 1000 microM) did not change MnSOD or HPRT mRNA. Neither H202 nor NO2-, breakdown products of SIN-1 and ONOO , had any effect on MnSOD mRNA expression; however, ONOO- and SIN-1 did not increase MnSOD protein content detectable by western blots, nor did they increase MnSOD enzymatic activity. Increased steady state [O2.-] in the presence of .NO yields ONOO , and ONOO has direct, stimulatory effects on MnSOD transcript expression.
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PMID:Peroxynitrite modulates MnSOD gene expression in lung epithelial cells. 974 82

In this study, we examined the sequential expression of several matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and growth factors as well as the presence of apoptosis in a model of pulmonary fibrosis induced in rats with paraquat and hyperoxia. Animals showing neither clinical nor morphological changes with this double aggression were classified as "resistant". Rats were killed at 1, 2, 3, and 6 wk, and lungs were used for collagen content, gene expression by real-time PCR, gelatinolytic activity by zymography, apoptosis by in situ DNA fragmentation, and protein localization by immunohistochemistry. Our results showed a significant decrease of collagenases MMP-8 and MMP-13, with an increase of TIMP-1 and transforming growth factor-beta. Immunoreactive TIMP-1 was increased in experimental rats and primarily localized in alveolar macrophages. Expression of gelatinases MMP-2 and MMP-9 mRNAs was not affected, but lung zymography revealed an increase in progelatinase B, progelatinase A, and its active form. Epithelial apoptosis was evident from the first week, whereas at later periods, interstitial cell apoptosis was also noticed. Resistant animals behave as controls. These findings suggest that an imbalance between collagenases and TIMPs, excessive gelatinolytic activity, and epithelial apoptosis participate in the fibrotic response in this experimental model.
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PMID:Unbalanced collagenases/TIMP-1 expression and epithelial apoptosis in experimental lung fibrosis. 1288 63

Matrix metalloproteinases (MMP) are likely effectors of normal lung development, especially branching morphogenesis, angiogenesis, and extracellular matrix degradation. Because hyperoxia exposure (>95% O(2)) from d 4 to 14 in newborn rat pups leads to arrest of alveolarization and mimics newborn chronic lung disease, we tested whether hyperoxia altered MMP-2 and -9 mRNA, protein, and enzymatic activity, and the mRNA and protein expression of the endogenous tissue inhibitor of MMP, TIMP-1. No changes due to hyperoxia exposure were observed in MMP-2 mRNA or pro-enzyme (72 kD) protein levels between d 6 and 14, although the overall protein mass and zymographic activity of the active (68 kD) enzyme were diminished (p < 0.05, ANOVA). However, hyperoxia significantly decreased levels of MMP-9 mRNA and pro-MMP-9 protein and diminished overall MMP-9 pro-enzyme activity. TIMP-1 mRNA was not elevated by hyperoxia until d 14, but protein levels were significantly (p < 0.001) elevated by hyperoxia from d 9 to 14. To estimate the potential of MMP inhibition to arrest alveolarization, administration of doxycycline (20 mg/kg, twice daily by gavage), a pan-MMP proteolysis inhibitor, arrested lung alveolarization. We conclude that hyperoxia decreases MMP-9 mRNA, protein, and activity and elevates TIMP-1 protein, and these changes have the potential to contribute to the arrest of normal lung development.
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PMID:Hyperoxia decreases matrix metalloproteinase-9 and increases tissue inhibitor of matrix metalloproteinase-1 protein in the newborn rat lung: association with arrested alveolarization. 1512 10

Matrix metalloproteinases (MMPs) regulate the formation of normal lung architecture. Extremely premature infants exposed to hyperoxia and mechanical ventilation often develop lung inflammation and injury. We hypothesized that an imbalance between MMPs and their tissue inhibitors plays a key role. Our hypothesis was tested to: 1) examine the ontogeny of lung MMPs and tissue inhibitors of metalloproteinases (TIMPs); and 2) determine the effects of hyperoxia and mechanical ventilation on lung MMPs and TIMPs in premature newborn baboons developing chronic lung disease/bronchopulmonary dysplasia (CLD/BPD). Lung specimens were obtained from five groups of gestational controls (GCs) sacrificed at 125, 140, 160, 175, and 185 (term) days of gestation, one fetal baboon model of CLD/BPD delivered at 125 days, and two at 140 days of gestation. Paraffin-embedded lung tissue sections were examined for pathological changes, and frozen lung specimens were analyzed for MMPs-1, -2, -8, and -9; TIMPs-1 and -2; and messenger RNA expression of type I collagen. In GCs, MMP-1 and -9 were elevated in the last trimester, whereas MMP-2 and -8 levels were decreased. Significant changes in lung architecture were noted in the BPD models. MMP-1 was increased in the 125-day model, but decreased in both 140-day models. MMP-8 and collagen mRNA levels were decreased, while MMP-9 and MMP-9 to TIMP-1 ratios were increased in all BPD models. We conclude that an imbalance between MMP-9 and TIMP-1 leading to excessive MMP-9 activity contributes to lung inflammation and edema in CLD/BPD.
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PMID:Increased lung matrix metalloproteinase-9 levels in extremely premature baboons with bronchopulmonary dysplasia. 1552 Oct 85

Extremely premature neonates requiring oxygen therapy develop an accumulation of reactive oxygen species (ROS), impaired alveolarization and dysmorphic pulmonary vasculature. Regulators of ROS (i.e. antioxidants), alveolarization (i.e. matrix metalloproteinases - MMPs) and microvascular maturation (i.e. vascular endothelial growth factor - VEGF) are altered in bronchopulmonary dysplasia (BPD). We tested the hypothesis that early treatment with MnTBAP, a superoxide dismutase mimetic and superoxide anion and peroxynitrite scavenger, alters lung biomarkers of angiogenesis and alveolarization during hyperoxia with intermittent hypoxia (IH) in neonatal rats. Neonatal rats were exposed to 50% O2 with brief IH episodes (12% O2) from P0 to P14, or to room air (RA). On P0, P1 & P2, the pups received a daily IP injection of 1, 5, or 10 mg/kg MnTBAP, or saline. At P14, the pups were either euthanized, or allowed to recover in RA until P21. RA littermates were similarly treated. Lung VEGF, sVEGFR-1, MMP-2, MMP-9 and TIMP-1 were determined. Low-dose MnTBAP (1 mg/kg) prevented the increase in lung VEGF induced by intermittent hypoxia noted in the control group. This dose was also effective for decreasing MMP-9 and MMP-9/TIMP-1 ratio suggesting an anti-inflammatory effect for MnTBAP. IH decreased MMP-2 with no ameliorating effect by MnTBAP. Our data demonstrate that brief, repeated intermittent hypoxia during hyperoxia can alter biomarkers responsible for normal microvascular and alveolar development. In addition to prevention of hypoxic events, the use of antioxidants needs to be explored as a possible therapeutic intervention in neonates at risk for the development of oxidative lung injury.
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PMID:Effects of a superoxide dismutase mimetic on biomarkers of lung angiogenesis and alveolarization during hyperoxia with intermittent hypoxia. 2409 57