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

The pulmonary endothelium is known to be sensitive to oxidant injury, including that of hyperoxia. Similar to effects of exposure to 80-95% O2, porcine platelet transforming growth factor (TGF)-beta 1 at concentrations of greater than or equal to 0.3 ng/ml inhibited proliferation and caused enlargement of bovine pulmonary artery endothelial cells after 24 h of incubation in room air. Uptake of [3H]thymidine, but not of [3H]deoxycytidine, was suppressed by both hyperoxia and TGF-beta 1. The cellular enlargement produced by TGF-beta 1 in room air was attenuated in the presence of anoxia, indicating a need for O2 for TGF-beta 1 to have an effect on cell size. In the presence of 20 microM FeCl3, both TGF-beta 1 and 80% O2 produced marked cellular desquamation from culture dishes. The antioxidants dimethyl sulfoxide and vitamin E partially counteracted the growth inhibitory effect of TGF-beta 1 on endothelial cells. In contrast to its effect on endothelial cells, TGF-beta 1 only moderately altered size and proliferation of smooth muscle cells from the same pulmonary vessels. Uptake of [3H]thymidine by smooth muscle cells was uninfluenced in 48 h by TGF-beta 1, and little, if any, desquamation of these cells occurred with TGF-beta 1 in the presence of 20 microM FeCl3. We propose from these experiments that TGF-beta 1 may produce an oxidant effect on vascular endothelium that is capable of causing injury to this tissue.
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PMID:TGF-beta 1 produces a "prooxidant" effect on bovine pulmonary artery endothelial cells in culture. 192 58

The epithelium of the pulmonary alveolus is a major target for oxidant injury, and its proper repair following injury is dependent on the proliferative response of its stem cells, the type 2 cells. We have recently shown that hyperoxia arrests proliferation of an immortalized type 2 cell line (SV40T-T2) and that expression of several growth-related genes, normally induced near the G1/S and boundary was altered with a block of translation of their mRNA. In the present study we examined the possible role of the insulin-like growth factor (IGF) system and of transforming growth factor-beta 1 (TGF-beta 1) in the arrest of proliferation induced by hyperoxia. We show that IGF-binding protein 2 (IGFBP-2) accumulates to higher levels in culture medium of SV40T-T2 cells whose proliferation has been arrested by hyperoxia. This proliferation arrest is associated with increased expression of IGFBP-2 mRNA and with induction of type 2 IGF receptor and IGF-II mRNAs. When O2-arrested cells were allowed to resume proliferation in normoxia, the level of expression of these genes rapidly decreased to control levels. We also, found that TGF-beta 1 was induced by O2 exposure, that TGF-beta 1 inhibited SV40T-T2 proliferation, and that TGF-beta 1 itself was a potent stimulator of IGFBP-2 expression. These studies suggest a regulatory link between components of the IGF system and TGF-beta 1 in hyperoxic control of cell proliferation of alveolar epithelial cells.
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PMID:Insulin-like growth factors, their binding proteins, and transforming growth factor-beta 1 in oxidant-arrested lung alveolar epithelial cells. 751

Hyperoxia causes a reproducible pattern of lung injury and recovery, characterized by proliferation of type II alveolar epithelial cells (AEC2) during the recovery phase. We measured TGF-beta peptide production by AEC2 and macrophages from lungs of adult male rats exposed to 100% oxygen for 48 h and then allowed to recover for up to 72 h in room air. TGF-beta peptide activity levels were measured using the PAI-1 promoter-luciferase mink lung epithelial cell assay and characterized with peptide specific inhibitory antibodies. Control AEC2 produced 997 +/- 54 pg active TGF-beta x 10(6) cells-1.24h-1 (mean +/- SD), of which > 70% was TGF-beta 3, while cultured macrophages produced 58 +/- 17 pg active TGF-beta x 10(6) macrophages-1.24 h-1, > 80% of which was TGF-beta 1. During hyperoxia and recovery, active TGF-beta 3 production by AEC2 decreased by 75%, with a nadir at 24 h recovery (P < 0.005). In contrast, TGF-beta peptide activity increased from undetectable levels in lung lavage from control rats to a peak of 1,470 +/- 743 pg/rat after 48 h oxygen exposure and 24 h recovery, while lavaged macrophage TGF-beta production in culture also increased threefold to a peak of 150 +/- 5 pg. 10(6) cells-1. 24 h-1 after 48 h oxygen exposure (P < 0.005). The nadir of active TGF-beta 3 production by AEC2 coincided with the peak of the AEC2 proliferative phase of repair as determined by BrdU incorporation and FACS analysis of freshly isolated AEC2. We conclude that active TGF-beta 3 production by AEC2 is dynamically downregulated during the proliferative phase of recovery from acute hyperoxic injury in rat. We speculate that decreased autocrine negative regulation of AEC2 proliferation by TGF-beta 3 may facilitate AEC2 proliferation during recovery from acute hyperoxic injury.
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PMID:Dynamics of TGF-beta 3 peptide activity during rat alveolar epithelial cell proliferative recovery from acute hyperoxia. 876 Jan 32

Hyperoxia-associated production of reactive oxygen species leads to neutrophil infiltration into the lungs and increased pulmonary proinflammatory cytokine expression. However, the initial events induced by hyperoxia, and leading to acute inflammatory lung injury, remain incompletely characterized. To explore this issue, we examined nuclear transcriptional regulatory factor (NF-kappaB and NF-IL-6) activation and cytokine expression in the lungs following 12 to 48 h of hyperoxia exposure. No increases in cytokine (IL-1beta, IL-6, IL-10, TGF-beta, TNF-alpha, IFN-gamma) expression nor in NF-kappaB activation were found after 12 h of hyperoxia. Following 24 h of hyperoxia, NF-kappaB activation and increased levels of TNF-alpha mRNA were present in pulmonary lymphocytes. By 48 h of hyperoxia, amounts of IFN-gamma and TNF-alpha protein as well as mRNA were increased in the lungs, and NF-kappaB continued to show activation, even though no histologic abnormalities were present. These results show that hyperoxia activates NF-kappaB in the lungs before any increase in proinflammatory cytokine protein occurs, and suggest that NF-kappaB activation may represent an initial event in the proinflammatory sequence induced by hyperoxia.
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PMID:Hyperoxia activates NF-kappaB and increases TNF-alpha and IFN-gamma gene expression in mouse pulmonary lymphocytes. 889 21

The final stage of lung development, alveolarization, continues after birth in humans and rodents. Clinical interventions, such as oxygen therapy, in the first week of life can adversely impact alveolar formation. We compared alveolarization in the rat neonate under normal vs. hyperoxic conditions, examining gelatinase, transforming growth factor (TGF)-beta, and the protease urokinase-type plasminogen activator (uPA) activities in whole lung and cultured type II alveolar epithelial cells (AEC2). The dynamic induction of gelatinase, TGF-beta, and uPA activities seen in neonatal lungs during the first days of life was significantly impacted by hyperoxia. In whole lung, gelatinase and TGF-beta activities were increased, while uPA activity was decreased. At the level of the epithelium, AEC2 isolated from hyperoxic rat pups early in life secreted less active TGF-beta, less active gelatinases, and less active uPA than control neonatal AEC2. AEC2 from hyperoxic pups also expressed increased levels of proliferating cell nuclear antigen early in life compared with control neonatal AEC2, suggesting that oxygen-induced proliferation and/or repair were occurring. The developmental profile of neonatal lung was perturbed within a day of initiating oxygen treatment, suggesting that putative palliative treatments should be coadministered with oxygen therapy.
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PMID:Dynamics of metalloproteinase-2 and -9, TGF-beta, and uPA activities during normoxic vs. hyperoxic alveolarization. 1222 51

Focal coronary artery blockage followed by further reperfusion injury is commonly involved in myocardial infarction. The injured heart has some inherent reparative responses. Although such natural healing mechanisms seem to be inefficient, a clear understanding of the underlying principles of myocardial healing holds the key to successful therapy. Under normoxic conditions, pO(2) ranges from 90 to <3 Torr in mammalian organs with the heart at approximately 35 Torr (5%) and arterial blood at approximately 100 Torr. Thus, "normoxia" for cells is an adjustable variable. In response to chronic moderate hypoxia, cells lower their normoxia set-point such that reoxygenation-dependent relative elevation of pO(2) (+DeltapO(2)) results in perceived hyperoxia. Perceived hyperoxia induces differentiation of cardiac fibroblasts to myofibroblasts in the peri-infarct region and represents a significant factor supporting myocardial healing. The oxygen-sensitive signaling pathways involved have been characterized and point towards a central role of p21, TGFbeta and p38MAPK. That low oxygen ambience serves as a cue to trigger angiogenesis is a well-accepted notion. Studies related to perceived hyperoxia establish that the sensing of oxygen environment is not limited to hypoxia. It demonstrates that in addition to being a trigger for injury as is widely recognized, reoxygenation insult has a built-in component of tissue remodeling in the peri-infarct region induced by perceived hyperoxia. Understanding of the underlying mechanisms of this and other myocardial healing responses should prove to be instrumental in developing productive therapeutic approaches to mend the infarcted heart.
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PMID:Perceived hyperoxia: oxygen-induced remodeling of the reoxygenated heart. 1648 58

The nematode Caenorhabditis elegans has complex, naturally variable behavioral responses to environmental oxygen, food, and other animals. C. elegans detects oxygen through soluble guanylate cyclase homologs (sGCs) and responds to it differently depending on the activity of the neuropeptide receptor NPR-1: npr-1(lf) and naturally isolated npr-1(215F) animals avoid high oxygen and aggregate in the presence of food; npr-1(215V) animals do not. We show here that hyperoxia avoidance integrates food with npr-1 activity through neuromodulation of a distributed oxygen-sensing network. Hyperoxia avoidance is stimulated by sGC-expressing oxygen-sensing neurons, nociceptive neurons, and ADF sensory neurons. In npr-1(215V) animals, the switch from weak aerotaxis on food to strong aerotaxis in its absence requires close regulation of the neurotransmitter serotonin in the ADF neurons; high levels of ADF serotonin promote hyperoxia avoidance. In npr-1(lf) animals, food regulation is masked by increased activity of the oxygen-sensing neurons. Hyperoxia avoidance is also regulated by the neuronal TGF-beta homolog DAF-7, a secreted mediator of crowding and stress responses. DAF-7 inhibits serotonin synthesis in ADF, suggesting that ADF serotonin is a convergence point for regulation of hyperoxia avoidance. Coalitions of neurons that promote and repress hyperoxia avoidance generate a subtle and flexible response to environmental oxygen.
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PMID:A distributed chemosensory circuit for oxygen preference in C. elegans. 2007 37

Prematurely born infants who require oxygen therapy often develop bronchopulmonary dysplasia (BPD), a debilitating disorder characterized by pronounced alveolar hypoplasia. Hyperoxic injury is believed to disrupt critical signaling pathways that direct lung development, causing BPD. We investigated the effects of normobaric hyperoxia on transforming growth factor (TGF)-beta and bone morphogenetic protein (BMP) signaling in neonatal C57BL/6J mice exposed to 21% or 85% O(2) between postnatal days P1 and P28. Growth and respiratory compliance were significantly impaired in pups exposed to 85% O(2), and these pups also exhibited a pronounced arrest of alveolarization, accompanied by dysregulated expression and localization of both receptor (ALK-1, ALK-3, ALK-6, and the TGF-beta type II receptor) and Smad (Smads 1, 3, and 4) proteins. TGF-beta signaling was potentiated, whereas BMP signaling was impaired both in the lungs of pups exposed to 85% O(2) as well as in MLE-12 mouse lung epithelial cells and NIH/3T3 and primary lung fibroblasts cultured in 85% O(2). After exposure to 85% O(2), primary alveolar type II cells were more susceptible to TGF-beta-induced apoptosis, whereas primary pulmonary artery smooth muscle cells were unaffected. Exposure of primary lung fibroblasts to 85% O(2) significantly enhanced the TGF-beta-stimulated production of the alpha(1) subunit of type I collagen (Ialpha(1)), tissue inhibitor of metalloproteinase-1, tropoelastin, and tenascin-C. These data demonstrated that hyperoxia significantly affects TGF-beta/BMP signaling in the lung, including processes central to septation and, hence, alveolarization. The amenability of these pathways to genetic and pharmacological manipulation may provide alternative avenues for the management of BPD.
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PMID:Hyperoxia modulates TGF-beta/BMP signaling in a mouse model of bronchopulmonary dysplasia. 1707 23

Hyperoxic rats treated with inosine during oxygen exposure have increased levels of active transforming growth factor (TGF)-beta in the bronchoalveolar lavage (BAL), yet alveolar epithelial type 2 cells (AEC2) isolated from these animals demonstrate less hyperoxia-induced DNA damage and increased expression of active Smad2. To determine whether TGF-beta1 signaling per se protected AEC2 against hyperoxic damage, freshly isolated AEC2 from hyperoxic rats were incubated with TGF-beta1 for 24 h and assayed for DNA damage by fluorescein-activated cell sorter analysis of TdT-mediated dUTP nick end labeling. TGF-beta1 was protective over a concentration range similar to that in BAL of inosine-treated hyperoxic animals (50-5,000 pg/ml). TGF-beta1 also augmented hyperoxia-induced DNA repair activity and cell migration, stimulated autocrine secretion of fibronectin, accelerated closure of a monolayer scratch wound, and restored hyperoxia-depleted VEGF secretion by AEC2 to normoxic levels. The TGF-beta receptor type I activin-like kinase-4, -5, and -7 inhibitor peptide SB-505124 abolished the protective effect of TGF-beta on hyperoxic DNA damage and increased TdT-mediated dUTP nick end labeling in normoxic cells. These data suggest that endogenous TGF-beta-mediated Smad signaling is required for AEC2 homeostasis in vitro, while exogenous TGF-beta1 treatment of hyperoxia-damaged AEC2 results in a cell that is equipped to survive, repair, migrate, secrete matrix, and induce new blood vessel formation more efficiently than AEC2 primed by hyperoxia alone.
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PMID:TGF-beta signaling promotes survival and repair in rat alveolar epithelial type 2 cells during recovery after hyperoxic injury. 1824 68

Despite tremendous technological and therapeutic advances, bronchopulmonary dysplasia (BPD) remains a leading cause of respiratory morbidity in very low birth weight infants, and there are no effective preventive and/or therapeutic options. We have previously reported that hyperoxia-induced neonatal rat lung injury might be prevented by rosiglitazone (RGZ). Here, we characterize 1) perturbations in wingless/Int (Wnt) and transforming growth factor (TGF)-beta signaling, and 2) structural aberrations in lung morphology following 7-day continuous in vivo hyperoxia exposure to neonatal rats. We also tested whether treatment of neonatal pups with RGZ, concomitant to hyperoxia, could prevent such aberrations. Our study revealed that hyperoxia caused significant upregulation of Wnt signaling protein markers lymphoid enhancer factor 1 (Lef-1) and beta-catenin and TGF-beta pathway transducers phosphorylated Smad3 and Smad7 proteins in whole rat lung extracts. These changes were also accompanied by upregulation of myogenic marker proteins alpha-smooth muscle actin (alpha-SMA) and calponin but significant downregulation of the lipogenic marker peroxisome proliferator-activated receptor-gamma (PPARgamma) expression. These molecular perturbations were associated with reduction in alveolar septal thickness, radial alveolar count, and larger alveoli in the hyperoxia-exposed lung. These hyperoxia-induced molecular and morphological changes were prevented by systemic administration of RGZ, with lung sections appearing near normal. This is the first evidence that in vivo hyperoxia induces activation of both Wnt and TGF-beta signal transduction pathways in lung and of its near complete prevention by RGZ. Hyperoxia-induced arrest in alveolar development, a hallmark of BPD, along with these molecular changes strongly implicates these proteins in hyperoxia-induced lung injury. Administration of PPARgamma agonists may thus be a potential strategy to attenuate hyperoxia-induced lung injury and subsequent BPD.
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PMID:Hyperoxia-induced neonatal rat lung injury involves activation of TGF-{beta} and Wnt signaling and is protected by rosiglitazone. 1930 12


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