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)

Impaired septal formation and decreased alveolarization are often caused by hyperoxic injury to the developing lung and are characteristic features of bronchopulmonary dysplasia. Dexamethasone, frequently administered to infants during oxygen exposure, also inhibits septal formation in the newborn lung. Vitamin A administration reduces the incidence of bronchopulmonary dysplasia in vitamin A-deficient premature infants, and retinoic acid improves alveolarization in newborn rats treated with dexamethasone, indicating that retinoic acid may be useful in preventing hyperoxia-induced impaired septation in bronchopulmonary dysplasia. To investigate whether treatment with retinoic acid during exposure to hyperoxia would improve septal formation, newborn rats exposed to > or =90% O(2) from d 3 of life to d 14 were treated with retinoic acid (d 3-13 of life) and/or dexamethasone (d 4-13 of life). In contrast with the effects of retinoic acid on dexamethasone-induced inhibition of alveolarization, we found that retinoic acid did not improve septal formation or decrease airspace size in animals exposed to hyperoxia alone or to hyperoxia plus dexamethasone. Retinoic acid did, however, increase collagen in airspace walls as demonstrated by staining and immunohistochemistry. There was no increase in procollagen mRNA by Northern hybridization analysis, indicating that retinoic acid-associated increases in lung collagen are likely due to posttranscriptional regulation. There was a trend toward increased survival in hyperoxia in animals treated with retinoic acid to the extent that combined therapy with retinoic acid and dexamethasone resulted in the greatest improvement in animal survival. These results suggest that although retinoic acid may be of benefit in hyperoxia-induced lung injury and may have important effects on lung matrix, it does not prevent impairment of septation or induce alveolar formation during exposure to hyperoxia.
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PMID:Effects of retinoic acid on airspace development and lung collagen in hyperoxia-exposed newborn rats. 1100 32

Nitric oxide (NO), a pro-oxidant gas, is used with hyperoxia (O(2)) to treat neonatal pulmonary hypertension and recently bronchopulmonary dysplasia, but great concerns remain regarding NO's potential toxicity. Based on reports that exposure to oxidant gases results in pulmonary extracellular matrix injury associated with elevated lavage fluid levels of extracellular matrix components, we hypothesized that inhaled NO with or without hyperoxia will have the same effect. We measured alveolar septal width, lung collagen content, lavage fluid hydroxyproline, hyaluronan and laminin levels in neonatal piglets after 5 days' exposure to room air (RA), RA + 50 ppm NO (RA + NO), O(2) (FiO(2) > 0.96) or O(2) + NO. Matrix metalloproteinase (MMP) activity and MMP-2 mRNA were also measured. In recovery experiments, we measured lung collagen content in piglets exposed to RA + NO or O(2) + NO and then allowed to recover for 3 days. The results show that lung collagen increased 4-fold in the RA + NO piglets, the O(2) and O(2) + NO groups had only a 2-fold elevation relative to RA controls. Unlike the RA + NO piglets, the O(2) and O(2) + NO groups had more than 20-fold elevation in lung lavage fluid hydroxyproline compared to the RA group. O(2) and O(2) + NO also had increased lung MMP activity, extravascular water, and lavage fluid proteins. MMP-2 mRNA levels were unchanged. After 3 days' recovery in room air, the RA + NO groups' lung collagen had declined from 4-fold to 2-fold above the RA group values. The O(2) + NO group did not decline. Alveolar septal width increased significantly only in the O(2) and O(2) + NO groups. We conclude that 5 days' exposure to NO does not result in pulmonary matrix degradation but instead significantly increases lung collagen content. This effect appears potentially reversible. In contrast, hyperoxia exposure with or without NO results in pulmonary matrix degradation and increased lung collagen content. The observation that NO increased lung collagen content represents a new finding and suggests NO could potentially induce pulmonary fibrosis.
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PMID:High-dose inhaled nitric oxide and hyperoxia increases lung collagen accumulation in piglets. 1104 69

Chronic hypoxia causes pulmonary hypertension, the mechanism of which includes altered collagen metabolism in the pulmonary vascular wall. This chronic hypoxic pulmonary hypertension is gradually reversible upon reoxygenation. The return to air after the adjustment to chronic hypoxia resembles in some aspects a hyperoxic stimulus and we hypothesize that the changes of extracellular matrix proteins in peripheral pulmonary arteries may be similar. Therefore, we studied the exposure to moderate chronic hyperoxia (FiO2 = 0.35, 3 weeks) in rats and compared its effects on the rat pulmonary vasculature to the effects of recovery (3 weeks) from chronic hypoxia (FiO2 = 0.1, 3 weeks). Chronically hypoxic rats had pulmonary hypertension (Pap = 26 +/- 3 mm Hg, controls 16 +/- 1 mm Hg) and right ventricular hypertrophy. Pulmonary arterial blood pressure and right ventricle weight normalized after 3 weeks of recovery in air (Pap = 19 +/- 1 mm Hg). The rats exposed to moderate chronic hyperoxia also did not have pulmonary hypertension (Pap = 18 +/- 1 mm Hg, controls 17 +/- 1 mm Hg). Collagenous proteins isolated from the peripheral pulmonary arteries (100-300 microm) were studied using polyacrylamide gel electrophoresis. A dominant low molecular weight peptide (approx. 76 kD) was found in hypoxic rats. The proportion of this peptide decreases significantly in the course of recovery in air. In addition, another larger peptide doublet was found in rats recovering from chronic hypoxia. It was localized in polyacrylamide gels close to the zone of alpha2 chain of collagen type I. It was bound to anticollagen type I antibodies. An identically localized peptide was found in rats exposed to moderate chronic hyperoxia. The apparent molecular weight of this collagen fraction suggests that it is a product of collagen type I cleavage by a rodent-type interstitial collagenase (MMP-13). We conclude that chronic moderate hyperoxia and recovery from chronic hypoxia have a similar effect on collagenous proteins of the peripheral pulmonary arterial wall.
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PMID:Hyperoxia and recovery from hypoxia alter collagen in peripheral pulmonary arteries similarly. 1152 43

Exposure of the newborn lung to hyperoxia is associated with impaired alveolar development. In newborn rats exposed to hyperoxia and studied at day 14 of life, retinoic acid (RA) treatment improved survival and increased lung collagen but did not improve alveolar development. To determine whether RA treatment during exposure to hyperoxia results in late improvement in alveolarization, we treated newborn rats with RA and hyperoxia from day 3 to day 14 and then weaned O2 to room air by day 20, and studied the animals on day 42. O2-exposed animals had larger mean lung volumes, larger alveoli, and decreased gas-exchange tissue relative to air-exposed animals, whereas RA-treated O2-exposed animals were not statistically different from air-exposed controls. Relative to control animals, elastin staining at day 14 was decreased in hyperoxia-exposed lung independent of RA treatment, and, at day 42, elastin staining was similar in all treatment groups. At day 14, elastin gene expression was similar in all treatment groups, whereas at day 42 lung previously exposed to hyperoxia showed increased elastin signal independent of RA treatment. These results indicate that RA treatment during hyperoxia exposure promotes septal formation without evidence of effects on elastin gene expression after 4 wk of recovery.
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PMID:Retinoic acid attenuates O2-induced inhibition of lung septation. 1237 50

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

We examined the effects of prolonged hyperoxia (75% O(2)) on lung structure and collagen metabolism in the subacute phase of lung injury induced by continuous infusion of endotoxin (LPS) in a rat model. Experimental groups included control, endotoxin alone, endotoxin plus hyperoxia, and hyperoxia alone. Endotoxin-treated rats received a bolus of LPS (10 mg/kg i.v.) followed by 500 microg.kg(-1).day(-1) in continuous infusion for 10 days. The bronchoalveolar lavage (BAL) fluid/plasma albumin concentration ratio, an index of capillary permeability, and neutrophil and macrophage counts in BAL fluid were highest in the endotoxin plus hyperoxia group. On pathological examination, prolonged hyperoxia exacerbated destruction of the alveolar wall and caused most prominent emphysematous changes in the endotoxin plus hyperoxia group. Lung tissue hydroxyproline concentration was significantly decreased in the hyperoxia group and increased in the endotoxin group. The latent forms of MMP-2 and MMP-9 increased in BAL fluid of the endotoxin- and/or hyperoxia-treated groups, whereas the activities of collagenase and gelatinase, and the active form of MMP-2 were all increased in the hyperoxia-treated groups. Added to endotoxin, prolonged hyperoxia degraded collagen, the major structural component of basement membranes, and caused emphysematous changes associated with activation of collagenase and MMP-2. Our observations suggest that, in the subacute phase of endotoxin-induced lung injury, prolonged hyperoxia causes pulmonary emphysematous changes with persistent injury to the alveolar capillary barrier. Collagenase and MMP-2 activated by hyperoxia, together with MMP-9, may play prominent roles in disruption of the alveolar basement membranes and degradation of collagen lining the alveolar walls.
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PMID:Hyperoxia-induced emphysematous changes in subacute phase of endotoxin-induced lung injury in rats. 1500 27

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

Retinoids play an important role in lung development and repair. We showed that retinoic acid (RA) inhibits O(2)-induced fibroblast proliferation in rat lung explants. IGF-1, which enhances the proliferation of human fetal lung fibroblasts and stimulates collagen production during lung injury, has an important role in the lung injury/repair process. Interactions of IGF-1 with its receptor are modulated by IGF-binding proteins IGFBPs. We hypothesized that RA alters IGFBP-2 and -3 in hyperoxia-exposed neonatal lung and alters collagen production. Neonatal rat lungs were cultured in room air or 95% O(2) and 5% CO(2) for 3 d with or without RA. IGFBP-2 and -3 were measured both in culture medium and in lung tissue. Type I collagen and procollagen propeptide were analyzed in the lung tissue. Hyperoxia induced an increase in type I collagen that was significantly inhibited in the presence of RA. IGFBP-2 and IGFBP-3 in the lungs were decreased in hyperoxia but significantly increased in hyperoxia plus RA. In the culture medium, IGFBP-2 and -3 were not increased with hyperoxia but significantly increased in the presence of RA plus hyperoxia. There was no increase in IGFBP-3 RNA transcript after RA treatment in either room air or O(2) exposure. In conclusion, RA modulates the secreted IGFBP-2 and -3 during O(2) exposure and inhibits the increase in collagen that occurs during lung injury. We speculate that RA protects against O(2)-induced neonatal lung injury through modulation of the IGFBPs.
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PMID:Modulation of IGF-binding protein-2 and -3 in hyperoxic injury in developing rat lung. 1605 36

Resolution of alveolar epithelial/capillary membrane damage after acute lung injury requires coordinated and effective tissue repair to reestablish a functional alveolar epithelial/capillary membrane barrier. We hypothesized that signaling pathways important in lung alveolar bud ontogeny are activated in the recovery and remodeling phases after profound oxidant stress lung injury in a murine model. To test this, we characterized the expression of noncanonical beta-catenin pathway proteins E-cadherin, integrin-linked kinase-1, and beta-catenin in mice undergoing normoxic recovery after exposure to butylated hydroxytoluene (BHT, ionol) and concomitant sublethal (75% O2) hyperoxia. Mice developed early acute lung injury with subsequent inflammation, collagen deposition, interstitial cellular proliferation, and lung architectural distortion. Reduced E-cadherin expression after 6 d of BHT and hyperoxia was accompanied by enhanced expression and nuclear localization of beta-catenin and increased integrin-linked kinase-1 expression during subsequent normoxic recovery. This resulted in increased expression of the cotranscriptional regulators TCF-1 and -3 and cyclin D1. Proliferation of murine lung epithelial-12 cells in vitro after 8 h of treatment with BHT quinone-methide and hyperoxia and 48 h of normoxic recovery was enhanced 2.7-fold compared with vehicle-treated control mice at the same time point. BHT/hyperoxia-exposed mice treated with the pan-caspase inhibitor z-ASP had increased acute lung injury and reduced survival despite the presence of TUNEL-positive cells, suggesting enhanced lung cell necrosis. Beta-catenin expression was reduced in z-ASP-co-treated lungs after BHT/hyperoxia. The noncanonical cadherin-beta-catenin axis is associated with fibroproliferative repair after BHT/hyperoxia exposure and may regulate epithelial proliferation and lung matrix remodeling and repair in response to lung injury.
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PMID:Beta-catenin in the fibroproliferative response to acute lung injury. 1627 59

The objective of the present study was to examine the impact of early stages of lung injury on ventilatory control by hypoxia and hypercapnia. Lung injury was induced with intratracheal instillation of bleomycin (BM; 1 unit) in adult, male Sprague-Dawley rats. Control animals underwent sham surgery with saline instillation. Five days after the injections, lung injury was present in BM-treated animals as evidenced by increased neutrophils and protein levels in bronchoalveolar lavage fluid, as well as by changes in lung histology and computed tomography images. There was no evidence of pulmonary fibrosis, as indicated by lung collagen content. Basal core body temperature, arterial Po(2), and arterial Pco(2) were comparable between both groups of animals. Ventilatory responses to hypoxia (12% O(2)) and hypercapnia (7% CO(2)) were measured by whole body plethysmography in unanesthetized animals. Baseline respiratory rate and the hypoxic ventilatory response were significantly higher in BM-injected compared with control animals (P = 0.003), whereas hypercapnic ventilatory response was not statistically different. In anesthetized, spontaneously breathing animals, response to brief hyperoxia (Dejours' test, an index of peripheral chemoreceptor sensitivity) and neural hypoxic ventilatory response were augmented in BM-exposed relative to control animals, as measured by diaphragmatic electromyelograms. The enhanced hypoxic sensitivity persisted following bilateral vagotomy, but was abolished by bilateral carotid sinus nerve transection. These data demonstrate that afferent sensory input from the carotid body contributes to a selective enhancement of hypoxic ventilatory drive in early lung injury in the absence of pulmonary fibrosis and arterial hypoxemia.
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PMID:Acute lung injury augments hypoxic ventilatory response in the absence of systemic hypoxemia. 1688 52


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