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)

Alveolar epithelial cell (AEC) migration mediated by matrix metalloproteinases (MMPs) is required for lung development and repair after injury such as hyperoxia. Of specific interest in lung remodeling are the gelatinases, which are upregulated in AEC after hyperoxia. We correlated migration and gelatinase production in AEC cultured from fetal, adult, and hyperoxic rats. Fetal AEC (19-20 days) had higher MMP-2 and MMP-9 gelatinase expression than adult AEC, with fivefold higher MMP-9 activity, and were migratory through gelatin, responding to epidermal growth factor, keratinocyte growth factor, and fibroblast growth factor-10. MMP-2 and MMP-9 expression and migratory activity could be detected from the time of plating. In contrast, adult AEC migrated and expressed MMP-2 and MMP-9 proteins only after 48 h of culture. AEC from hyperoxic rats were significantly more migratory through gelatin than control adult AEC, with significantly higher MMP-9 activity. Inhibition of MMPs with doxycycline reduced the migration of AEC from hyperoxic rats to the level of control adult AEC. Fibronectin-cultured "hyperoxic" AEC acquired a temporary capacity for migration similar to the A549 lung cancer cell line, which is both highly migratory and invasive and is derived from the AEC type 2 lineage. These data suggest that MMP activity is associated with a migratory phenotype in fetal, hyperoxic, and transformed AEC in vitro, and we speculate that MMPs may play a key mechanistic role in AEC migration in vivo during lung development and repair.
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PMID:Migration and gelatinases in cultured fetal, adult, and hyperoxic alveolar epithelial cells. 1143 18

The aim of this study was to determine the role of matrix metalloproteinases (MMPs) in the pathogenesis of acute lung injury induced by hyperoxia. Twenty-three pigs were exposed in sealed cages to >80% oxygen (for 24-120 h) or room air. Correlation between MMP-2/MMP-9 activity, measured by gelatin zymography in bronchoalveolar lavage fluid (BALF), and the histological findings and pathological parameters were examined in detail. Sources of these MMPs in the hyperoxic lung were analysed by immunohistochemistry. The histological progression of acute lung injury in this model ranged from the early exudative to the early proliferative phase of diffuse alveolar damage (DAD). MMP-2 and -9 activities were elevated under prolonged hyperoxic exposure. MMP-9 activity correlated significantly with the oxygen tension in arterial blood/inspiratory oxygen fraction, the lung wet-to-dry weight ratio, and the number of neutrophils in BALF, whereas MMP-2 activity did not correlate at all with these factors. MMP-9 activity correlated more closely with the pathological findings of DAD than did MMP-2 activity. Strong MMP-9 expression was observed in neutrophils, alveolar macrophages as well as alveolar lining epithelial cells. These results suggest that matrix metalloproteinase. which may derive from neutrophils recruited into airspaces, plays an important role in the pathogenesis of hyperoxic diffuse alveolar damage
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PMID:Expression of matrix metalloproteinases in pigs with hyperoxia-induced acute lung injury. 1175 34

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

A major limitation in thrombolysis for acute ischemic stroke is the restricted time window for safe and effective therapy. Any method that can extend the reperfusion time window would be important. In this study, we show that normobaric hyperoxia extends the time window for effective reperfusion from 1 to 3 hours in rats subjected to focal cerebral ischemia. Normobaric hyperoxia did not increase cellular markers of superoxide generation or brain levels of matrix metalloproteinase-9. Normobaric hyperoxia may be a clinically feasible adjunct method for significantly increasing the time window for effective thrombolytic therapy in acute ischemic stroke.
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PMID:Normobaric hyperoxia extends the reperfusion window in focal cerebral ischemia. 1578 65

An imbalance in matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) leads to excessive or insufficient tissue breakdown, which is associated with many disease processes. The TIMP-3 null mouse is a model of MMP/TIMP imbalance, which develops air space enlargement and decreased lung function. These mice responded differently to cecal ligation and perforation (CLP)-induced septic lung injury than wild-type controls. The current study addresses whether the TIMP-3 knockout lung is susceptible to different types of insults or only those involving sepsis, by examining its response to lipopolysaccharide (LPS)-induced sepsis, mechanical ventilation (MV), and hyperoxia. TIMP-3 null noninjured controls of each insult consistently demonstrated significantly higher compliance vs. wild-type mice. Null mice treated with LPS had a further significantly increased compliance compared with untreated controls. Conversely, MV and hyperoxia did not alter compliance in the null lung. MMP abundance and activity increased in response to LPS but were generally unaltered following MV or hyperoxia, correlating with compliance alterations. All three insults produced inflammatory cytokines; however, the response of the null vs. wild-type lung was dependent on the type of insult. Overall, this study demonstrated that 1) LPS-induced sepsis produced a similar response in null mice to CLP-induced sepsis, 2) the null lung responded differently to various insults, and 3) the null susceptibility to compliance changes correlated with increased MMPs. In conclusion, this study provides insight into the role of TIMP-3 in response to various lung insults, specifically its importance in regulating MMPs to maintain compliance during a sepsis.
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PMID:Differential response of TIMP-3 null mice to the lung insults of sepsis, mechanical ventilation, and hyperoxia. 1580 39

Acute lung injury is a side effect of therapy with a high concentration of inspired oxygen in patients. The molecular mechanism underlining this effect is poorly understood. In this study, we report that overexpression of Stat3C, a constitutive active form of STAT3, in respiratory epithelial cells of a doxycycline-controlled double-transgenic mouse system protects lung from inflammation and injury caused by hyperoxia. In this mouse line, >50% of transgenic mice survived exposure to 95% oxygen at day 7, compared with 0% survival of wild-type mice. Overexpression of STAT3C delays acute capillary leakage and neutrophil infiltration into the alveolar region. This protection is mediated at least partially through inhibition of hyperoxia-induced synthesis and release of matrix metalloproteinase (MMP)-9 and MMP-12 by neutrophils and alveolar resident cells. In some MMP-9(-/-) mice, prolonged survival was observed under hyperoxic condition. The finding supports a concept that activation of the Stat3 pathway plays a role to prevent hyperoxia-induced inflammation and injury in the lung.
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PMID:Overexpression of Stat3C in pulmonary epithelium protects against hyperoxic lung injury. 1590 71

We tested the hypothesis that hyperoxia or pressure exposure differentially activates expression of cytokines and/or matrix modeling proteins in human airway epithelial cells. Calu-3 epithelial cell monolayers were cultured on transwell plates with the apical surface exposed to gas. Following establishment of baseline, plates were placed in a chamber and exposed to: control (21% O (2); atm), hyperoxia (60% O (2); atm), pressure (21% O (2); 40 cm H (2)O), and combination (60% O (2); 40 cm H (2)O). At 72 hour of exposure, monolayers were assessed for integrity, viability, and expression of interleukin (IL)-6, IL-8 and matrix metalloproteinases (MMPs) -2, -7, and -9. Compared with controls, hyperoxia had lower transepithelial resistance ( P < 0.001) and greater IL-6 secretion ( P < 0.01), and pressure had lower cell viability ( P < 0.001) and greater IL-8 secretion ( P < 0.001). Hyperoxia resulted in more latent MMP-2 ( P < 0.05) and MMP-7 ( P < 0.001). Pressure was associated with a rise in MMPs independent of oxygen exposure ( P < 0.05). Hyperoxia and pressure differentially affected MMP activities in Calu-3 cells and may lead to the different functional and structural abnormalities observed in these in vitro studies.
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PMID:Dissociation between the effects of oxygen and pressure on matrix metalloproteinase-2, -7, and -9 expression in human airway epithelial cells. 1872 Mar 22

Early blood-brain barrier (BBB) disruption resulting from excessive neurovascular proteolysis by matrix metalloproteinases (MMPs) is closely associated with hemorrhagic transformation events in ischemic stroke. We have shown that normobaric hyperoxia (NBO) treatment reduces MMP-9 increase in the ischemic brain. The aim of this study was to determine whether NBO could attenuate MMP-9-mediated early BBB disruption following ischemic stroke. Rats were exposed to NBO (95% O(2)) or normoxia (30% O(2)) during 90-min middle cerebral artery occlusion, followed by 3-hour reperfusion. NBO-treated rats showed a significant reduction in Evan's blue extravasation in the ischemic hemisphere compared with normoxic rats. Topographically, Evan's blue leakage was mainly seen in the subcortical regions including the striatum, which was accompanied by increased gelatinolytic activity and reduced immunostaining for tight-junction protein, occludin. Increased gelatinolytic activities and occludin protein loss were also observed in isolated ischemic microvessels. Gel gelatin zymography identified that MMP-9 was the main enzymatic source in the cerebral microvessels. Incubation of brain slices or isolated microvessels with purified MMP-9 revealed specific degradation of occludin. Inhibition of MMP-9 by NBO or MMP-inhibitor, BB1101, significantly reduced occludin protein loss in ischemic microvessels. These results suggest that NBO attenuates early BBB disruption, and inhibition of MMP-9-mediated occludin degradation is an important mechanism for this protection.
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PMID:Normobaric hyperoxia attenuates early blood-brain barrier disruption by inhibiting MMP-9-mediated occludin degradation in focal cerebral ischemia. 1918 98

Oxygen toxicity appears to contribute to the pathogenesis of adverse neurological outcome in survivors of preterm birth. In infant rodent brains, hyperoxia triggers widespread apoptotic neurodegeneration, induces proinflammatory cytokines and inhibits growth factor signaling cascades. Since a tissue-protective effect has been observed for recombinant erythropoietin (rEpo), we hypothesized that rEpo would influence the expression of proinflammatory cytokines and matrix metalloproteinase (MMP)-2 and MMP-9. Six-day-old Wistar rats were exposed to 80% oxygen for 2-48 h and received 20,000 IU rEpo i.p. Sex-matched littermates kept in room air and injected with normal saline or rEpo served as controls. Treatment with rEpo significantly reduced hyperoxia-induced upregulation of the proinflammatory cytokines IL-1beta and IL-18 in infant rodent brains on the mRNA and protein levels. In parallel, gelatin zymography in hyperoxia-treated immature rat brains revealed an upregulation of active MMP-2 which was reduced by concomitant rEpo treatment. Furthermore, hyperoxia induced upregulation of MMP-9 following 12 h of oxygen exposure and this was attenuated by rEpo treatment. Our results suggest that rEpo generates its protective effect against oxygen toxicity through a reduction of proinflammatory mediator levels.
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PMID:Erythropoietin attenuates hyperoxia-induced cell death by modulation of inflammatory mediators and matrix metalloproteinases. 1967 68


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