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At least 19 recordsLinked to original sources
PubMed2004

Basic calcium phosphate crystal-induced prostaglandin E2 production in human fibroblasts: role of cyclooxygenase 1, cyclooxygenase 2, and interleukin-1beta.

OBJECTIVE: To elucidate the mechanism of basic calcium phosphate (BCP) crystal-induced prostaglandin E(2) (PGE(2)) production in human foreskin fibroblasts (HFFs), to identify the signaling pathway involved in the induction of cyclooxygenase 2 (COX-2) messenger RNA (mRNA) by BCP crystals, to examine the effect of BCP crystals on interleukin-1beta (IL-1beta) mRNA expression, and to investigate the potential of phosphocitrate to abrogate the BCP crystal-induced effects. METHODS: PGE(2) levels were quantified using a commercial enzyme immunoassay kit. COX-2 and COX-1 transcript levels were quantified using real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Induction of IL-1beta and COX-2 mRNA was examined by end-point RT-PCR. COX-2 protein expression was assessed by Western blotting. RESULTS: PGE(2) production measured 4 and 30 hours after BCP crystal treatment was higher in BCP crystal-treated (mean +/- SEM 1,891 +/- 273 pg/microg and 1,792 +/- 233 pg/microg, respectively) than in untreated (88 +/- 5 pg/microg and 205 +/- 93 pg/microg, respectively) HFFs. The PGE(2) produced after 4 hours was sensitive to inhibition with NS398, a selective COX-2 inhibitor, implying that it was COX-2 mediated, whereas the PGE(2) produced at 30 hours could not be completely inhibited by NS398. Real-time RT-PCR demonstrated a 23-fold increase in COX-2 mRNA that was maximal at 4 hours, whereas analysis of mRNA for COX-1 showed up-regulation of transcript peaking at 24 hours poststimulation (1.75-fold increase). The protein kinase C and phosphatidylinositol 3-kinase signal-transduction inhibitors bisindolylmaleimide I and LY294002, respectively, blocked BCP crystal-induced COX-2 mRNA in HFFs. In addition, BCP crystals were found to up-regulate the proinflammatory cytokine IL-1beta (maximal at 8 hours). The induction of both COX-2 and IL-1beta by BCP crystals was attenuated when the cells were treated with phosphocitrate. CONCLUSION: These findings indicate that BCP crystals may be an important amplifier of PGE(2) production through induction of the COX enzymes and the proinflammatory cytokine IL-1beta.

Calcium Phosphates↗
PubMed1998

Differential effects of inhibitors of cyclooxygenase (cyclooxygenase 1 and cyclooxygenase 2) in acute inflammation.

The anti-inflammatory activity of drugs more selective for cyclooxgenase isoform inhibition (cyclooxygenase 1, cyclooxygenase 2), were compared in rat carrageenin-induced pleurisy. Suppression of inflammation by cyclooxygenase 2-selective inhibitors, NS-398 (N-[-2-cyclohexyloxy]-4-nitrophenyl methanesulphonamide) and nimesulide (4-nitro-2-phenoxy-methanesulfonanilide), and by piroxicam and aspirin, more selective for cyclooxygenase 1, was measured. Piroxicam and aspirin significantly inhibited inflammatory cell influx, exudate and prostaglandin E2 formation, 6 h after carrageenin injection. Cyclooxygenase 2 inhibitors had little effect on these parameters with NS-398 alone reducing prostaglandin E2 levels, but increasing levels of leukotriene B4. In contrast, at 3 h after carrageenin injection, cyclooxygenase 2 inhibitors significantly inhibited all inflammatory parameters however suppression with piroxicam and aspirin was greater, and more pronounced than at 6 h. NS-398 and nimesulide dosing did not reduce thromboxane B2 production from platelets isolated from rats with carrageenin-induced pleurisy, demonstrating that at the doses used, cyclooxygenase 2 inhibitors did not inhibit cyclooxygenase 1, as platelets contain only this isoform. Therefore, in the rat carrageenin-induced pleurisy, drugs more selective for the inhibition of cyclooxygenase 1 attenuate inflammation over a wider time frame than cyclooxygenase 2-selective drugs, suggesting a significant role for cyclooxygenase 1 in this model. Inhibition of cyclooxygenase 2 by NS-398 however, resulted in an increase in the potent chemoattractant leukotriene B4.

Animals↗
PubMed2003

Evaluation of the contribution of cyclooxygenase 1 and cyclooxygenase 2 to the production of PGE2 and PGF2 alpha in epithelial cells from bovine endometrium.

In ruminants, the production of prostaglandins by the endometrium is critical for recognition of pregnancy. In the absence of an embryonic signal, luteolytic pulses of PGF(2 alpha) are released by the uterus. In contrast, the presence of a viable conceptus reduces the production of PGF(2 alpha) relative to PGE(2) and prevents luteolysis through the release of trophoblastic interferon (IFN-tau). Initially, it was thought that epithelial and stromal endometrial cells were specialized in the production of a single type of prostaglandin. However, purified cell populations of both types of cell can produce PGF(2 alpha) and PGE(2); therefore, selective production of PGF(2 alpha) and PGE(2) must be regulated within each type of cell. Two distinct prostaglandin synthases, cyclooxygenase 1 and cyclooxygenase 2, are involved in prostaglandin production and each may catalyse the production of a different prostaglandin. This possibility was investigated in cultured epithelial cells from bovine endometrium. Cells were treated with oxytocin or arachidonic acid, and expression of cyclooxygenase 1 and cyclooxygenase 2 proteins was monitored over time and correlated with prostaglandin accumulation. Cells were also treated with increasing doses of inhibitors of cyclooxygenase 1 or cyclooxygenase 2 (non-steroidal anti-inflammatory drugs; NSAIDs) with or without arachidonic acid or oxytocin: flurbiprofen (0-50 micromol l(-1)) was used as a non-selective inhibitor; valeryl salicylate (0-500 micromol l(-1)) was used as a cyclooxygenase 1 inhibitor and NS-398 (0-1 micromol l(-1)) was used as a cyclooxygenase 2 inhibitor. After stimulation with arachidonic acid or oxytocin, prostaglandin production and expression of cyclooxygenase 2 protein were increased. All inhibitors were able to block basal and stimulated prostaglandin production. These results indicate that in endometrium most, if not all, prostaglandin production is probably processed through cyclooxygenase 2.

Animals↗
PubMed2001

Clinicopathologic association of cyclooxygenase 1 and cyclooxygenase 2 expression in gastric adenocarcinoma.

OBJECTIVE: To evaluate the association of clinicopathologic factors and prognostic value with the expression of cyclooxygenase 1 and 2 in patients with gastric adenocarcinoma. SUMMARY BACKGROUND DATA: Epidemiologic studies have indicated that nonsteroidal antiinflammatory drugs reduce the risk of colon cancer by as much as 40% and also decrease the risk of gastric cancer. Recently, gastric cancer was found to express constitutive cyclooxygenase 1 and inducible cyclooxygenase 2 isoenzymes. Nonsteroidal antiinflammatories, which may function as cyclooxygenase inhibitors, inhibited the growth of gastric cancer cells. These two isoenzymes' expressions associated with traditional clinicopathologic factors have not been fully evaluated, and their prognostic value for determining survival in patients remains to be clarified. METHODS: Seventy-one specimens resected from patients with gastric adenocarcinoma were investigated by immunohistochemical stain against cyclooxygenase 1 and 2. The 71 specimens were divided into stain-positive and stain-negative groups. Correlations between cyclooxygenase 1 and 2 expression, various clinicopathologic factors (including vascular invasion and Helicobacter pylori infection), and prognosis were studied. RESULTS: The cyclooxygenase 2-positive group was significantly correlated with vascular invasion and H. pylori infection by univariate and multivariate analysis. In patients with cyclooxygenase 2-positive cancer, the prognosis was significantly poorer than in those with cyclooxygenase 2-negative cancer. However, multivariate analysis showed that vascular invasion, serosal invasion, and lymph node metastasis were independent prognostic factors for patients with gastric cancer, but cyclooxygenase 2 expression was not. There was no significant correlation between cyclooxygenase 1 expression and clinicopathologic factors and prognosis. CONCLUSIONS: Upregulated cyclooxygenase 2 expression was associated with H. pylori infection in gastric cancer and was also strongly correlated with positive vascular invasion, which was an independent prognostic factor for poorer survival in this study. The usefulness of cyclooxygenase 2 inhibitors in the prevention or treatment of gastric cancer remains undetermined but deserves further investigation.

Adenocarcinoma↗
PubMed2005

Intron 1 retaining cyclooxygenase 1 splice variant is induced by osmotic stress in human intestinal epithelial cells.

The biological roles of intron 1 retaining cyclooxygenase (Cox) 1 splice variants Cox-3 and PCox-1a (Cox-1ir) are not known. In humans, Cox-3 transcription has previously been shown to occur in the brain and in the aorta. However, conclusive evidence regarding the existence of a human Cox-3 protein is lacking. We studied the expression of intron 1 retaining cyclooxygenase 1 splice variants in the human colon cancer cell line Caco-2 and in human colonic tissue samples. In Caco-2 cells, their transcription was induced up to 47-fold by osmotic stress. The corresponding protein, however, could not be detected by Western blotting. In human colonic tissue samples derived from intact and inflamed areas, a low level of Cox-1ir mRNA (1500 +/- 1280 copies per 100 ng total RNA; mean+/-standard deviation; n = 20) was also found. In Caco-2 cells, induction of Cox-1ir under osmotic stress was reversed by addition of the organic osmolyte betaine. Under hypertonic but not under isotonic conditions, splice variant-specific degradation of Cox-1ir mRNA using RNA interference resulted in increased production of fully spliced Cox-1 and Cox-2 mRNA (P = 0.002). In summary, our results indicate that the intron 1 retaining Cox-1 splice variant RNA molecules are expressed by human intestinal epithelial cells in a controlled manner, are most likely not translated and play a regulatory role in the cyclooxygenase mediated epithelial osmoregulation.

Alternative Splicing↗
PubMedDate not supplied

New immunohistologic findings on the differential role of cyclooxygenase 1 and cyclooxygenase 2 in nasal polyposis.

BACKGROUND: Cyclooxygenase 1 (Cox-1) plays a key role in arachidonic acid metabolism and in the pathophysiology and immunology of nasal polyposis in patients suffering from aspirin intolerance. We hypothesize that Cox-2 also might be relevant in the etiology of nasal polyps of aspirin-tolerant patients by their effects on inflammatory mediators as well as on microvascular permeability. METHODS: Fifty-two surgical specimens were immunohistochemically labeled for Cox-1 and Cox-2. Specimens were taken from chronically inflamed mucosa (n = 19) and from nasal polyps (n = 19) during endonasal sinus surgery. Controls were obtained from healthy nasal respiratory mucosa (n = 14), harvested during turbinate surgery in patients with nasal obstruction without inflammatory disease. Staining intensities were semiquantitatively assessed and statistically analyzed. RESULTS: In chronically inflamed tissue the expression of Cox-1 and Cox-2 was strongly labeled. However, in nasal polyps the staining pattern of Cox-1 was similar, but Cox-2 expression in epithelial cells was significantly less than in inflamed, nonpolypous specimens. CONCLUSION: These data suggest that while Cox-1 is strongly up-regulated, Cox-2 expression is significantly lower in epithelial cells of nasal polyps than in those of chronic sinusitis without polyps. The relevance of this finding has to be discussed with respect to the regulatory function of Cox on the inflammatory reaction in nasal respiratory mucosa and its hypothetical role in alterations of capillary permeability via vascular permeability factor/vascular endothelial growth factor.

Adult↗
PubMed1998

Expression of cyclooxygenase 1 and cyclooxygenase 2 in human synovial tissue: differential elevation of cyclooxygenase 2 in inflammatory joint diseases.

OBJECTIVE: To compare the expression of the cyclooxygenase (COX) isoforms, COX-1 and COX-2, in synovial tissue samples between patients with inflammatory arthritis (i.e., rheumatoid arthritis [RA], ankylosing spondylitis [AS], or psoriatic arthritis [PsA]) and patients with osteoarthritis (OA). METHODS: Paraffin-embedded sections of synovial tissue from patients with OA (n = 18), RA (n = 35), AS (n = 9), and PsA (n = 16) were immunostained for COX-1 and COX-2. Staining intensity was quantified videodensitometrically from specific synovial cell areas. In addition, samples of OA and RA synovial tissue were analyzed for levels of COX-1 and COX-2 messenger RNA (mRNA) using reverse transcriptase-polymerase chain reaction. RESULTS: Strong COX-2 immunostaining was observed in synovial blood vessel endothelium, synovial lining cells, chondrocytes, and subsynovial fibroblast-like cells in patients with inflammatory arthritides. In the blood vessels, the mean (+/-SD) optical density (MOD) of staining was elevated, especially in AS samples (2.73 +/- 0.63), but also in PsA (1.99 +/- 0.66) and RA samples (1.54 +/- 0.73), in comparison with OA synovial tissue (0.84 +/- 0.30; P < 0.01 versus other groups). COX-1 staining was almost exclusively localized in synovial lining cells, with no significant differences in the MOD between the diseases. COX-2 mRNA expression was higher in RA than in OA samples (P < 0.05). CONCLUSION: The expression of COX-2, but not the expression of COX-1, was found to be elevated in a disease-related pattern in the synovial tissue from patients with RA, AS, or PsA in comparison with OA samples, and was especially high in AS synovial tissue. These results may improve our understanding of the pathogenesis of different arthritic diseases, and may have implications for the use of selective COX-2 inhibitors in the treatment of inflammatory joint symptoms.

Adult↗
PubMed1999

Spatiotemporal expression of cyclooxygenase 1 and cyclooxygenase 2 during delayed implantation and the periimplantation period in the Western spotted skunk.

Embryonic development in the western spotted skunk is arrested after blastocyst formation for about 200 days. This developmental arrest is believed to be due to insufficiency of uterine conditions to support continuous development. Implantation and decidualization are defective in cyclooxygenase 2 (Cox2)-, but not Cox1-, deficient mice. We therefore used Northern and in situ hybridization to investigate changes in uterine expression of Cox1 and Cox2 genes during various stages of pregnancy in the spotted skunk. Cox1 was constitutively expressed at all stages of pregnancy examined, but it did exhibit localized up-regulation in the trophoblast and necks of uterine glands at early implantation sites. Cox2 expression was highly regulated with little or no expression during delayed implantation. Cox2 expression was first detected in the uterus and trophoblast prior to blastocyst attachment and remained detectable for 5-6 days after blastocyst attachment. Cox2 expression was also localized in the luminal and glandular epithelia of uterine segments located between implantation chambers. Changes in Cox expression were not correlated with the abrupt increase in uterine weight that occurs simultaneously with renewed embryonic development but was correlated with an influx of serum proteins into the uterus observed in a previous study.

Animals↗
PubMed2000

Localisation of cyclooxygenase 1 and cyclooxygenase 2 in Helicobacter pylori related gastritis and gastric ulcer tissues in humans.

BACKGROUND: Prostaglandin endoperoxide synthase/cyclooxygenase (COX) is the key enzyme in gastric mucosal protection and repair but its cellular localisation in the human stomach is still unclear. AIMS: To investigate immunohistochemically the cellular distribution of COX-1 and COX-2 proteins in the human stomach with or without gastritis or ulceration. PATIENTS AND METHODS: Tissues were obtained by surgical resection of gastric ulcers associated with perforation (n = 9) or by biopsy from Helicobacter pylori positive patients with gastric ulcers (n = 45) and H pylori negative healthy subjects (n = 15). COX expression was detected by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR), western blotting, and light and electron microscopic immunohistochemistry. RESULTS: COX-2 mRNA and protein were detected in gastric ulcer tissues but not in intact gastric mucosa. COX-1 mRNA and protein were detected in the intact mucosa. COX-2 immunostaining was exclusively localised in macrophages and fibroblasts between necrotic and granulation tissues of the ulcer bed. The percentage of COX-2 expressing cells was significantly higher in open than in closed ulcers, and in gastritis than in gastric mucosa without H pylori infection. COX-1 immunoreactivity localised in lamina propria mesenchymal cells was similar in various stages of ulcer disease and in intact gastric mucosa. Electron microscopic immunohistochemistry revealed both COX-1 and COX-2 on the luminal surfaces of the endoplasmic reticulum and nuclear envelope of macrophages and fibroblasts. CONCLUSIONS: Our results showed that COX-2 protein was induced in macrophages and fibroblasts in gastric ulcers and H pylori related gastritis, suggesting its involvement in the tissue repair process.

Adult↗
PubMed2006

Differential expression of cyclooxygenase 1 and cyclooxygenase 2 in the bovine oviduct.

The aim of the present study was to investigate the enzymes for the local prostaglandin (PG) biosynthesis present in the bovine oviduct during the estrous cycle to influence early reproductive events. Bovine oviducts were classified into four phases: pre-ovulatory, post-ovulatory, early-to-mid luteal, and late luteal phase, subdivided further into ipsi- or contralateral site and separated into ampulla or isthmus. Oviductal cells were gained by flushing the oviductal regions. Quantitative real-time reverse transcriptase-PCR was performed for the secretory and cytosolic phospholipases A(2) (sPLA(2)IB, cPLA(2)alpha, and cPLA(2)beta) and cyclooxygenases (COX-1 and COX-2) as the first step enzymes of PG synthesis. COX-1 and cPLA(2)beta showed significant highest mRNA expression around and before ovulation compared with the luteal phase respectively. sPLA(2)IB and cPLA(2)alpha mRNA expression was unregulated during the estrous cycle. Regional differences in mRNA content were found for sPLA(2)IB with higher mRNA expression in the ampulla than in the isthmus. Western blot analysis revealed the highest COX-1 protein content in the early-to-mid luteal phase. Immunohistochemistry demonstrated that COX-1 was localized in epithelial and smooth muscle cells, whereas COX-2 was only localized in epithelial cells. COX-2 showed a differential distribution within the epithelial cell layer suggesting a regulation on a cellular level, although the COX-2 mRNA and protein amounts did not vary throughout the estrous cycle. A COX activity assay of oviductal cells revealed that COX activity originated predominantly from COX-1 than from COX-2. Treatment of primary oviductal cells with 10 pg/ml 17beta-estradiol or 10 ng/ml progesterone resulted in a higher expression of COX-2 and cPLA(2)alpha, but not of the other enzymes. The expression pattern of these enzymes suggests that an estrous-cycle dependent and region-specific PG synthesis in the bovine oviduct may be required for a successful reproduction.

Animals↗
PubMed1996

Comparative effects of selective cyclooxygenase 1 and cyclooxygenase 2 inhibitors on myeloperoxidase and 3 alpha-hydroxysteroid dehydrogenase.

The clinical efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) is believed to result from the ability of these compounds to inhibit the inducible isoform of the enzyme cyclooxygenase, COX2. The gastrointestinal and renal side effects of these drugs, in contrast, are thought to relate to their ability to inhibit the constitutive isozyme, COX1. There is structural and pharmacological evidence that suggests that NSAIDs may also inhibit two unrelated enzymes, myeloperoxidase (MP) and 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD), potentially with untoward consequences for the patient. Our laboratories have been investigating a new structural class of potential COX inhibitors, the tri-cyclic aromatics. In this study we have examined the inhibitory potency of selected compounds for the enzymes human COX1, human COX2, human MP, and rat liver 3 alpha-HSD. The compounds selected span a range of COX isoform selectivities, from specific for COX2 to selective for COX1 only, and include three representative tri-cyclic aromatics. We found that compounds within the tri-cyclic aromatic class do not act as potent inhibitors of either myeloperoxidase or 3 alpha-HSD. These results demonstrate the unique inhibitor selectivity that can be achieved with the tri-cyclic aromatics. Examples of COX1 selective, and COX2 selective inhibitors within this structural class are presented.

3-Hydroxysteroid Dehydrogenases↗
PubMed2001

Non-steroidal anti-inflammatory drugs with activity against either cyclooxygenase 1 or cyclooxygenase 2 inhibit colorectal cancer in a DMH rodent model by inducing apoptosis and inhibiting cell proliferation.

BACKGROUND: Standard non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of colorectal cancer by 40-60% but the mechanism by which this occurs is uncertain. Selective cyclooxygenase 2 inhibitors are potentially ideal chemopreventive agents as they are less toxic than standard NSAIDs. No study has compared the efficacy of these drugs at clinically relevant doses in a tumour model. AIMS: To assess the efficacy of a range of NSAIDs with varying activity against the two cyclooxygenase isoforms in a rodent colorectal carcinogen model at anti-inflammatory doses and to explore the effect of NSAIDs on the rate of tumour apoptosis and proliferation. METHODS: Colorectal tumours were induced in six week old Sprague-Dawley rats with five weekly doses of 1,2 dimethylhydrazine. Test agents were: indomethacin 2 mg/kg/day, meloxicam 0.6 mg/kg/day, celecoxib 6 mg/kg/day, and sulindac sulphone 40 mg/kg/day. Sulindac was tested at its chemoprotective dose of 20 mg/kg/day. After 23 weeks the number and volume of tumours per animal were recorded. Histology was performed. Tumour apoptosis was quantified on haematoxylin-eosin sections. Tumour proliferation was quantified using an immunohistochemical stain for bromodexoyuridine incorporation. RESULTS: Test agents effectively reduced the number and volume of tumours developing in the treatment period. In all groups there was an increase in the rate of tumour apoptosis and a reduced rate of proliferation. CONCLUSIONS: These data suggest that the chemopreventive effect of NSAIDs is independent of their cyclooxygenase inhibitory profile. One potential mechanism for their action may be through induction of apoptosis and inhibition of proliferation.

Adenocarcinoma↗
PubMed2003

Cooperation of cyclooxygenase 1 and cyclooxygenase 2 in intestinal polyposis.

Membrane arachidonic acid is converted by cyclooxygenase (COX) into prostaglandin (PG) G(2) and then to PGH(2) which is subsequently metabolized to PGE(2) by PGE synthase (PGES). Both COX-1 and COX-2 play critical roles in intestinal polyp formation, whereas COX-2 is also expressed in cancers of a variety of organs. Likewise, inducible microsomal PGES (mPGES-1) is expressed in several types of cancer, although its role in benign polyp formation has not been investigated. We demonstrated recently that most COX-2-expressing cells in the polyps are stromal fibroblasts. Here we show colocalization of COX-1, COX-2 and mPGES in the intestinal polyp stromal fibroblasts of Apc(Delta 716) mice, a model for familial adenomatous polyposis. Contrary to COX-2 that was induced only in polyps >1 mm in diameter, COX-1 was found in polyps of any size. In polyps >1 mm, not only COX-2 but also mPGES was induced in the stromal fibroblasts where COX-1 had already been expressed. Although polyp number and size were markedly reduced in COX-1 (-/-) or COX-2 (-/-) compound mutant Apc mice, both COX-2 and mPGES were induced in the COX-1 (-/-) polyps, whereas COX-1 was expressed in the COX-2 (-/-) polyps. We found also in human familial adenomatous polyposis polyps that COX-2 and mPGES were induced in the COX-1-expressing fibroblasts. On the basis of these results, we propose that COX-1 expression in the stromal cells secures the basal level of PGE(2) that can support polyp growth to approximately 1 mm, and that simultaneous inductions of COX-2 and mPGES support the polyp expansion beyond approximately 1 mm by boosting the stromal PGE(2) production.

Animals↗
PubMed2002

Cyclooxygenase 1 and cyclooxygenase 2 expression is abnormally regulated in human nasal polyps.

BACKGROUND: There is evidence that impairment of prostanoid metabolism might be involved in the pathogenesis of nasal polyps (NPs). Prostanoids are synthesized by 2 cyclooxygenase (Cox) enzymes, one constitutive (Cox-1) and another inducible (Cox-2). OBJECTIVE: The aim of these studies was to investigate Cox-1 and Cox-2 regulation in NPs of aspirin-tolerant human patients compared with that seen in nasal mucosa (NM). METHODS: Cultured explants from human NPs and healthy mucosa from patients undergoing polypectomy and corrective nasal surgery, respectively, were examined for Cox-1 and Cox-2 expression by means of semiquantitative competitive PCR and Western blotting. RESULTS: Cox-1 mRNA was spontaneously upregulated in cultured NM but not in NPs. A spontaneous but delayed upregulation of Cox-2 mRNA was found in NPs (24 hours) compared with that seen in NM (6 hours). After cytokine stimulation (IFN-gamma, IL-1beta, and TNF-alpha), the induction of Cox-2 mRNA and protein was also faster in NM (1 hour) than in NPs (4 hours). CONCLUSION: These data showing an abnormal regulation of Cox-1 and Cox-2 in NPs from aspirin-tolerant patients reinforce the concept that prostanoid metabolism might be important in the pathogenesis of inflammatory nasal diseases and suggest a potential role for this alteration in the formation of NPs.

Adolescent↗
PubMed2000

High cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2) contents in mouse lung tumors.

Mouse lung tumorigenesis is a convenient model for examining all stages of lung adenocarcinoma (AC) progression. Because enhanced cyclooxygenase 2 (COX-2) expression has been observed in advanced human AC, we investigated the intracellular concentrations of the two cyclooxygenases, cyclooxygenase 1 (COX-1) and COX-2, at different times after carcinogen administration to A/J mice. The concentrations of both proteins were much higher in urethane-induced adenomas and carcinomas compared with control A/J mouse lung tissue (P < 0.03 and P < 0.01 in adenomas and AC, respectively, for COX-1; P < 0.003 and P < 0.004 in adenomas and AC, respectively, for COX-2). Small benign tumors that arose spontaneously in 13-month-old mice also stained for COX-1 and COX-2, showing that this elevated enzyme content does not depend on chemical induction. COX-1 and COX-2 immunostaining was observed in normal bronchiolar and alveolar epithelia, alveolar macrophages and bronchiolar smooth muscle. This is the first report of the cellular distribution of COX-1 and COX-2 in murine lungs and the first in any species to demonstrate their co-localization. COX content in isolated bronchiolar Clara cells, a putative cell of tumor origin, was equal to that found in tumors, suggesting that the high enzyme content in neoplasms is due to their proportionally high concentration of these tumor precursor cells. Different patterns of COX-1 and COX-2 expression were observed in tumors of different growth patterns; only occasional small foci stained in solid adenomas, while most cells in papillary adenomas were immunoreactive. This staining pattern was also seen in adenocarcinomas, but some of the papillary portions also included focally stained and unstained regions. The continued expression during neoplastic progression of these specialized enzymes present in normal cells of tumor origin suggests their function in maintenance of the neoplastic state.

Animals↗
PubMed2003

Dexamethasone differentiates NG108-15 cells through cyclooxygenase 1 induction.

Cyclooxygenase (COX) is a key enzyme in the conversion of arachidonic acid into prostanoids which participate in various cellular functions including apoptosis, mitogenesis, inflammation, immune modulation and differentiation. Moreover, the synthetic glucocorticoid, dexamethasone has immune modulating and anti-inflammatory effects in vivo. Recently, dexamethasone was found to enhance retinoic acid-induced neuronal differentiation. In this study, we investigated the mechanisms of dexamethasone-mediated neuronal differentiation. Immunoblotting and morphological analysis demonstrated that dexamethasone induced neuronal differentiation through COX 1 induction. This phenomenon was inhibited by indomethacin, a COX inhibitor. In addition, the addition of exogenous prostaglandin E2 (PGE2), a substance produced by the COX-mediated pathway, triggered neurite outgrowth of cells treated with COX inhibitor. Taken together, COX 1 appears to play an important role in dexamethasone-mediated neuronal differentiation.

Animals↗
PubMed1998

Cyclooxygenases 1 and 2.

Cyclooxygenase (COX), first purified in 1976 and cloned in 1988, is the key enzyme in the synthesis of prostaglandins (PGs) from arachidonic acid. In 1991, several laboratories identified a product from a second gene with COX activity and called it COX-2. However, COX-2 was inducible, and the inducing stimuli included pro-inflammatory cytokines and growth factors, implying a role for COX-2 in both inflammation and control of cell growth. The two isoforms of COX are almost identical in structure but have important differences in substrate and inhibitor selectivity and in their intracellular locations. Protective PGs, which preserve the integrity of the stomach lining and maintain normal renal function in a compromised kidney, are synthesized by COX-1. In addition to the induction of COX-2 in inflammatory lesions, it is present constitutively in the brain and spinal cord, where it may be involved in nerve transmission, particularly that for pain and fever. PGs made by COX-2 are also important in ovulation and in the birth process. The discovery of COX-2 has made possible the design of drugs that reduce inflammation without removing the protective PGs in the stomach and kidney made by COX-1. These highly selective COX-2 inhibitors may not only be anti-inflammatory but may also be active in colon cancer and Alzheimer's disease.

Animals↗
PubMedDate not supplied

Effects of intravenous administration of FR122047 (a selective cyclooxygenase 1 inhibitor) and FR188582 (a selective cyclooxygenase 2 inhibitor) on prostaglandin-E2-induced aqueous flare elevation in pigmented rabbits.

PURPOSE: Two isoforms of cyclooxygenase (COX-1 and COX-2) exist. To determine in vivo effects of the intravenous administration of FR122047 (a selective COX-1 inhibitor), FR188582 (a selective COX-2 inhibitor), diclofenac sodium or dexamethasone phosphate disodium on prostaglandin-E2 (PGE2)-induced aqueous flare elevation and mRNA levels for COX-1 and COX-2 in pigmented rabbits. METHODS: To produce aqueous flare elevation in rabbits, PGE2, 25 microg/ml, was applied to the cornea with the use of a glass cylinder. FR122047, FR188582, diclofenac sodium or dexamethasone phosphate disodium was intravenously injected before PGE2 application. Aqueous flare was measured with a laser flare-cell meter. The mRNA levels for COX-1 and COX-2 in the iris-ciliary body were determined by real-time polymerase chain reaction. RESULTS: FR122047, FR188582 and diclofenac sodium (15 micromol/kg each) injected intravenously 30 min before PGE2 application inhibited 29 +/- 5, 40 +/- 12 and 50 +/- 9% of aqueous flare elevation, respectively. Simultaneous injection of FR122047 (15 micromol/kg) and FR188582 (15 micromol/kg) 30 min before PGE2 application inhibited 61 +/- 8% of flare elevation. Dexamethasone phosphate disodium (15 micromol/kg) injected intravenously 300 min before PGE2 application inhibited 68 +/- 8% of aqueous flare elevation. Less than 3-fold changes in mRNA levels for COX-1 and COX-2 in the iris-ciliary body were noted after PGE2, FR122047, FR188582, diclofenac sodium or dexamethasone phosphate disodium treatment. CONCLUSION: It is possible that enzyme activities of both COX-1 and COX-2 may be involved in the mechanism of PGE2-induced aqueous flare elevation in pigmented rabbits.

Animals↗