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)

To assess the roles of cyclooxygenase inhibition and hyperoxia in regulating pulmonary perfusion, we studied 13 dogs with diffuse granulomatous lung disease (DGLD) and 13 normal dogs. Baseline observations were obtained at fractional inspired O2 (FIO2) 0.21 and 1.0 and repeated after infusion of meclofenamate (Mec; n = 8) or saline (n = 5). Resistance to flow was evaluated from the pulmonary end-diastolic gradient (PDG) and by ohmic pulmonary vascular resistance (PVR). Distribution of blood flow was evaluated with sulfur hexafluoride in DGLD and with multiple inert gas alveolar ventilation-perfusion (VA/Q) plots in normal dogs. Before infusion, there were no differences between the saline and Mec groups at either FIO2. Saline induced no significant changes at either FIO2. After Mec in DGLD, PDG at FIO2 0.21 rose from 4 +/- 2 to 6 +/- 4 mmHg (P < 0.04), PVR increased from 297 +/- 98 to 484 +/- 181 dyn.s.cm-5.m-2 (P < 0.01), whereas shunt flow (Qs/Qt) fell form 13.6 +/- 12.0 to 6.2 +/- 5.3% (P < 0.03). At FIO2 1.0 PDG rose from 3 +/- 2 to 4 +/- 3 mmHg (P < 0.02), PVR increased from 262 +/- 78 to 374 +/- 139 dyn.s.cm-5.m-2 (P < 0.01), whereas Qs/Qt fell from 14.5 +/- 13.3 to 6.4 +/- 5.2% (P < 0.02). After Mec in normal dogs, PDG at FIO2 0.21 rose from 3 +/- 1 to 4 +/- 1 mmHg (P < 0.015) and PVR increased from 256 +/- 92 to 340 +/- 101 dyn.s.cm-5.m-2 (P < 0.05); at FIO2 1.0 PDG and PVR were unchanged from preinfusion levels. In normal dogs, no parameters of VA/Q changed significantly with hyperoxia or Mec. These data suggest that perivascular inflammation enhances perfusion in DGLD by elaboration of vasodilator prostaglandins (PG). By inhibiting PG synthesis, Mec selectively increases resistance in diseased lung at FIO2 0.21 and lowers Qs/Qt. In contrast, there was vasoconstriction without flow redistribution in normal dogs, suggesting that vasodilator PGs contribute to the low tone in the normal pulmonary bed. The vasodilation without flow redistribution in both models during hyperoxia after Mec suggests an effect of O2 that is related neither to PG synthesis nor to hypoxic vasoconstriction.
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PMID:Role of cyclooxygenase inhibition and hyperoxia in regulating pulmonary perfusion in dogs. 773 53

Recently, we demonstrated that chronic exposure to hyperoxia causes in vivo airway muscarinic receptor hyperresponsiveness in the developing rat [Am. J. Physiol. 262 (Lung Cell. Mol. Physiol. 6): L263-L269, 1992]. To test whether airway cholinergic hyperresponsiveness might result from intrinsic alterations in smooth muscle contractility, we measured the effect of in vivo hyperoxia on the contractile force elicited by acetylcholine (ACh) of isometrically mounted tracheal rings in vitro. Tracheal rings were obtained from 3-wk-old rats exposed to air or to > 95% O2 for 8 days. Muscarinic responses were determined by measuring the force elicited by exposure to increasing concentrations of ACh. Responses were normalized to the morphometrically determined tracheal smooth muscle cross-sectional area in a plane perpendicular to the axis of force generation. In vivo O2 exposure significantly increased maximal ACh-induced stress generation (response to 10(-3) M ACh: air, 15.92 +/- 1.37 g/mm2; O2, 21.78 +/- 1.52 g/mm2; P = 0.010). The ACh-induced stress generation of cylinders from hyperoxic rats was substantially reduced by both epithelial removal and treatment with the cyclooxygenase inhibitor indomethacin. We conclude that in vivo hyperoxic exposure increases tracheal smooth muscle contractile function in vitro and that epithelium-derived prostaglandin(s) contributes to the observed increase in maximal contractile responsiveness.
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PMID:Exposure of immature rats to hyperoxia increases tracheal smooth muscle stress generation in vitro. 817 85

We examined the effect of hyperoxia on arachidonic acid (AA) metabolism in bovine carotid artery endothelial cells (CAEC) and pulmonary artery endothelial cells (PAEC). Confluent monolayers were exposed to hyperoxic gases (95% O2 or 60% O2) from 12-72 h. Control cells were incubated under normoxic condition (air-5% CO2). After exposure of the cells to normoxic or hyperoxic conditions, prostaglandin (PG) synthesis activity was analyzed in cell homogenates using thin layer chromatography; release of 6-keto-PGF1 alpha, a stable metabolite of PGI2, into the culture medium was measured using a radioimmunoassay. The major metabolites formed from exogenously supplied 14C-AA were 6-keto-PGF1 alpha and a small amount of PGE2. Hyperoxia (95% O2) decreased the synthesis of these cyclooxygenase products beginning at 24 h; moderate hyperoxia (60% O2) had no such effect. There was no significant difference between CAEC and PAEC with respect to the depletion effect of hyperoxia. After 72 h of exposure to 95% O2, endothelial injury was observed in CAEC but not in PAEC. We conclude that hyperoxia decreases cyclooxygenase activity in endothelial cells, and that this decrease is dependent on the severity of the hyperoxia. In addition, CAEC are more susceptible to hyperoxia-induced injury than PAEC. The depletion of cyclooxygenase activity and the resultant effect on PGI2 and PGE2 production may be a factor in the development of hyperoxia-induced endothelial injury.
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PMID:Hyperoxia decreases cyclooxygenase activity in endothelial cells. 834 23

We tested the hypothesis that hyperoxia does not cause adequate constriction of choroidal vessels of the newborn (1 to 5 days old) pig, resulting in increased O2 delivery to the retina, possibly due to excess production and/or effects of vasodilators such as nitric oxide (NO). Hyperoxia (100% O2, 45 minutes) led to a decrease in retinal blood flow (RBF) of both newborn and juvenile (5 to 6 weeks old) pigs and also reduced choroidal blood flow (ChBF) in juvenile but not in newborn pigs; the absence of hyperoxia-induced ChBF response in the newborn was associated with a rise in choroidal O2 delivery. Ibuprofen (prostaglandin G/H synthase inhibitor) and 1,3-dimethyl-2-thiourea (a free radical scavenger) did not modify the choroidal hemodynamic responses to hyperoxia in newborn pigs. However, in newborn animals treated with the NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME), hyperoxia caused a decrease in blood flow and O2 delivery to the choroid. Consistent with these effects of L-NAME, hyperoxia induced an increase in choroidal cGMP in newborn pigs ventilated with 100% O2 and stimulated nitrite production in isolated choroids exposed to hyperoxia from newborn but not juvenile pigs; these effects were inhibited by NOS blockers. Also, both constitutive and inducible NOS activities were higher in choroidal tissues from newborn than from juvenile animals. In addition, the vasorelaxant effect of the NO donor sodium nitroprusside in vitro was also greater on choroids from newborn than from juvenile pigs. Finally, L-NAME prevented the hyperoxia-induced increase in peroxidation products in the choroid of newborns. It is concluded that hyperoxia does not lead to a decrease in blood flow and O2 delivery to the choroid of the newborn because of increased NO synthesis and effects; since the choroid is the main source of O2 supply to the retina, the present data contribute in providing an explanation for the increased susceptibility of the immature neonate to hyperoxia-induced retinopathy.
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PMID:Increased nitric oxide synthesis and action preclude choroidal vasoconstriction to hyperoxia in newborn pigs. 878 83

We investigated the role of leukotrienes (LT) in hyperoxia-induced changes in lung parenchyma in neonatal rat pups. Rat pups were exposed to 21% O(2) (air) or >95% O(2) from days 4 to 14 after birth and were administered the 5-lipoxygenase (5-LO) inhibitor and LTD4 receptor antagonist Wy-50295, 5-LO-activating protein inhibitor MK-0591, or vehicle from days 3 to 14. All measurements were done on days 12-14. There was a significant (P < 0.05) increase in peptido-LT output from lung slices of animals exposed to O(2) compared with air-exposed animals. Both Wy-50295 and MK-0591 significantly lowered (P < 0.05) peptido-LT output in O(2)-exposed animals. The 6-ketoprostaglandin F(1alpha) output was increased similarly in both vehicle- and drug-treated O(2)-exposed animals. O(2) exposure also caused a significant increase in bronchoalveolar lavage fluid protein and extravascular lung water that could not be ameliorated by Wy-50295 or MK-0591. Hyperoxia-induced inhibition of alveolarization, indicated by a significantly (P < 0.05) lower parenchymal tissue density, specific internal surface area, and airspace perimeter-to-area ratio, and a significantly (P < 0.05) higher mean linear intercept and airspace unit volume than air-exposed animals, was prevented by both Wy-50295 and MK-0591. Although hyperoxia had no effect on septal thickness, Wy-50295 caused significant thickening in both air- and O(2)-exposed pups. Our studies provide evidence that hyperoxia-induced peptido-LT may mediate O(2)-induced inhibition of alveolarization and that this is not caused by an arachidonic acid shunt to cyclooxygenase.
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PMID:Leukotrienes are indicated as mediators of hyperoxia-inhibited alveolarization in newborn rats. 912

Dogs of mixed breed (n = 7) were anesthetized, right lung atelectasis was established, and the cyclooxygenase pathway was blocked with ibuprofen. Measurements of pulmonary gas exchange were performed (fractional concentration of inspired O2 = 0.95) after infusions of prostaglandin F2alpha (PGF2alpha; 2 microg . kg-1 . min-1), ventilation with nitric oxide (NO; 40 ppm), or both (PGF2alpha + NO) in random order. The arterial PO2 (PaO2) under control conditions was 117 +/- 16 Torr (shunt = 33 +/- 2.5%), was unchanged with NO alone (PaO2 = 114 +/- 17 Torr; shunt = 35.7 +/- 3. 1%), but was significantly improved with PGF2alpha alone (PaO2 = 180 +/- 28 Torr; shunt = 23.2 +/- 2.8%) and with the combination of PGF2alpha + NO (PaO2 = 202 +/- 30 Torr; shunt = 20.9 +/- 2.5%). The addition of NO did not significantly enhance the effectiveness of the PGF2alpha on PaO2. Simulation of these data in a computer model, combining pulmonary gas exchange and pulmonary blood flow, reproduced the results on the basis that vasoconstriction with PGF2alpha was maximal under hypoxia in the atelectatic lung and reduced by hyperoxia in the ventilated lung, consistent with the hypothesis of O2 dependence of PGF2alpha vasoconstriction.
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PMID:Improved oxygenation with prostaglandin F2alpha with and without inhaled nitric oxide in dogs. 951 3

Oxygen exposure for a sufficient duration at high partial pressure results in pulmonary edema in humans and animals. Although the specific mediators of oxygen toxicity are unknown, evidence suggests that oxygen-based radicals such as superoxide anion (O2.) are increased in the lungs in the presence of hyperoxia and contribute to this injury. A series of isomeric prostanoid compounds, the isoprostanes, are formed by the free radical-initiated lipid peroxidation of arachidonic acid (AA). One of these isomers, 8-iso-PGF2alpha, is elevated in the bronchial alveolar lavage fluid of rats exposed to 90% oxygen for 48 h and is associated with a significant increase in protein accumulation in the pulmonary extravascular space. Alveolar macrophages (AMs) are capable of producing large quantities of (O2.), suggesting a role in pulmonary oxygen toxicity. We hypothesized that isolated rat AMs exposed to hyperoxia generate increased amount of 8-iso-PGF2alpha. AMs were exposed to air or 90% oxygen for 6, 12, 24, 48, 72, 96, and 120 h in the absence and presence of AA and/or calcium ionophore (A23187) and 8-iso-PGF2alpha was measured in the culture media. Exposure of primary cultures of AMs to 90% oxygen resulted in a significant increase in 8-iso-PGF2alpha in the media (25 +/- 2 pg/mL) compared with air-exposed controls (14 +/- 1 pg/mL). The addition of 10 microM AA and 2 microM A23187 to the culture media resulted in a marked increase in 8-iso-PGF2alpha production by AMs exposed to air and 90% oxygen. However, treatment of AMs with the combination of AA and A23187, followed by exposure to 90% oxygen for 72 h, resulted in a 27-fold increase in 8-iso-PGF2alpha compared with media alone and 90% oxygen. AMs metabolized free and phospholipid-bound AA to 8-iso-PGF2alpha, an activity enhanced in the 90% oxygen environment. Finally, acetylsalicylic acid, a cyclooxygenase inhibitor and free radical scavenger, reduced but did not abolish production of 8-iso-PGF2alpha. This study provides evidence that AMs produce a free radical-mediated isomeric prostaglandin compound that may be involved in pulmonary oxygen toxicity.
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PMID:8-ISO-PGF2alpha production by alveolar macrophages exposed to hyperoxia. 956 55

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

Although reductions in retinal blood flow (RBF) in response to acute hyperoxia are well described, the mechanistic basis of this response has yet to be clarified. The present study was undertaken in order to determine the possible involvement of two arachidonic acid-derived vasoconstrictors, the cyclooxygenase metabolite thromboxane and the cytochrome P450 metabolite 20-HETE, as well as the involvement of the peptide endothelin and superoxide free radical. Fluorescein videoangiography was performed on the intact eyes of isoflurane-anesthetized newborn piglets. RBF responses to 20 min of hyperoxia were calculated from the angiograms off-line, using changes in mean arteriovenous transit times and arteriolar and venular diameters. The effect of hyperoxia (PaO2=351+/-9 mmHg; n=39) on RBF was examined in each animal under control conditions and again after intravitreal perivascular administration of drugs that block the synthesis or receptors of known vasoconstrictors. Estimated RBF decreased by a maximum of 42+/-3% in the 7 animal groups in response to 20 min of hyperoxia. The magnitude and time course of the change in RBF resulting from two successive hyperoxic challenges did not differ, and were unaffected by intravitreal administration of vehicle. The response to hyperoxia was attenuated 46+/-6 (n=6; P=0.001) after intravitreal CGS 22652 (2 nmol), a combined thromboxane synthesis inhibitor and receptor antagonist. DDMS (12.5 nmol), a competitive inhibitor of the P450 enzyme omega-hydroxylase that forms 20-HETE, blocked hyperoxic constriction by 23+/-7% (n=6; P=0.01). Intravitreal pretreatment with TBC 1241z (2 nmol), a receptor antagonist of the peptide endothelin, blocked the hyperoxic response by 26+/-5% (n=6; P=0.01). A combination of CGS 22652 (2 nmol), DDMS (12.5 nmol), and TBC 1241z (2 nmol), blocked the hyperoxic flow response by 51+/-3% (n=5; P=0.003). Administration of a combination of superoxide dismutase (10 U intravitreally, 10000 U kg-1 of the polyethylene glycol-conjugate intravenously) and catalase (10 U intravitreally, 10000 U kg-1 intravenously) was without effect on hyperoxia-induced reductions in RBF (n=5). The present results indicate that the arachidonic acid metabolites thromboxane and 20-HETE, and the peptide endothelin, participate in mediating the acute reduction in RBF in response to hyperoxia.
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PMID:Mechanisms of hyperoxia-induced reductions in retinal blood flow in newborn pig. 977 17

The issue of whether the acinar microvessel response to alveolar hypoxia and hypercapnia is impaired in injured lungs has not been vigorously addressed, despite the importance of knowing whether it is or not when treating patients with serious lung injury in terms of permissive hypercapnia. Applying a real-time laser confocal luminescence microscope, we studied hypoxia- and hypercapnia-induced changes in the diameter of the intra-acinar arterioles, venules, and capillaries of isolated rat lungs harvested from animals exposed for 48 h to 21% O(2) (group N) or 90% O(2) (group H). Measurements were made with and without inhibition of nitric oxide (NO) synthase (NOS) by N(omega)-nitro-L-arginine methyl ester or of cyclooxygenase (COX) by indomethacin at different basal vascular tones evoked by thromboxane A(2) (TXA(2)) analog. Hypoxia in the absence of TXA(2) contracted arterioles in group N but not in group H. Attenuated hypoxia-induced arteriole constriction was restored almost fully by inhibiting NOS and partially by inhibiting COX. Hypercapnia induced venule dilation in group N, but did not dilate venules in group H, irrespective of TXA(2). NOS inhibition in hypercapnia unexpectedly enhanced venule and arteriole dilation in group H. These responses no longer occurred when NOS and COX were inhibited simultaneously. In conclusion, microvessel reactions to hypoxia and hypercapnia are abnormal in hyperoxia-injured acini, in which NO directly attenuates hypoxia-induced arteriole constriction, whereas COX inhibited by excessive NO impedes hypercapnia-induced microvessel dilation.
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PMID:Nitric oxide differentially attenuates microvessel response to hypoxia and hypercapnia in injured lungs. 1040 72


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