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

To assess the effects of exposure of the lung to hyperoxic conditions on reactivity of pulmonary microcirculation to hypoxic stimulation, we measured hypoxia-elicited overall pulmonary pressor changes (HPV) and microvascular diameter changes in intraacinar arterioles, venules, and capillaries in isolated perfused rat lungs exposed to a hyperoxic environment (90% O2). To estimate the importance of vasoactive prostaglandins and nitric oxide (NO) for HPV modification, we examined the roles of constitutive and inducible forms of cyclooxygenase (COX-1 and COX-2) and those of NO synthase (eNOS and iNOS). Indomethacin was used for inhibiting both COX-1 and COX-2, while NS-398 was used as a selective inhibitor of COX-2. Both eNOS and iNOS were suppressed by L-NAME, whereas iNOS alone was inhibited by aminoguanidine. Microvascular diameter was measured with a real-time confocal laser scanning luminescence microscope. We found that (1) exposure to hyperoxia caused overall HPV and arteriolar constriction to be attenuated; (2) the blunted HPV was restored by L-NAME but not by aminoguanidine, indomethacin, or NS-398; and (3) arteriolar constriction was improved by either L-NAME, aminoguanidine, or indomethacin but only slightly by NS-398. In conclusion, attenuation of overall HPV in hyperoxia-exposed lungs is explicable mainly by excessive NO generated via eNOS, while impaired arteriolar constriction is caused by NO yielded by eNOS and iNOS as well as by vasodilating prostaglandin(s) produced by COX-1.
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PMID:Impaired hypoxic vasoconstriction in intraacinar microvasculature in hyperoxia-exposed rat lungs. 970 Jan 41

The aims of this study were to investigate the effect of hyperoxia on O2(-.), H2O2 and .NO generation and iNOS mRNA levels in rat type II pneumocytes in vitro and the possible protective effect of the lazaroid U-74389G. Rat type II pneumocytes were exposed, 36 h after isolation, to air, 60% or 85% O2 for 48 h. At the beginning of the experiment and 24 h later, the cells were exposed for 30 min to either 30 microM U-74389G or only the vehicle for the lazaroid (control). Exposure to 60% and 85% O2 decreased nitrite production 2.9-fold and 3.9-fold, and increased O2(-.) and H2O2 generation 4.6-fold and 6.7-fold, respectively. In the 85% O2-exposed cells, hyperoxia increased lipid peroxidation (thiobarbituric acid reactive substances, TBARS production) 2-fold and iNOS mRNA production 5.4-fold. U-74389G prevented the decrease in nitrite and the rise in O2(-.) and H2O2 production, the increase in TBARS and the rise in iNOS mRNA after hyperoxia. We conclude that exposure of type II pneumocytes in vitro to subtoxic oxygen levels leads to a disturbance in the .NO-O2(-.) balance despite increased iNOS mRNA levels. The lazaroid U-74389G appears to be a useful compound in the protection of hyperoxic lung injury by restoration of this .NO-O2(-.) balance and prevention of TBARS formation.
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PMID:Protective effects of the lazaroid U-74389G against hyperoxia in rat type II pneumocytes. 980 60

The effects of nitric oxide (NO) and metalloproteinases (MMP-2 and MMP-9) in the pathogenesis of hyperoxia-induced lung damage in newborn rats were examined. Three-day-old rat pups were subjected to hyperoxia (> or = 95% O2) or room air for 7 and 14 days. Some animals were treated with NG-L-nitro-L-arginine methyl ester (L-NAME, 10 mg kg(-1), s.c., daily). Histology, morphometry, oedema, Ca2+-dependent and -independent NO synthase (NOS) activities, expression of NOS isoforms and the activities of MMP-2 and MMP-9 were measured in lungs of hyperoxic and control animals. Exposure of rats to hyperoxia for 7 days resulted in alveolar sac injury characterized by the presence of cellular debris, red cell extravasation and inflammatory infiltration with mononuclear cells. Lung water content, epithelial, smooth muscle layers and total airway thickness was similar to controls. In contrast, exposure of rats to hyperoxia for 14 days resulted in lung oedema, inflammation and epithelial proliferation. Hyperoxia caused a decrease in Ca2+-dependent NOS activity, an effect that was associated with increased expression of eNOS protein. In control rats, Ca2+-dependent NOS activity and expression of eNOS were reduced at 14 days. Hyperoxia caused 10 fold increase in the activity of Ca2+-independent NOS that remained significantly elevated after 14 days of exposure to hyperoxia. The activity of this enzyme was unchanged in control rats. In lungs of hyperoxic rats, the immunoblot showed time-dependent, biphasic expression (peak at 7 days) of iNOS. The profile of expression of iNOS in control rats was similar. The activities of MMPs were increased in lungs of hyperoxic animals. The L-NAME treatment of hyperoxic animals reduced lung oedema and epithelial proliferation, but enhanced the activities of MMPs. L-NAME exerted no significant effects in control rats. It is concluded that increased generation of NO contributes to the pathogenesis of hyperoxia-induced lung damage in newborn rats.
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PMID:The role of nitric oxide and metalloproteinases in the pathogenesis of hyperoxia-induced lung injury in newborn rats. 988 73

Although hyperoxic exposure is an important contributor to the development of bronchopulmonary dysplasia and nitric oxide (NO) has been implicated in the pulmonary response to oxygen, the role of NO in mediating chronic neonatal lung injury is unclear. Therefore, rat pups were exposed to normoxia or hyperoxia (>95% O2) from d 21 to 29. After the rats were killed, their lungs were removed for analysis of nitric oxide synthase (NOS) expression, NO activity as measured by 3',5'-cyclic guanosine monophosphate (cGMP) assay, and lung pathology. Hyperoxia caused 5-fold and 2-fold increases in inducible (i) NOS and endothelial (e) NOS levels, respectively. NO activity was assessed by measuring cGMP levels after normoxic or hyperoxic exposure in the presence and absence of NOS blockade with either aminoguanidine (AG) or Nomega-nitro-L-arginine (L-NNA). cGMP levels were elevated in hyperoxic versus normoxic rats (287+/-15 versus 106+/-9 pmol/mg protein, respectively, p < 0.001), and this increase in cGMP was attenuated after NOS blockade with either AG or L-NNA. Hyperoxic exposure significantly increased lung/body weight ratios and induced histologic changes of interstitial and alveolar edema; however, these hyperoxia-induced histologic changes were not altered by NOS blockade with AG or L-NNA. We conclude that hyperoxic exposure of rat pups up-regulated both iNOS and eNOS and increased NO activity as measured by cGMP levels derived from both iNOS and eNOS. Blockade of NOS reduced cGMP levels in the hyperoxic rat pups; however, it did not seem to reverse the pathologic consequences of hyperoxic exposure.
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PMID:Effects of hyperoxia on nitric oxide synthase expression, nitric oxide activity, and lung injury in rat pups. 989 Jun 2

The effect of hyperoxia on nitric oxide (NO) production in intact animals is unknown. We described the effects of hyperoxia on inducible nitric oxide synthase (iNOS) expression and NO production in the lungs of rats exposed to high concentrations of oxygen. Animals were placed in sealed Plexiglas chambers and were exposed to either 85% oxygen (hyperoxic group) or 21% oxygen (negative control group). Animals were anesthetized after 24 and 72 h of exposure and were ventilated via a tracheotomy. We measured NO production in exhaled air (E(NO)) by chemiluminescence. The lungs were then harvested and processed for detection of iNOS by immunohistochemistry and Western blotting analysis. The same experiments were repeated in animals exposed to hyperoxia for 72 h after they were infused with L-arginine. We used rats that were injected intraperitoneally with Escherichia coli lipopolysaccharide to induce septic shock as a positive control group. Hyperoxia and septic shock induced expression of iNOS in the lung. However, E(NO) was elevated only in septic shock rats but was normal in the hyperoxic group. Exogenous infusion of L-arginine after hyperoxia did not increase E(NO). To exclude the possibility that in the hyperoxic group NO was scavenged by oxygen radicals to form peroxynitrite, lungs were studied by immunohistochemistry for the detection of nitrotyrosine. Nitrotyrosine was found in septic shock animals but not in the hyperoxic group, further suggesting that NO is not synthesized in rats exposed to hyperoxia. We conclude that hyperoxia induces iNOS expression in the lung without an increase in NO concentration in the exhaled air.
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PMID:Inducible nitric oxide synthase in the lung and exhaled nitric oxide after hyperoxia. 1048 72

Molecular oxygen (O(2)) regulates the expression of a variety of genes. We hypothesized that O(2) tension may regulate iNOS expression in rat liver through the production of reactive oxygen species (ROS) and the reduction of intracellular glutathione (GSH) levels. To investigate this hypothesis, we determined the effects of hyperoxia upon iNOS induction (both at the protein and mRNA level) and the intracellular concentration of GSH in an isolated in vitro perfused rat liver preparation. To study the potential involvement of ROS in the intracellular signaling pathway linking changes in oxygen tension to gene expression, we repeated these determinations in the presence of the thiol antioxidant N-acetyl-L-cysteine (NAC). We found that 95% O(2) tension caused a significant induction of the iNOS protein and mRNA levels paralleled by a significant fall in intracellular GSH concentration. The addition of NAC (1 mM) to the perfusate during hyperoxia blocked the induction of iNOS and restored GSH levels. These results indicate that molecular O(2) regulates the expression of iNOS in rat liver at the transcriptional level, most likely through the production of ROS and the reduction of intracellular GSH levels.
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PMID:Regulation of iNOS expression and glutathione levels in rat liver by oxygen tension. 1091 23

The objective of this study was to determine whether endogenous nitric oxide (NO), specifically the inducible NO synthase isoform (iNOS: NOS II), reduces or amplifies lung injury in mice breathing at a high oxygen tension. Previous studies have shown that exogenous (inhaled) NO protects against hyperoxia-induced lung injury, and that endogenous NO derived from iNOS inhibits leukocyte recruitment and protects against lung injury induced by lipopolysaccharide. In the present study, hyperoxia (> 98% O(2) for 72 h) induced acute lung injury in both wild-type and iNOS-deficient mice as determined by elevated albumin and lactate dehydrogenase levels in bronchoalveolar lavage fluid (BALF) and by increased extravascular lung water. Lung injury was greater in iNOS-deficient mice than in wild-type mice and was associated with an increased number of polymorphonuclear leukocytes in BALF. iNOS messenger RNA expression levels increased in the lungs of wild-type hyperoxic mice. Nitrotyrosine, a marker of reactive NO species, was expressed in both wild-type and iNOS-deficient mice in hyperoxia, indicating an iNOS-independent pathway for protein nitration. We conclude that iNOS is capable of reducing pulmonary leukocyte accumulation and lung injury. The data indicate that iNOS induction serves as a protective mechanism to minimize the effects of acute exposure to hyperoxia.
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PMID:Antiinflammatory properties of inducible nitric oxide synthase in acute hyperoxic lung injury. 1130 31

The extent to which endogenously generated nitric oxide alters Na(+) transport across the mammalian alveolar epithelium in vivo has not been documented. Herein we measured alveolar fluid clearance and nasal potential differences in mice lacking the inducible form of nitric oxide synthase [iNOS; iNOS(-/-)] and their corresponding wild-type controls [iNOS(+/+)]. Alveolar fluid clearance values in iNOS(+/+) and iNOS(-/-) anesthetized mice with normal oxygenation and acid-base balance were ~30% of instilled fluid/30 min. In both groups of mice, fluid absorption was dependent on vectorial Na(+) movement. Amiloride (1.5 mM) decreased alveolar fluid clearance in iNOS(+/+) mice by 61%, whereas forskolin (50 microM) increased alveolar fluid clearance by 55% by stimulating amiloride-insensitive pathways. Neither agent altered alveolar fluid clearance in iNOS(-/-) mice. Hyperoxia upregulated iNOS expression in iNOS(+/+) mice and decreased their amiloride-sensitive component of alveolar fluid clearance but had no effect on the corresponding values in iNOS(-/-) mice. Nasal potential difference measurements were consistent with alveolar fluid clearance in that both groups of mice had similar baseline values, which were amiloride sensitive in the iNOS(+/+) but not in the iNOS(-/-) mice. These data suggest that nitric oxide produced by iNOS under basal conditions plays an important role in regulating amiloride-sensitive Na(+) channels in alveolar and airway epithelia.
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PMID:Lack of amiloride-sensitive transport across alveolar and respiratory epithelium of iNOS(-/-) mice in vivo. 1150 1

Alterations of pulmonary surfactant and increases in inducible nitric oxide synthase (iNOS) have been implicated in the pathophysiology of acute lung injury. It was hypothesised that these two observations are related and that alterations of the endogenous surfactant, due to either sepsis or hyperoxia, would be reduced in mice lacking the iNOS gene compared to wild-type mice. Wild-type and iNOS (-/-) mice were randomised into sham or sepsis, and in a separate experiment animals were randomised to normoxia or hyperoxia exposure for 48 h. Lungs were lavaged and analysed for total surfactant levels and surfactant subfractions (large (LA) and small (SA) aggregates). Both sepsis groups had decreased SA compared to sham groups with no significant difference between the two genotypes. Mice exposed to hyperoxia had a decreased amount of total surfactant when compared to normoxia controls and there was no significant difference between the two genotypes. It is concluded that inducible nitric oxide synthase does not influence the amount of pulmonary surfactant or surfactant subfractions recovered in lavage after 18 h of sepsis or 48 h of hyperoxia.
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PMID:Sepsis and hyperoxia effects on the pulmonary surfactant system in wild-type and iNOS knockout mice. 1216 67

The aim of the present study was to compare microvessel responses to hypercapnic and isocapnic acidosis in hyperoxia-injured lungs and to assess the role of constitutive and inducible forms of nitric oxide synthase (NOS) and cyclo-oxygenase (COX). Real-time confocal luminescence microscopy was used to measure changes in the diameter of acinar arterioles, venules and capillaries in response to stimulation with hypercapnic and isocapnic acidosis in isolated rat lungs injured by 90% oxygen exposure for 48 h. Observations were made with and without inhibition of constitutive (endothelial constitutive NOS (ecNOS) and COX-1) and inducible isoforms (iNOS and COX-2) of NOS and COX. Upregulation of NOS was assessed by measuring enzyme levels in lung homogenates by Western blot analysis and enhancement of the COX-related pathway was judged from perfusate concentrations of 6-ketoprostaglandin F1alpha. ecNOS and COX-1, but not iNOS and COX-2, were upregulated in hyperoxia-injured lungs. The nitric oxide produced by ecNOS attenuated COX-1 activity in injured arterioles and venules, but carbon dioxide enhanced it, leading to paradoxical dilatation of these microvessels under hypercapnic conditions with ecNOS inhibition. Although a high hydrogen ion concentration was unnecessary for excitation of COX-1, venule constriction in response to H+ was enhanced by COX-1 inhibition. Constitutive, but not inducible, isoforms of cyclo-oxygenase and nitric oxide synthase play an important role in abnormal microvessel responses to carbon dioxide and hydrogen ions in hyperoxia-injured lungs.
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PMID:NOS and COX isoforms and abnormal microvessel responses to CO2 and H+ in hyperoxia-injured lungs. 1216 83


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