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Query: UMLS:C0242706 (hyperoxia)
 5,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To evaluate the regulation of endothelial cell Cu,Zn-SOD, we have exposed bovine pulmonary artery endothelial cells in culture to hyperoxia and hypoxia, second messengers or related agonists, hormones, free radical generating systems, endotoxin, and cytokines and have measured Cu,Zn-SOD protein of these cells by an ELISA developed in our laboratory. Control preconfluent and confluent cells in room air contained 196 +/- 18 ng Cu,Zn-SOD/10(6) cells. A23187 (0.33 microM), forskolin (10 microM), isobutylmethylxanthine (0.1 mM), dexamethasone (1 microM), triiodothyronine (1 microM) and retinoic acid (1 microM) failed to alter this level of Cu,Zn-SOD. Exposure to anoxia and hyperoxia both elevated the level approximately 1.5-2.0-fold over 20% oxygen-exposed controls at 48-72 hr. Similarly, exposures to glucose oxidase (0.0075 units/ml), menadione (12.5 microM), xanthine-xanthine oxidase (10 microM, 0.03 units/ml) and H2O2 (0.0005%) increased the level up to two-threefold over controls at 24-48 hr. Lipopolysaccharide, TGF beta 1, TNF alpha, and Il-1 also increased levels of cellular Cu,Zn-SOD, but only in proliferating cells. Il-2, Il-4, interferon-gamma, and GM-CSF had no effect on Cu,Zn-SOD. All treatments that elevated SOD resulted in inhibition of cellular growth, but decreased growth of cells at confluence alone was not associated with increased Cu,Zn-SOD. We propose from these studies that Cu,Zn-SOD of endothelial cells is not under conventional second messenger or hormonal regulation, but that up-regulation of the enzyme is associated with (and perhaps stimulated by) free-radical or oxidant production that also may be influenced by availability of certain cytokines under replicating conditions.
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PMID:Regulation of Cu,Zn-superoxide dismutase in bovine pulmonary artery endothelial cells. 133 80

To form a large diffusible interface capable of conducting respiratory gases to and from the circulation, the lung must undergo extensive cell proliferation, branching morphogenesis, and alveolar saccule formation, to generate sufficient surface area. In addition, the cells must differentiate into at least 40 distinct lung cell lineages. Specific transcriptional factors, peptide growth factor receptor-mediated signaling pathways, extracellular matrix components, and integrin-signaling pathways interact to direct lung morphogenesis and lung cell lineage differentiation. Branching mutants of the respiratory tracheae in Drosophila have identified several functionally conserved genes in the fibroblast growth factor signaling pathway that also regulate pulmonary organogenesis in mice and probably also in man. Key transcriptional factors including Nkx2.1, hepatocyte nuclear factor family forkhead homologues, GATA family zinc finger factors, pou and homeodomain proteins, as well as basic helix-loop-helix factors, serve as master genes to integrate the developmental genetic instruction of lung morphogenesis and cell lineage determination. Lung mesenchyme serves as a 'compleat' inducer of lung morphogenesis by secreting soluble peptide growth factors. In general, peptide growth factors signaling through cognate receptors with tyrosine kinase intracellular signaling domains such as epidermal growth factor receptor, fibroblast growth factor receptors, hepatocyte growth factor/scatter factor receptor, c-met, insulin-like growth factor receptor, and platelet-derived growth factor receptor, stimulate lung morphogenesis, while the cognate receptors with serine/threonine kinase intracellular signaling domains, such as the transforming growth factor-beta receptor family are inhibitory. The extracellular matrix also plays a key role in determining branching morphogenesis. Pulmonary neuroendocrine (PNE) cells differentiate earliest in gestation among lung epithelial cells. PNE cells are principally derived from endoderm and not neural crest. PNE cells have been proposed to function as airway chemoreceptors, while PNE cell secretory granules contain many bioactive substances such as GRP which may direct proliferation of adjacent epithelial cells. Mammalian achaete-schute homolog-1 null mutant mice do not develop PNE cells. Candidate molecular switches in the transition from a quiescent to a proliferative alveolar epithelial cell (AEC) phenotype and back again following acute hyperoxia, include autocrine peptide growth factor signaling pathways and cell cycle regulatory elements. AEC type 2 also appear capable of reversible transdifferentiation into AEC type 1 and intermediate phenotypes in response to cues from extracellular matrix and cell shape, as well as soluble factors. Evidence for expression of telomerase by alveolar epithelial stem cells, which correlates with self-renewal potential, is now beginning to emerge. Lung regeneration following lobectomy in juvenile rodents is associated with co-ordinated cell proliferation, re-expression of elastin and formation of alveoli. Retinoic acid has recently shown promise as a stimulator of alveolization in juvenile rats. Our future goal is to devise new rational and gene therapeutic strategies to stimulating lung growth and maturation, ameliorating lung injury, augmenting lung repair, and inducing lung regeneration. The ideal agent or agents would therefore mimic the instructive role of lung mesenchyme, correctly inducing the temporospatial pattern of lung cell lineages necessary to restore pulmonary gas diffusing capacity.
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PMID:Commitment and differentiation of lung cell lineages. 1039 10

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

Hyperoxic exposure of the developing lung leads to characteristic peribronchial and mesenchymal fibroproliferative changes. We hypothesize that O2-induced changes in the neonatal lung are mediated by Insulin-like growth factor 1 (IGF-1) and IGF-1 receptor (IGF-1R). Lung explant cultures were prepared from 3-day-old neonatal rat pups and exposed to room air or 95% O2 for 72 h. Western blots and immunohistochemistry were used to determine if hyperoxia stimulated IGF-1 and IGF-1R, and to identify the cell types involved. Retinoic acid was used to learn if this would inhibit oxygen-induced cell proliferation. Hyperoxia induced a significant increase in thymidine incorporation (control, 54 +/- 9; hyperoxia, 254 +/- 24 dpm/nM DNA; mean +/- SEM; N = 3; P < 0.05). This was inhibited by 5 x 10(-5) M RA (149 +/- 18 dpm/nM DNA; P < 0.05) and by anti-IGF-1 antibody (115 +/- 25 dpm/nM DNA; P < 0.05; N = 3). BrdU labeling in the mesenchymal cells was significantly increased in mesenchymal cells after exposure to oxygen (91% higher than the room air control) but not in epithelial cells. This increase was inhibited in the presence of retinoic acid. Western blots showed IGF-1 protein was increased after 72 h of O2 exposure compared to room air exposure (57 +/- 7 compared to 32 +/- 5 densitometric units; P < 0.05; N = 3). The increase was inhibited when the cultures were exposed to 95% O2 in the presence of anti-IGF-1 antibody (28 +/- 4; P < 0.05; N = 3). IGF-1 protein decreased in the presence of retinoic acid after oxygen exposure but not in room air. Immunostaining of O2-exposed lung showed IGF-1 was most abundant in airway and alveolar epithelial cells. We conclude that hyperoxia increases cell proliferation by stimulating IGF-1 in the neonatal rat lung. Interaction of IGF-1 and IGF-1R is an important cell-cell communication mechanism in the developmental and repair processes of hyperoxic neonatal lung injury.
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PMID:Regulation of cell proliferation by insulin-like growth factor 1 in hyperoxia-exposed neonatal rat lung. 1191 39

A heparin-binding growth factor, midkine, is the product of a retinoic acid-responsive gene. Since retinol plays critical roles in lung development and treatment of bronchopulmonary dysplasia, and midkine has been implicated in the maturation of lung explants and in cytoprotection, we herein examined midkine expression during postnatal development of the lungs and hyperoxic lung injury. Midkine protein transiently increased to a maximum level at around 4 days postnatal. Immunohistochemistry revealed that the amounts of midkine increased in resident alveolar cells, but not in smooth muscle cells or the large airway epithelium. If neonatal mice were exposed to >95% oxygen, lung development was impaired and midkine expression was suppressed. In contrast, when adult mouse lungs as well as in vitro cultured lung adenocarcinoma cells were exposed to hyperoxia, midkine expression was not affected. Furthermore, a pronounced induction of midkine by retinoic acid was observed in neonatal lungs. The results indicate that midkine expression is associated with postnatal lung development, but not necessarily with hyperoxic cell damage.
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PMID:Midkine expression is associated with postnatal development of the lungs. 1220 52

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

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

Oxidative stress is considered important for the pathogenesis of Alzheimer disease (AD), which is characterized by the formation of senile plaques rich in amyloid beta-protein (Abeta). Abeta cytotoxicity has been found dependent on lysosomes, which are abundant in AD neurons and are shown to partially co-localize with Abeta. To determine whether oxidative stress has any influence on the relationship between lysosomes and Abeta1-42 (the most toxic form of Abeta), we studied the effect of hyperoxia (40% versus 8% ambient oxygen) on the intracellular localization of Abeta1-42 (assessed by immunocytochemistry) in retinoic acid differentiated SH-SY5Y neuroblastoma cells maintained in serum-free OptiMEM medium. In control cells, Abeta1-42 was mainly localized to small non-lysosomal cytoplasmic granules. Only occasionally Abeta1-42 was found in large (over 1 microm) lysosomal-associated membrane protein 2 positive vacuoles, devoid of the early endosomal marker rab5. These large Abeta1-42 -containing lysosomes were not detectable in the presence of serum (known to suppress autophagy), while their number increased dramatically (up to 24-fold) after exposure of cells to hyperoxia during 5 days. Activation of autophagy by hyperoxia was confirmed by transmission electron microscopy. Furthermore, an inhibitor of autophagic sequestration 3-methyladenine prevented the accumulation of Abeta1-42 -positive lysosomes due to hyperoxia. In parallel experiments, intralysosomal accumulation of Abeta1-40 following oxidative stress has been found as well. The results suggest that Abeta can be autophagocytosed and its accumulation within neuronal lysosomes is enhanced by oxidative stress.
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PMID:Autophagy of amyloid beta-protein in differentiated neuroblastoma cells exposed to oxidative stress. 1629 50

Supplemental oxygen is frequently used in the treatment of infants having pulmonary insufficiency, but prolonged hyperoxia may contribute to the development of bronchopulmonary dysplasia in these infants. Cytochrome P4501A enzymes have been implicated in hyperoxic lung injury. Retinoic acid (RA) plays a key role in lung development. Here, we tested the hypotheses that newborn rats exposed to a combination of RA and hyperoxia would be less susceptible to lung injury than those exposed to hyperoxia only and that modulation of CYP1A enzymes by RA contribute to the beneficial effects of RA against hyperoxic lung injury. Newborn rats exposed to hyperoxia for 7 days showed higher lung weight/body weight ratios compared with those exposed to RA + hyperoxia. Hyperoxia for 7 days also caused a significant increase in hepatic and pulmonary CYP1A1/1A2 expression compared with air-breathing controls. RA + hyperoxia treatment lowered the expression of these genes. Seven to 30 days after withdrawal of hyperoxia, the animals showed marked induction of hepatic and pulmonary CYP1A1/1A2 expression, but animals that had been given RA + hyperoxia displayed lower expression of these enzymes. On postnatal days 22 or 38, the hyperoxic animals displayed retarded lung alveolarization; however, the RA + hyperoxia-exposed animals showed improved alveolarization. The improved alveolarization in animals given RA + hyperoxia, in conjunction with the attenuation of CYP1A1 and 1A2 expression in these animals, suggests that this phenomenon may play a role in the beneficial effects of RA.
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PMID:Attenuation of oxygen-induced abnormal lung maturation in rats by retinoic acid: possible role of cytochrome P4501A enzymes. 1649 85

To investigate the protective effect of retinoic acid (RA) on hyperoxic lung injury and the role of RA as a modulator on mitogen-activated protein kinases (MAPKs), gastation 21 d Sprague-Dawley (SD) fetuses (term = 22 d) were delivered by hysterotomy. Within 12-24 h of birth, premature rat pups were randomly divided into 4 groups (n=12 each): air-exposed control group (group I); hyperoxia-exposed group (group II), air-exposed plus RA group (group III), hyperoxia-exposed plus RA group (group IV). Group I, III were kept in room air, and group II, IV were placed in 85 % oxygen. The pups in groups III and IV were intraperitoneally injected with RA (500 microg/kg every day). All lung tissues of premature rat pups were collected at the 4th day after birth. Terminal transferase d-UTP nick end labeling (TUNEL) staining was used for the detection of cell apoptosis. The expression of PCNA was immunohistochemically detected. Western blot analysis was employed for the determination of phosphorylated and total nonphosphorylated ERKs, JNKs or p38. Our results showed that lungs from the pups exposed to hyperoxia for 4 d exhibited TUNEL-positive nuclei increased markedly throughout the parenchyma (P<0.01), and decreased significantly after RA treatment (P<0.01). The index of PCNA-positive cells was significantly decreased (P<0.01), and was significantly increased by RA treatment (P<0.01). The air-space size was significantly enlarged, secondary crests were markedly decreased in hyperoxia-exposed animals. RA treatment improved lung air spaces and secondary crests in air-exposed pups, but had no effect on hyperoxia-exposure pups. Western blotting showed that the amounts of JNK, p38 and ERK proteins in hyperoxia-exposure or RA-treated lung tissues were same as those in untreated lung tissues (P>0.05), whereas activation of these MAPKs was markedly altered by hyperoxia and RA. After hyperoxia exposure, p-ERK1/2, p-JNK1/2 and p-p38 were dramatically increased (P<0.01), whereas p-JNK1/2 and p-p38 were markedly declined and p-ERK1/2 was further elevated by RA treatment (P<0.01). It is concluded that RA could decrease cell apoptosis and stimulate cell proliferation under hyperoxic condition. The protection of RA on hyperoxia-induced lung injury was related to the regulation of MAP kinase activation.
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PMID:Mechanism of retinoic acid and mitogen-activated protein kinases regulating hyperoxia lung injury. 1685 Jul 40


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