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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The dynamics and mechanisms of extracellular release of hydrogen peroxide (H2O2) from bovine pulmonary artery endothelial cells (EC) subjected to anoxia, hypoxia, and hypoxia followed by reoxygenation were examined using various inhibitors of enzymatic systems in intact cells and by direct measurement of H2O2 production from isolated EC plasma membranes. Extracellular H2O2 was measured with a fluorometric assay. EC exposed to hypoxia (3% O2) and anoxia (0% O2) released less H2O2 (29.6 +/- 1.3% and 4.2 +/- 0.7%, respectively) compared with EC exposed to normoxia (20% O2). The extracellular release of H2O2 from EC previously exposed to hypoxia for 24 h increased immediately after reoxygenation (20% O2) to 272 +/- 48%, as compared with EC exposed continuously to normoxia (100% release). Inhibition of xanthine oxidase (XO) by allopurinol did not reduce the release of H2O2 from cells exposed to normoxia or hypoxia followed by reoxygenation. Furthermore, inhibitors of cyclooxygenase (indomethacin), phospholipase A2 (quinacrine and chlorpromazine), nitric oxide synthase (L-arginine analogs), the mitochondrial electron transport chain (rotenone and cyanide), and cytochrome P-450 (methoxypsoralen) had no or minimal effect on this release. On the other hand, inhibitors of protein kinase C (calphostin and staurosporine) and NADPH oxidase (diphenyliodonium) reduced the release of H2O2 from EC in a dose-dependent manner in both exposure groups. In separate experiments, plasma membranes isolated from EC were found to produce H2O2 in the presence of NADH or NADPH as electron donors. This was inhibited by diphenyliodonium but not by allopurinol.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1995 Jan
PMID:Release of hydrogen peroxide in response to hypoxia-reoxygenation: role of an NAD(P)H oxidase-like enzyme in endothelial cell plasma membrane. 752 30

Adenosine triphosphate (ATP) acting through epithelial nucleotide receptors exerts multiple physiologic actions on airway mucociliary clearance and caliber. However, the effect of ATP on arachidonate metabolism in the airway remains unknown. In this study, the ability of ATP to regulate eicosanoid production was studied in vitro in full-thickness rabbit tracheal strips and separately in rabbit epithelial explant cultures. In the freshly isolated strips, ATP increased prostaglandin E2 (PGE2) release in a dose-dependent fashion, with an activation threshold at 10 microM ATP and a 3.5-fold increase in PGE2 output at 1 mM ATP. Epithelium removal decreased 1 mM ATP-evoked PGE2 release by 68%. Reverse-phase, high-pressure liquid chromatography (HPLC) of media from 3H-arachidonic acid-incubated epithelial explants exposed to 1 mM ATP demonstrated increased output of the cyclooxygenase products PGE2 and prostaglandin F2a (PGF2a). Other identifiable eicosanoids did not increase. The concentration-response for ATP-induced PGE2 release by explants was similar to that of tracheal strips. PGE2 release by 1 mM ATP was 27% of that elicited by ionomycin (10 microM) and was markedly inhibited by indomethacin (10 microM). Purinoceptor agonist-stimulated PGE2 release by the epithelium yielded a rank order of potency of uridine triphosphate (UTP) > or = ATP > 2-methylthio-ATP (2MeSATP) >> alpha,beta-methyleneadenosine-5'-triphosphate (AMP-CPP) > or = adenosine. These results indicate that ATP, acting primarily through an epithelial P2-purinoceptor similar to the P2a subtype, stimulates eicosanoid metabolism in rabbit airway epithelium via the cyclooxygenase pathway, producing PGE2 as the predominant species.
Am J Respir Cell Mol Biol 1995 Oct
PMID:Eicosanoid production in rabbit tracheal epithelium by adenine nucleotides: mediation by P2-purinoceptors. 754 70

Allergen challenge of sensitized Brown-Norway (BN) rats results in increased excretion of cysteinyl-leukotrienes (cLTs) in bile. It is unclear whether this reflects an increased capacity of lung cells to synthesize 5-lipoxygenase products, and, if so, which cells are of primary importance. We have examined the effects of allergen challenge on the capacity of a mixture of isolated lung cells from ovalbumin (OA)-sensitized BN rats to synthesize LTs and other eicosanoids. Cells were isolated by enzymatic digestion of lung tissue before and either 6 or 24 h after challenge of sensitized rats with either OA or saline. A23187-induced synthesis of eicosanoids by these cells was measured using high-pressure liquid chromatography. OA challenge resulted in a significant influx of neutrophils into the lungs and a significant increase in the synthesis of 5-lipoxygenase products, in particular LTB4, by lung cells after 6 h. There was a positive correlation between the percentage of neutrophils in unfractionated lung cells and the amounts of LTB4 produced by these cells. OA challenge had little or no effect on the production of cLTs and the cyclooxygenase product 12-hydroxy-5,8,10-heptadecatrienoic acid. There was a significant increase in the infiltration of eosinophils into the lungs 24 h after OA challenge but no increase in the production of cLTs by lung cells at this time, suggesting that eosinophils from BN rats are unlikely to be the major site for the production of these substances. This was confirmed in experiments with partially purified eosinophils obtained from Sephadex-treated rats. In contrast, cLTs were major products of arachidonic acid metabolism by alveolar macrophages from BN rats. We conclude that allergen challenge results in an increased capacity of lung cells to synthesize 5-lipoxygenase products, in particular LTB4. Macrophages, rather than eosinophils, may be an important site for the synthesis of cLTs in BN rat lungs.
Am J Respir Cell Mol Biol 1995 Oct
PMID:Cellular infiltration and eicosanoid synthesis in brown Norway rat lungs after allergen challenge. 754 78

Activation of N-methyl-D-aspartate (NMDA) receptors is required for induction of some lasting changes in nervous system structure and function. The cellular mechanisms involved in transducing receptor stimulation into long-lasting changes in cellular activity are unknown. Immediate-early genes (IEGs) have been implicated in the conversion of short term stimuli to long term changes in cellular phenotype, by regulation of gene expression. Activation of NMDA receptors on dentate gyrus neurons triggers the transcriptional activation of several IEGs. To determine whether the same intracellular pathways transduce the signal from this ligand-gated ion channel to the nucleus, we compared NMDA induction of two IEGs. NMDA was sufficient to produce a striking increase in both c-fos and NGFI-A mRNAs in dentate granule neurons, in a calcium-dependent manner. The induction of both IEGs was blocked by structurally distinct inhibitors of phospholipase A2, an enzyme that catalyzes phospholipid degradation and formation of arachidonic acid. Arachidonic acid itself is catalyzed to biologically active metabolites by multiple enzymes, including cyclooxygenase and lipoxygenase. Selective inhibitors of cyclooxygenase attenuated NMDA induction of c-fos but not NGFI-A. Conversely, structurally distinct inhibitors of lipoxygenase blocked NMDA induction of NGFI-A but not c-fos. The signaling pathways linking NMDA receptors to the transcriptional activation of c-fos and NGFI-A are related but distinct. We suggest that phospholipase A2 and the arachidonic acid cascade play a pivotal role in NMDA receptor regulation of gene expression.
Mol Pharmacol 1995 Jun
PMID:N-methyl-D-aspartate receptors activate transcription of c-fos and NGFI-A by distinct phospholipase A2-requiring intracellular signaling pathways. 760 50

The effect of the synthetic antiprogestin RU486 on luteal function in late pregnant rats was studied by evaluating the activities of the enzymes 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) and 20 alpha-hydroxysteroid dehydrogenase (20 alpha-HSD). RU486 (2 mg/kg) administered to rats on day 18 of pregnancy at 10.00 h induced preterm delivery 26.4 +/- 0.35 h (n = 8) after treatment. Luteal 3 beta-HSD activity increased 24 and 34 h after RU486 injection, but a significant and progressive decrease started at 48 h with the maximal reduction 72 h after RU486 treatment, when compared with controls. Serum progesterone concentration decreased at the time of 3 beta-HSD activity reduction. Interestingly, 20 alpha-HSD activity started to increase 58 h after RU486 injection. The administration of the cyclooxygenase inhibitor, diclofenac (1.3 mg/kg), on days 17-19 of pregnancy to RU486-treated rats, delayed abortion and the duration of delivery, and prevented the decrease in 3 beta-HSD and the increase in 20 alpha-HSD activities observed 58 h after antiprogesterone treatment. RU486 administered intrabursally (1 microgram per ovary) on day 20 (14.00-15.00 h) increased 3 beta-HSD and decreased 20 alpha-HSD luteal activities at 18.00 h on day 21 of pregnancy, without modifying serum progesterone concentration, when compared with normal pregnant rats. In conclusion, the luteolytic process after preterm delivery induced by RU486 administration in late pregnant rats is characterized by a decrease in luteal 3 beta-HSD activity and circulating progesterone, which may trigger the increase in luteal 20 alpha-HSD activity. Prostaglandins seems to be involved in the increase of 20 alpha-HSD activity and therefore, in the demise of corpora lutea.
J Steroid Biochem Mol Biol 1995 Jun
PMID:Luteolytic action of RU486: modulation of luteal 3 beta-hydroxysteroid dehydrogenase and 20 alpha-hydroxysteroid dehydrogenase activities in late pregnant rats. 777 60

Because interleukin-1 beta (IL-1 beta) increases the synthesis of prostaglandin E2 (PGE2) in human lung fibroblasts, the effect of IL-1 beta on the expression of two isozymes of cyclooxygenase (cyclooxygenase-1 and -2) in human embryonic lung fibroblasts (IMR-90) was investigated in terms of three parameters (PGE2 release, cyclooxygenase activity, and mRNA). When the cells were incubated with IL-1 beta, both the PGE2 release to the culture medium and the cyclooxygenase activity in the cell lysate increased in a dose- and time-dependent manner, and both were inhibited by NS-398 (a cyclooxygenase-2-specific inhibitor). Dexamethasone and interleukin-4 (IL-4) inhibited the IL-1 beta-induced PGE2 synthesis; the former inhibited the IL-1 beta-induced cyclooxygenase activity whereas the latter failed. As analyzed by Northern blot, cyclooxygenase-1 mRNAs (3.0 Kb and 5.0 Kb) were detected with resting cells and did not increase by the addition of IL-1 beta. In contrast, the cyclooxygenase-2 mRNA (4.4 Kb) was undetectable with resting cells, but was increased dramatically up to 4 to 8 h by the addition of IL-1 beta. Dexamethasone inhibited the IL-1 beta-induced mRNA expression of cyclooxygenase-2 whereas IL-4 failed. These results indicate that IL-1 beta induces cyclooxygenase-2 rather than cyclooxygenase-1 in IMR-90 cells and this induction is responsible for the augmentation of PGE2 production stimulated with IL-1 beta. However, the inhibition of the IL-1 beta-induced PGE2 synthesis by IL-4 was not mediated by the down-regulation of cyclooxygenase-2.
Am J Respir Cell Mol Biol 1995 Mar
PMID:Induction of cyclooxygenase-2 is responsible for interleukin-1 beta-dependent prostaglandin E2 synthesis by human lung fibroblasts. 787 3

The pharmacological properties of the alpha 2-adrenergic receptors regulating the release of norepinephrine were investigated in human kidney cortex. Slices were preincubated with [3H]norepinephrine, superfused in the presence of desipramine, and stimulated electrically. Two procedures were used to estimate the affinity of alpha-adrenergic antagonists at the autoreceptors. First, pEC30 values (negative logarithms of antagonist concentrations that increased the electrically evoked overflow of tritium by 30%) were determined. Second, antagonist pKd values were determined against the overflow-inhibiting effect of the alpha 2 receptor-selective agonist UK 14,304. Antagonist pEC30 values correlated well with the respective pKd values (r = 0.96, p < 0.01). The site of action of the phenylethylamine norepinephrine, as well as of the imidazoline derivative UK 14,304, is an alpha 2-adrenergic receptor. Neither the cyclooxygenase inhibitor indomethacin nor the adenosine receptor antagonist 8-sulfophenyltheophylline changed the concentration-inhibition curve of UK 14,304. When compared with binding data from the literature, the pEC30 values correlated best with the antagonist affinities at alpha 2c binding sites in an opossum kidney cell line and rat brain cortex (r > or = 0.95, p < 0.001) and at the affinities of alpha 2c sites obtained in COS cells transfected with either the human alpha 2-C4 or rat RG10-alpha 2 gene (r > or = 0.95, p < 0.01). In contrast, the correlations with alpha 2A, alpha 2B, and alpha 2D sites were not as good. Moreover, the alpha 2-autoreceptors in human kidney cortex were very similar to the alpha 2C-adrenergic receptors mediating prostaglandin synthesis in rabbit aorta but differed from alpha 2A- and alpha 2D-autoreceptors in rabbit and rat tissues. It is concluded that in human kidney cortex prejunctional autoreceptors are alpha 2C.
Mol Pharmacol 1994 Jun
PMID:Alpha 2-adrenergic receptors of the alpha 2c subtype mediate inhibition of norepinephrine release in human kidney cortex. 791 16

The homeostasis and ephemerality of the corpus luteum (CL) involves an intriguing interplay amongst pituitary, placental and intraovarian regulators. Recent findings have indicated a local pathway of synthesis for the cyclooxygenase-derived prostaglandins (PGs) in luteal cells of all mammalian species investigated. Thus, an autocrine or paracrine role of intraluteal PGs in modulation of luteal steroidogenesis is implicated. The presence of immune cells in the ovary indicates a constitutive role of these cells and their secretory products, in particular the cytokines, some of which have been demonstrated to greatly influence luteal PG and progesterone production. Despite the plentitude of investigations, a precise role for PGs other than PGF2 alpha in regulation of CL function is still obscure, mainly lacking evidence of cell-specific expression of various classes of PG receptors and their intracellular signaling mechanisms.
Mol Cell Endocrinol 1994 Apr
PMID:Auto/paracrine role of prostaglandins in corpus luteum function. 805 64

Tumor necrosis factor-alpha (TNF), an inflammatory cytokine released by macrophages, may be a mediator of lung injury during septicemia. We previously reported that the cyclooxygenase inhibitor ibuprofen and histamine receptor antagonists cimetidine (H2 antagonist) and diphenhydramine (H1 antagonist) attenuate lung injury and reduce circulating TNF surges during porcine sepsis. Since pulmonary alveolar macrophages (PAM) may participate in early sepsis by producing TNF, we hypothesized that the TNF activity of PAM is reduced by ibuprofen, cimetidine, and diphenhydramine. To test this, we examined changes in PAM-derived TNF bioactivity and cell viability of freshly isolated porcine PAM during exposure to bacterial endotoxin (LPS), ibuprofen, cimetidine, and diphenhydramine. The TNF activity (% L929 cytotoxicity of PAM conditioned medium) was elevated in LPS-stimulated PAM cultures (15 to 25% increase at 1 to 6 h and 40 to 43% increase at 6 to 48 h, compared with non-LPS-stimulated cultures), and ibuprofen (150 micrograms/ml) added with LPS decreased the TNF activity for 24 h (20 to 28% reduction at 1 to 24 h). Ibuprofen added 1 h after LPS was less effective in reducing the PAM-derived TNF activity (20 to 22% reduction at 2 to 6 h). Cimetidine (112 micrograms/ml) reduced the TNF activity of LPS-stimulated PAM cultures during the first 4 h of LPS exposure (15 to 24% decrease at 1 to 4 h). Diphenhydramine (150 micrograms/ml) attenuated the PAM-derived TNF activity but also decreased viability of PAM, indicating a toxic effect of this agent on PAM.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1993 Feb
PMID:Pharmacologic reduction in tumor necrosis factor activity of pulmonary alveolar macrophages. 809 99

The relaxant action of adenine nucleotides was studied in isolated rabbit trachealis to assess the presence of P2-purinoceptors in the airways, their cellular location, and pharmacologic properties. Strips of tracheal smooth muscle with intact epithelium were incubated in tissue baths and contracted with 1 microM acetylcholine. Over a dose range of 0.1 microM to 1 mM, ATP and ADP were significantly more potent than adenosine in relaxing tracheal smooth muscle. Significant relaxations were also elicited by AMP-PCP, AMP-CPP, and AMP-PNP, three ATP analogs stable to enzymatic hydrolysis to adenosine. In the absence of acetylcholine, neither ATP nor AMP-CPP exerted any contractile effect on the tracheal strips. In tissues selectively denuded of epithelium, ATP-, ADP-, and AMP-PCP-induced relaxations were markedly reduced. ATP-induced relaxation was also inhibited by the P2y-purinoceptor antagonist Reactive Blue 2 (RB2) (50 to 300 microM) and partially reduced by the cyclooxygenase inhibitor indomethacin (10 microM), whereas adenosine-induced relaxation was not significantly affected by these agents. These results suggest that ATP can induce smooth muscle relaxation in acetylcholine-contracted tracheal strips through a distinct P2-purinoceptor. This receptor appears to be located on the epithelium where its relaxant effect is mediated in part by release of one or more cyclooxygenase products. Additional relaxation at high ATP concentrations may occur through enzymatic hydrolysis of ATP to adenosine and interaction at P1-purinoceptors.
Am J Respir Cell Mol Biol 1994 Feb
PMID:Relaxation of rabbit tracheal smooth muscle by adenine nucleotides: mediation by P2-purinoceptors. 811 Apr 78


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