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

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-induced lung disease is associated with prominent intraalveolar fibrin deposition. Fibrin turnover is tightly regulated by the concerted action of proteases and antiproteases, and inhibition of plasmin-mediated proteolysis could account for fibrin accumulation in lung alveoli. We show here that lungs of mice exposed to hyperoxia overproduce plasminogen activator inhibitor-1 (PAI-1), and that PAI-1 upregulation impairs fibrinolytic activity in the alveolar compartment. To explore whether increased PAI-1 production is a causal or only a correlative event for impaired intraalveolar fibrinolysis and the development of hyaline membrane disease, we studied mice genetically deficient in PAI-1. We found that these mice fail to develop intraalveolar fibrin deposits in response to hyperoxia and that they are more resistant to the lethal effects of hyperoxic stress. These observations provide clear and novel evidence for the pathogenic contribution of PAI-1 in the development of hyaline membrane disease. They identify PAI-1 as a major deleterious mediator of hyperoxic lung injury.
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PMID:Plasminogen activator inhibitor-1 in acute hyperoxic mouse lung injury. 898 9

Plasma tissue plasminogen activator (tPA) has long been considered to be the product of the endothelial cells that line the various parts of the vascular system regardless of vessel size or location. To determine whether this was truly the case in vivo, the distribution of tPA in the endothelium of the mouse lung and other tissues was evaluated. Immunohistochemical analysis of normal lung tissue showed positive staining limited to the endothelial cells of the bronchial arteries regardless of size with few cells of the pulmonary circulation associated with tPA. The pulmonary vessels that did contain endothelial cell-derived tPA were consistently between 7 and 30 microns in diameter. No capillary or large vessel pulmonary endothelium ever stained positive. These results were also observed in primate lung tissue where the bronchial endothelium of all vessels, even down to capillary size, contained tPA while none of the pulmonary endothelium did. Prolonged exposure of mice to hyperoxic conditions promotes acute lung injury and associated inflammation. Using this model, the effect of inflammation on endothelial cell tPA expression was evaluated. A 4.5-fold increase in the number of pulmonary vessels staining positive for tPA was observed after 66 hours with all of these vessels having a diameter between 7 and 30 microns. Again, none of the endothelium of large arteries or veins nor the capillaries had tPA. Whole tissue tPA mRNA increased dramatically with hyperoxia and in situ hybridization analysis showed tPA mRNA in the endothelium of the same types of vessels as antigen. The tPA localized to both the bronchial and pulmonary endothelium was active with neither tPA-PAI-1 complexes nor urokinase found in perfused lung tissue. These results indicate that endothelial cell tPA expression, either constitutive or induced by a pathologic event, is a function of a highly select group of endothelial cells which are defined by their association with vessels of discrete size and/or anatomic location. Thus, the widely held concept that the steady state level of plasma tPA is maintained through its constitutive production by all endothelial cells of the vascular system is invalid. Also suggested is the possibility that endothelial cell tPA might play a broader role than simply maintaining vessel patency as a component of the fibrinolytic pathway and contribute to complex dynamic processes such as inflammation.
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PMID:The expression of endothelial tissue plasminogen activator in vivo: a function defined by vessel size and anatomic location. 904 44

Keratinocyte growth factor (KGF) has been used successfully to prevent alveolar damage induced by oxygen exposure in rodents. However, this treatment was used intratracheally and before oxygen exposure, which limited its clinical application. In the present study, mice were treated with the recombinant human KGF intravenously before (days -2 and -1) or during (days 0 and +1) oxygen exposure. In both cases, lung damage was attenuated. KGF increased the number of cells incorporating bromodeoxyuridine (BrdU) in the septa and in bronchial epithelium of air-breathing mice but not of oxygen-exposed mice, indicating that the protective effect of KGF is not necessarily associated with proliferation. Oxygen-induced damage of alveolar epithelium and, unexpectedly, of endothelium was prevented by KGF treatment as seen by electron microscopy. We investigated the effect of KGF on different mechanisms known to be involved in oxygen toxicity. The induction of p53, Bax, and Bcl-x mRNAs during hyperoxia was to a large extent prevented by KGF. Surfactant proteins A and B mRNAs were not markedly modified by KGF. The anti-fibrinolytic activity observed in the alveoli during hyperoxia was to a large extent prevented by KGF, most probably by suppressing the expression of plasminogen activator inhibitor-1 (PAI-1) mRNA and protein. As PAI-1 -/- mice are more resistant to hyperoxia, KGF might act, at least in part, by decreasing the expression of this protease inhibitor and by restoring the fibrinolytic activity into the lungs.
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PMID:Keratinocyte growth factor protects alveolar epithelium and endothelium from oxygen-induced injury in mice. 1032 1

The aims of this study were to examine the effect of oxygen, in the presence or absence of exogenous growth factors, on the release of plasminogen activators and plasminogen activator inhibitor-1 by cultured human retinal pigment epithelial cells. Antigen and activity levels of urokinase, tissue plasminogen activator and plasminogen activator inhibitor were measured in conditioned media after cells were exposed to three different oxygen environments: hypoxia, normoxia and hyperoxia. Overall proteolytic balance was determined by zymography. The effects of exogenous basic fibroblast growth factor and transforming growth factor-beta were also examined. it was found that retinal pigment epithelial cells released urokinase, tissue plasminogen activator and plasminogen activator inhibitor in measurable quantities. After 48 h, urokinase levels were highest at normoxia, reaching 7.2ng/10(6) cells (+/-2.0 SEM), whereas plasminogen activator inhibitor 1 levels were highest at hyperoxia, reaching 67.5ng/10(6) cells (+/-3.7 SEM). Tissue plasminogen activator levels were minimal (<0.5ng/10(6) cells) and unaffected by both oxygen and growth factors. Overall proteolytic activity was also greatest at normoxia. Fibroblast growth factor stimulated urokinase production dose-dependently, but plasminogen activator inhibitor only minimally. Transforming growth factor-beta stimulated plasminogen activator inhibitor production dose-dependently but urokinase only at higher concentrations. These results suggest that both oxygen tension and growth factors may interact to modulate the proteolytic properties of the human retinal pigment epithelium.
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PMID:Oxygen modulates the release of urokinase and plasminogen activator inhibitor-1 by retinal pigment epithelial cells. 1131 55

The urokinase plasminogen activator system plays a central role in malignant tumour progression. Both tumour hypoxia and enhancement of urokinase plasminogen activator, urokinase plasminogen activator-receptor and plasminogen activator inhibitor type 1 have been identified as adverse prognostic factors. Upregulation of urokinase plasminogen activator or plasminogen activator inhibitor type 1 could present means by which hypoxia influences malignant progression. Therefore, the impact of hypoxia on the expression pattern of the urokinase plasminogen activator system in rat DS-sarcoma in vivo and in vitro was examined. In the in vivo setting, tumour cells were implanted subcutaneously into rats, which were housed under either hypoxia, atmospheric air or hyperoxia. For in vitro studies, DS-sarcoma cells were incubated for 24 h under hypoxia. Urokinase plasminogen activator and urokinase plasminogen activator-receptor expression were analysed by flow cytometry. Urokinase plasminogen activator activity was measured using zymography. Plasminogen activator inhibitor type 1 protein levels in vitro and in vivo were examined with ELISA. PAI-1 mRNA levels were determined by RT-PCR. DS-sarcoma cells express urokinase plasminogen activator, urokinase plasminogen activator-receptor, and plasminogen activator inhibitor type 1 in vitro and in vivo. The urokinase plasminogen activator activity is enhanced in DS-sarcomas compared to normal tissues and rises with increasing tumour volume. The oxygenation level has no impact on the urokinase plasminogen activator activity in cultured DS-sarcoma cells or in solid tumours, although in vitro an increase in plasminogen activator inhibitor type 1 protein and mRNA expression after hypoxic challenge is detectable. The latter plasminogen activator inhibitor type 1 changes were not detectable in vivo. Hypoxia has been demonstrated to contribute to the upregulation of some components of the system in vitro, although this effect was not reproducible in vivo. This may indicate that the serum level of plasminogen activator inhibitor type 1 is not a reliable surrogate marker of tumour hypoxia.
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PMID:Expression pattern of the urokinase-plasminogen activator system in rat DS-sarcoma: role of oxygenation status and tumour size. 1195 98

Oxidative stress is an important factor in the pathogenesis of bronchopulmonary dysplasia (BPD), a chronic lung disease of premature infants characterized by arrested alveolar and vascular development of the immature lung. We investigated differential gene expression with DNA microarray analysis in premature rat lungs exposed to prolonged hyperoxia during the saccular stage of development, which closely resembles the development of the lungs of premature infants receiving neonatal intensive care. Expression profiles were largely confirmed by real-time RT-PCR (27 genes) and in line with histopathology and fibrin deposition studied by Western blotting. Oxidative stress affected a complex orchestra of genes involved in inflammation, coagulation, fibrinolysis, extracellular matrix turnover, cell cycle, signal transduction, and alveolar enlargement and explains, at least in part, the pathological alterations that occur in lungs developing BPD. Exciting findings were the magnitude of fibrin deposition; the upregulation of chemokine-induced neutrophilic chemoattractant-1 (CINC-1), monocyte chemoattractant protein-1 (MCP-1), amphiregulin, plasminogen activator inhibitor-1 (PAI-1), secretory leukocyte proteinase inhibitor (SLPI), matrix metalloproteinase-12 (MMP12), p21, metallothionein, and heme oxygenase (HO); and the downregulation of fibroblast growth factor receptor-4 (FGFR4) and vascular endothelial growth factor (VEGF) receptor-2 (Flk-1). These findings are not only of fundamental importance in the understanding of the pathophysiology of BPD, but also essential for the development of new therapeutic strategies.
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PMID:Gene expression profile and histopathology of experimental bronchopulmonary dysplasia induced by prolonged oxidative stress. 1499 Mar 57

Bronchopulmonary dysplasia is a leading cause of mortality and morbidity in preterm infants despite improved treatment modalities. Pentoxifylline, a phosphodiesterase inhibitor, inhibits multiple processes that lead to neonatal hyperoxic lung injury, including inflammation, coagulation, and edema. Using a preterm rat model, we investigated the effects of pentoxifylline on hyperoxia-induced lung injury and survival. Preterm rat pups were exposed to 100% oxygen and injected subcutaneously with 0.9% saline or 75 mg/kg pentoxifylline twice a day. On day 10, lung tissue was harvested for histology, fibrin deposition, and mRNA expression, and bronchoalveolar lavage fluid was collected for total protein concentration. Pentoxifylline treatment increased mean survival by 3 days (P = 0.0018) and reduced fibrin deposition by 66% (P < 0.001) in lung homogenates compared with untreated hyperoxia-exposed controls. Monocyte chemoattractant protein-1 expression in lung homogenates was decreased, but the expressions of TNF-alpha, IL-6, matrix metalloproteinase-12, tissue factor, and plasminogen activator inhibitor-1 were similar in both groups. Total protein concentration in bronchoalveolar lavage fluid was decreased by 33% (P = 0.029) in the pentoxifylline group. Pentoxifylline treatment attenuates alveolar fibrin deposition and prolongs survival in preterm rat pups with neonatal hyperoxic lung injury, probably by reducing capillary-alveolar protein leakage.
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PMID:Pentoxifylline reduces fibrin deposition and prolongs survival in neonatal hyperoxic lung injury. 1520 86

High-tidal-volume mechanical ventilation and hyperoxia used in patients with acute lung injury (ALI) can induce alveolar coagulopathy and fibrin depositions within the airways. Hyperoxia has been shown to increase ventilator-induced lung injury (VILI), but the mechanisms that regulate interaction between high-tidal-volume mechanical ventilation and hyperoxia are unclear. We hypothesized that mechanical stretch with hyperoxia synergistically augmented neutrophil infiltration and production of plasminogen activator inhibitor-1 (PAI-1) via the nuclear factor-kappaB (NF-kappaB) pathway. C57BL/6 mice (n=5 per group) were exposed to high-tidal-volume (30 mL/kg) or low-tidal-volume (6 mL/kg) mechanical ventilation with room air or hyperoxia for 1 to 5h after 2-microg/g NF-kappaB inhibitor (SN-50) administration. Nonventilated mice with room air or hyperoxia served as control groups. Evans blue dye, myeloperoxidase, electrophoretic mobility shifting of nuclear protein, and inflammatory cytokine were measured. The expression of tumor necrosis factor-alpha (TNF-alpha) and PAI-1 were studied by immunohistochemistry. The addition of hyperoxia to high-tidal-volume ventilation-augmented lung injury, as demonstrated by increased microvascular leak, neutrophil migration into the lung, TNF-alpha and active PAI-1 production, DNA binding activity of NF-kappaB, and NF-kappaB activation. No statistically significant increase of neutrophil infiltration and inflammatory cytokine production was found in the mice ventilated at 6 mL/kg using hyperoxia. Hyperoxia-induced augmentation of VILI was attenuated in mice with pharmacologic inhibition of NF-kappaB activity by SN-50. We conclude that hyperoxia increased high-tidal-volume-induced cytokine production and neutrophil influx through activation of the NF-kappaB pathway.
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PMID:Role for nuclear factor-kappaB in augmented lung injury because of interaction between hyperoxia and high stretch ventilation. 1984 Jul 62

Retinal pericyte loss and neovascularization are characteristic features of diabetic retinopathy. Gemigliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, has shown robust blood-glucose lowering effects in type 2 diabetic patients, but its effects on diabetic retinopathy have not yet been reported. We evaluated the efficacy of gemigliptin on retinal vascular leakage in db/db mice, which is an animal model for type 2 diabetes, and neovascularization in oxygen-induced retinopathy (OIR) mice, which is an animal model for ischemic proliferative retinopathy. Gemigliptin (100mg/kg/day) was orally administered to the db/db mice for 12weeks. C57BL/6 mice on postnatal day 7 (P7) were exposed to 75% hyperoxia for 5days, followed by exposure to room air from P12 to P17 to induce OIR. Gemigliptin (50mg/kg/day) was intraperitoneally injected daily from P12 to P17. Retinal neovascularization was analyzed in flat-mounted retinas on P17. We determined the efficacy and possible mechanism of gemigliptin on high glucose-induced apoptosis of primary human retinal pericytes. The oral administration of gemigliptin for 4months significantly ameliorated retinal pericyte apoptosis and vascular leakage in the db/db mice. Gemigliptin also ameliorated retinal neovascularization in the OIR mice. Gemigliptin attenuated the overexpression of plasminogen activator inhibitor-1 (PAI-1) in the retinas of diabetic and OIR mice. Gemigliptin and PAI-1 siRNA significantly inhibited pericyte apoptosis by inhibiting the overexpression of PAI-1, which is induced by high glucose. Our results suggest that gemigliptin has potent anti-angiogenic and anti-apoptotic activities via suppressing DPP-4 and PAI-1, and the results support the direct retinoprotective action of gemigliptin.
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PMID:Gemigliptin, a dipeptidyl peptidase-4 inhibitor, inhibits retinal pericyte injury in db/db mice and retinal neovascularization in mice with ischemic retinopathy. 2639 Dec 52


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