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)

We have previously shown that administration of the antioxidant butylated hydroxytoluene (BHT) to mice produces lung damage that can be markedly potentiated by hyperoxia resulting in pulmonary fibrosis. In the present studies using this model, we show that: (1) in animals treated with BHT-O2, prednisolone given for 12 successive days does prevent excessive collagen accumulation provided lung collagen is measured immediately after terminating steroid therapy, whereas a rebound effect occurs later on; (2) limitation of steroid treatment to the first 6 days after acute lung injury enhances accumulation of collagen, whereas steroids given later, on Days 7 through 12, have an alleviating effect; (3) indomethacin under the conditions described is not an effective treatment.
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PMID:Potentiation of butylated-hydroxytoluene-induced acute lung damage by oxygen. Effects of prednisolone and indomethacin. 662 43

An early proliferative response of mesothelial and subpleural cells has been reported in animals after inhalation or intratracheal (I.T.) instillation to the lung of long asbestos fibers, which also induce pulmonary fibrosis. To determine whether this cell proliferation is directly related to asbestos exposure or is a nonspecific response to injury, we examined [3H]thymidine (3HT) uptake by cells at the pleura after exposing mice to 5 days of hyperoxia, to intravenous (I.V.) (3 mg) or I.T. (0.15 mg) bleomycin, to I.T. (1 mg) silica, and to I.T. (0.1 mg) crocidolite asbestos of mixed length. All exposures induced acute lung injury, as shown by high levels of protein in lavage fluid. After hyperoxia, the percentage of total lung cells labeled by 3HT in autoradiographs was high for only a few days, as repair took place with no increase in fibroblast growth and no subsequent development of fibrosis. Particle or bleomycin exposure induced a prolonged increase in 3HT uptake with enhanced fibroblast labeling over a 4- to 6-wk period. In each case, labeled subpleural cells, mainly fibroblasts, increased up to 10-fold in the first 2 to 4 wk. At the same time, 3HT uptake by mesothelial cells ranged from 1.4 to 3% compared with almost zero in controls and in oxygen-exposed mice after a few days upon return to air. These results indicate that mesothelial and subpleural cell proliferation occurs after various types of injury to the lung. The close temporal association between 3HT uptake by mesothelial cells and fibroblasts during the reparative phase suggests that mesothelial cells may respond to the same cytokines that trigger interstitial fibrosis.
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PMID:Mesothelial cell proliferation: a nonspecific response to lung injury associated with fibrosis. 750 11

Studies have implicated active oxygen species (AOS) in the pathogenesis of various lung diseases. Many chemical and physical agents in the environment are potent generators of AOS, including ozone, hyperoxia, mineral dusts, paraquat, etc. These agents produce AOS by different mechanisms, but frequently the lung is the primary target of toxicity, and exposure results in damage to lung tissue to varying degrees. The lung has developed defenses to AOS-mediated damage, which include antioxidant enzymes, the superoxide dismutases [copper-zinc (CuZnSOD) and manganese-containing (MnSOD)], catalase, and glutathione peroxidase (GPX). In this review, antioxidant defenses to environmental stresses in the lung as well as in isolated pulmonary cells following exposure to a number of different oxidants, are summarized. Each oxidant appears to induce a different pattern of antioxidant enzyme response in the lung, although some common trends, i.e., induction of MnSOD following oxidants inducing inflammation or pulmonary fibrosis, in responses to oxidants occur. Responses may vary between the different cell types in the lung as a function of cell-cycle or other factors. Increases in MnSOD mRNA or immunoreactive protein in response to certain oxidants may serve as a biomarker of AOS-mediated damage in the lung.
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PMID:Regulation of antioxidant enzymes in lung after oxidant injury. 752 4

Sublethal exposure to hyperoxia in vivo induces oxidative damage that leads to destruction of the pulmonary endothelium, pleural effusion, and eventual pulmonary fibrosis. DNA is a potential target for reactive oxygen species in this system; the principle types of damage to DNA during hyperoxia are single-strand breaks and oxidant damage to bases. Poly(ADP-ribosyl)ation, a posttranslational modification of nuclear proteins, is stimulated by strand breaks in DNA and is required for effective repair of many types of DNA lesions. In this study we have measured lung tissue NAD+ and poly(ADP-ribose) concentrations in response to hyperoxia and niacin deficiency in rats. Male weaning Fischer-344 rats consumed niacin-deficient (ND) or niacin-replete pair-fed (PF) diets for 7 d. Rats from each diet group (n = 6) were then housed in normobaric 85% oxygen for 5 d. Normoxic controls were maintained in air. Hyperoxia increased lung poly(ADP-ribose) concentration by 35% in PF rats, but did not significantly increase levels in ND rats. Niacin deficiency decreased lung NAD+ in normoxic rats, but surprisingly, this deficit was partially reversed by hyperoxia. Liver NAD+ levels increased by 21% during hyperoxia in both diet groups. Heart and kidney NAD+ were unaffected by hyperoxia. Blood was the only tissue measured in which NAD+ was decreased by hyperoxia. Dietary treatment did not affect the increase in the lung wt/b. wt. ratio resulting from hyperoxia. This is the first report in the literature of lung tissue poly(ADP-ribose) measurement. Results show that hyperoxia causes a marked increase in lung poly (ADP-ribose) concentration, but also suggest an adaptation of whole-animal NAD+ metabolism to hyperoxia during niacin deficiency.
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PMID:Lung poly(ADP-ribose) and NAD+ concentrations during hyperoxia and niacin deficiency in the Fischer-344 rat. 872 36

Fibroblast proliferation and extracellular matrix accumulation are crucial in the pathogenesis of lung fibrosis. Fibroblast growth factor (FGF)-1 participates in both processes, but its role in lung fibrogenesis has not been evaluated. We analyzed the expression of FGF-1 and of FGF receptor (FGFR) in a model of lung fibrosis induced in rats with paraquat plus hyperoxia. Experimental and control animals were killed at 48 h and 2, 4, and 8 wk, and the lungs were studied by in situ hybridization, immunohistochemistry, and Northern blot. In normal lungs, scattered macrophages contained FGF-1. In contrast, at all times examined, the injured lungs exhibited FGF-1 transcript and the immunoreactive protein, mainly in alveolar epithelial cells and macrophages. In advanced fibrotic lesions, fibroblasts also appeared stained. Northern blot corroborated the upregulation of FGF-1 mRNA. FGFR was not observed in normal lungs, whereas it was strongly increased in the damaged lungs and was virtually immunolocalized in the same cell types as the corresponding ligand. These findings suggest that FGF-1 and FGFR are actively synthesized during the development of pulmonary fibrosis.
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PMID:Upregulation of acidic fibroblast growth factor during development of experimental lung fibrosis. 927 59

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

We used a prematurely born rat/hyperoxia model of bronchopulmonary dysplasia (BPD) to test whether keratinocyte growth factor (KGF) treatment would protect against the development of several serious (cardio-)pulmonary complications of early life exposure to hyperoxia. KGF significantly protected against hyperoxic lethality (13-day survival rate = 50/64 (78%) for the O(2)-KGF vs. 29/66 (44%) for the O(2)-saline group, p < 0.001). Although KGF failed to protect against hyperoxic inhibition of normal postnatal alveoli formation and early pulmonary fibrosis, KGF consistently had a significant protective/preventive effect against the development of pulmonary hypertension during hyperoxia as reflected in comparative right ventricular hypertrophy: mean increase = +35% above normal for the O(2)-saline group vs. +3% for the O(2)-KGF premature rat group (p < 0.01).
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PMID:Protective effect of keratinocyte growth factor against lung abnormalities associated with hyperoxia in prematurely born rats. 1274 56

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

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

Nitrosamines are carcinogens formed in the mammalian organism from amine precursors contained in food, beverages, cosmetics and drugs. The potent carcinogen, NNK, and the weaker carcinogen, NNN, are nitrosamines formed from nicotine. Metabolites of the nitrosamines react with DNA to form adducts responsible for genotoxic effects. We have identified NNK as a high affinity agonist for the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) whereas NNN bound with high affinity to epibatidine-sensitive nAChRs. Diethylnitrosamine (DEN) bound to both receptors but with lower affinity. High levels of the alpha7nAChR were expressed in human small cell lung cancer (SCLC) cell lines and in hamster pulmonary neuroendocrine cells (PNECs), which serve as a model for the cell of origin of human SCLC. Exposure of SCLC or PNECs to NNK or nicotine increased expression of the alpha7nAChR and caused influx of Ca(2+), activation of PKC, Raf-1, ERK1/2, and c-myc, resulting in the stimulation of cell proliferation. Signaling via the alpha7nAChR was enhanced when cells were maintained in an environment of 10-15% CO(2) similar to that in the diseased lung. Hamsters with hyperoxia-induced pulmonary fibrosis developed neuroendocrine lung carcinomas similar to human SCLC when treated with NNK, DEN, or nicotine. The development of the NNK-induced tumors was prevented by green tea or theophylline. The beta-adrenergic receptor agonist, isoproterenol or theophylline blocked NNK-induced cell proliferation in vitro. NNK and nicotine-induced hyperactivity of the alpha7nAChR/RAF/ERK1/2 pathway thus appears to play a crucial role in the development of SCLC in smokers and could be targeted for cancer prevention.
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PMID:Nitrosamines as nicotinic receptor ligands. 1745 20


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