• Title, Summary, Keyword: cyclooxygenase metabolites

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The Role of Cyclooxygenase Metabolites in the Pathogenetic Mechanism of Endotoxin-Induced Acute Lung Injury in Domestic Pigs (내독소에 의한 돼지의 급성 폐손상에서 Cyclooxygenase 대사물의 역할에 관한 연구)

  • Yoo, Chul-Gyu;Jeong, Ki-Ho;Choi, Hyung-Seok;Lee, Hyuk-Pyo;Kim, Young-Whan;Han, Sung-Koo;Shim, Young-Soo;Kim, Keun-Youl;Han, Yong-Chol
    • Tuberculosis and Respiratory Diseases
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    • v.39 no.1
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    • pp.42-54
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    • 1992
  • Background:It has been suggested that the cyclooxygenase metabolites play an important role in changes of early hemodynamic parameters in the endotoxin-induced acute lung injury. But there have been many debates about their role in the late increase of alveolar-capillary permeability, and it is not known whether they act directly or indirectly through oxygen free radicals which have been known to be produced during the metabolic process of cyclooxygenase pathway. So we performed this study to identify the pathogenetic role of cyclooxygenase metabolites in the endotoxin-induced acute lung injury in domestic pigs. Method: We infused endotoxin into 8 domestic pigs; endotoxin only (n=3), and pretreatment with indomethacin (n=5). We observed the sequential changes in hemodynamic parameters, the concentration of plasma oxidized glutathione (GSSG) in pulmonary arterial and venous blood, and albumin content in bronchoalveolar lavage fluid (BALF). Results: 1) While cardiac output decreased, mean pulmonary arterial pressure, pulmonary vascular resistance, and alveolar-arterial oxygen difference increased over phase 1 (0-2hr) and phase 2 (2-4.5hr) by endotoxin, indomethacin attenuated the decrease in cardiac output during phase 1 and increase in mean pulmonary arterial pressure, pulmonary vascular resistance, and alveolar-arterial oxygen difference during both phases. 2) The increase in plasma GSSG content during phase 2 was not attenuated by indomethacin. 3) The content of BALF albumin was significantly lower in indomethacin groups than that of endotoxin group. Conclusion: These results suggest that it is likely that cyclooxygenase metabolites have an effect on endotoxin-induced acute lung injury during both phases probably through direct action.

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Study on the Action by PAF on IL-1 Modulation in Alveolar Macrophages: Involvement of Endogenous Arachidonate Metabolites and Intracellular $Ca^{++}$ Mobilization

  • Lee, Ji-Hee;Kim, Won-Ki;Hah, Jong-Sik
    • The Korean Journal of Physiology and Pharmacology
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    • v.2 no.2
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    • pp.241-249
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    • 1998
  • Platelet-activating factor(PAF) enhanced interleukin-1(IL-1) activity by the interaction with a specific receptor in rat alveolar macrophages. In this study, we investigated the role of endogenous arachidonate metabolites and intracellular calcium mobilization in the PAF-induced IL-1 activity. Alveolar macrophages were preincubated with 5-lipoxygenase and cyclooxygenase inhibitors 30 min before the addition of PAF and lipopolysaccharide(LPS). After 24h culture, IL-1 activity was measured in the supernate of sample using the thymocyte proliferation assay. Inhibition of 5-lipoxygenase by nordihydroguaiaretic acid and AA-861 completely blocked the PAF-induced enhancement of IL-1 activity with $IC_{50}\;of\;2\;{\mu}M\;and\;5\;{\mu}M$, respectively. In contrast, the inhibition of cyclooxygenase pathway by indomethacin and ibuprofen resulted in the potentiation in PAF-induced IL-1 activity with maximal effect at $1\;{\mu}M\;and\;5\;{\mu}M$, respectively. In addition, leukotriene $B_4$ and prostaglandin $E_2$ production were observed in PAF-stimulated alveolar macrophage culture. As could be expected, 5-lipoxygenase and cyclooxygenase inhibitors abolished PAF- stimulated leukotriene $B_4$ and prostaglandin $E_2$ production, respectively. The effects of PAF on intracellular calcium mobilization in alveolar macrophages were evaluated using the calcium-sensitive dye fura-2 at the single cell level. PAF at any dose between $10^{-16}\;and\;10^{-8}$ M did not increase intracellular calcium. Furthermore, there was no effective change of intracellular calcium level when PAF was added to alveolar macrophages in the presence of LPS or LPS+LTB4, and 4, 24 and 48h after treatment of these stimulants. Together, the results indicate that IL-1 activity induced by PAF is differently regulated through subsequent induction of endogenous 5-lipoxygenase and cyclooxygenase pathways, but not dependent on calcium signalling pathway.

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Effects of Antiiflammatory Agents on Acetaldehyde Induced Cytotoxicity (Acetaldehyde 유도 세포독성에 대한 항염증제의 영향)

  • 이수환;이병훈;김강석;문창규
    • Journal of Food Hygiene and Safety
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    • v.8 no.3
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    • pp.157-161
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    • 1993
  • In order to get infonnations on the development of alcohol induced cardiovascular disorders, primary cultured vascular smooth muscle cells (PVSMC) were treated with acetaldehyde, one of the most reactive metabolites of ethanol. Acetaldehyde caused the striking release of lactate dehydrogenase (LDH) from PVSMC and it stimulated the prostaglandin synthesis in the same system. But it didn't induce cyclooxygenase activity. lipoxygenase inhibitors-propyl gallate and nordihydroguaiaretic acid could reverse the effect of acetaldehyde, but dexamethasone, a phospholipase $A_2\;(PIA_2)$ inhibitor and cyclooxygenase inhibitors except indomethacin could not protect the cells from acetaldehyde toxicity. These results indicate that enhanced prostaglandin synthesis by acetaldehyde is not a direct cause of cell death, but secondary effect due to the activation of PIAl and also, the roles of the lipoxygenase metabolites and/or $PIA_2$ activity itself might be more important in the cytotoxicity of acetaldehyde.

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The Effect of Indomethacin on the Production of Eicosanoids and Edema during Ischemia-Reperfusion Injury in Skeletal Muscle

  • Chung, Yoon-Jae;Sohn, Byung-Kyu;Hyun, Kwang-Soon;Yoo, Sang-Hee;Ryu, Hyong-Kyun;Kim, Hyung-Gun
    • The Korean Journal of Physiology and Pharmacology
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    • v.4 no.6
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    • pp.525-530
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    • 2000
  • During reperfusion of skeletal muscle after ischemia, lipid mediators, mainly eicosanoids, are released and may have a role in the pathogenesis of reperfusion injury. To validate the role of eicosanoids in the ischemia-reperfusion induced functional deficits in skeletal muscle, we compared muscle edema and the changes of eicosanoid concentration in the rat hind limb after ischemia-reperfusion injury by application of tourniquet. After 4 hours of ischemia, reperfusion was established for 4 hours by releasing tourniquet. To assess tissue damage, edema, and wet/dry weight ratios were determined and the eicosanoid concnentrations were measured by the HPLC. The muscle edema and the release of cyclooxygenase metabolites were not induced by the ischemia itself rather they were significantly increased by reperfusion. Indomethacin treatment ameliorated limb edema and decreased the release of $6-keto-PGF_{1{\alpha}},$ thromboxane $B_2,$ and $PGE_2$ inducedby reperfusion. But the inhibitory effect of indomethacin on edema (35%) was relatively low than the inhibitory effect on release of cyclooxygenase metabolites (up to 69%) by reperfusion. These results support the view that cyclooxygenase products may play a significant role in the formation of muscle injury by ischemia-reperfusion and suggest that nonsteroidal antiinflammatory agents might be partially beneficial to the management of acute limb ischemia-reperfusion injury.

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Simultaneous HPLC Analysis of Arachidonic Acid Metabolites in Biological Samples with Simple Solid Phase Extraction

  • Kim, Hyung-Gun;Huh, Young-Na;Park, Kun-Suk
    • The Korean Journal of Physiology and Pharmacology
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    • v.2 no.6
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    • pp.779-786
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    • 1998
  • A reversed-phase high-performance liquid chromatogrphy (RP-HPLC) has been developed to analyze the metabolites of arachidonic acid based on the specificities of ultraviolet absorption of these various metabolites and is sensitive to the nanogram level. This procedure makes it possible to extract complex mixtures of eicosanoids efficiently with a single step and to analyze them simultaneously by RP-HPLC from biological samples using octadesylsilyl silica extraction column and $PGB_2$ as an internal standard. The cyclooxygenase products {prostaglandin $(PG)D_2,\;PGE_1,\;PGE_2,\;PGF_{1{\alpha}},\;PGF{2{\alpha}},\;6-keto-PGF_{1{\alpha}},$ and thromboxane $B_2(TXB_2)}$ and lipid peroxidation product, isoprostanes, of arachidonic acid were monitored by one isocratic HPLC system at 195 nm wavelength. The lipoxygenase products ${leukotriene(LT)B_4,\;LTC_4,\;LTD_4,$ and 5-hydroxyeicosatetraenoic acid (5-HETE), 12-HETE, 15-HETE} were measured by another isocratic HPLC system at 280 nm for LTs and 235 nm for HETEs. This method provides a simple and reliable way to extract and assess quantitatively the final arachidonic acid metabolites.

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Effects of the Geijibokryunghwan on Carrageenan-induced Inflammation and COX-2 in Hepatoma Cells

  • Joo, Shin-Tak;Ban, Chang-Gyu;Park, Soon-Gi;Park, Won-Hwan
    • Journal of Physiology & Pathology in Korean Medicine
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    • v.20 no.4
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    • pp.1027-1031
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    • 2006
  • In oriental medicine, Geijibokryunghwan(GBH) was used to improvement various symptoms created by the thrombosis. We investigated the effects of an oriental medicinal prescriptions, Geijibokryunghwan (GBH) consisting of herbs of Cinnamomi Ramufus (Geiji; 桂枝), Poria cocos (Bokrung; 茯?), Moutan Cortex Radicis(Modanpi; 牧丹皮), Paeoniae Radix (Jakyak; 芍藥) and Persicae Semen (Doin; 桃仁) on tumor growth-inhibitory activity and cancer chempreventive activity in assays representing three maior stages of carcinogenesis. Cancer chempreventive agents include nonsteroidal anti-inflammatory drugs (NSAIDS) such as indomethacin, aspirin, piroxicam, and sulindac, all of which inhibit cyclooxygenase (COX). Effects of the GBH extracts on carrageenan-induced edema Inflammation using female (C57BL/6XC3H) Fl (B6C3Fl ) mice and tumorigenesis were examined. Finally, cyclooxygenase metabolites were determined after extracts treatment. These data suggest that GBH extracts merits investigation as a potential cancer chempreventive agent in humans.

Proinflammatory Effects of Bacterial Lipopolysaccharide (LPS) in Rainbow Trout (Oncorhynchus mykiss) Macrophage Cells

  • Hong Suhee;Jeong Hyun Do
    • Fisheries and aquatic sciences
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    • v.6 no.3
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    • pp.130-134
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    • 2003
  • Proinflammatory effects of bacterial lipopolysaccharide (LPS) have been assessed by analysing the induction of two inflammatory genes, $interleukin-1\beta$ $(IL-1\beta)$ and cyclooxygenase-2 (COX-2), in rainbow trout (Oncorhynchus mykiss) macrophage cells. Production of a metabolite of arachidonic acid by COX-2, prostaglandin $E_2\;(PGE_2)$, was also analysed in macrophage cells after LPS stimulation. Northern blot analysis revealed that LPS $(5{\mu}g/mL)$ significantly upregulated $IL-1\beta$ (54 times) and COX-2 (40.7 times) gene expression in macrophage cells after 4 h stimulation. According to RT-PCR (Reverse Transcription Polymerase Chain Reaction) analysis, $IL-1\beta$ gene induction in LPS stimulated macrophage cells was started within 1h and significantly increased thereafter until 4h. Meanwhile, COX-2 gene induction by LPS was delayed in comparison with $IL-1\beta$ gene induction as a faint band was observed after 4h stimulation in head kidney macrophage cells. LPS also significantly increased $PGE_2$ production in head kidney leucocytes, presumably via activating COX-2 expression that metabolites arachidonic acid to $PGE_2$. In conclusion, it was demonstrated that LPS could induce two main inflammatory and immune related genes, $IL-1\beta$ and COX-2, and increase $PGE_2$ production in trout head kidney macrophage cells, representing a strong inflammatory activity.

Conjugated Linoleic Acid Reduction of Vascular Endothelial Growth Factor Expression in Murine Mammary Tumor Cells through Alteration of Prostaglandin E2

  • Kim, Jung-Hyun;Hubbard, Neil E.;Lim, Debora;Erickson, Kent L.
    • Preventive Nutrition and Food Science
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    • v.11 no.1
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    • pp.1-5
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    • 2006
  • Conjugated linoleic acid (CLA) is a group of positional and geometric isomers of linoleic acid that have been used to reduce the incidence, growth and metastasis of breast, colon, prostate and gastric cancer in animals. CLA could reduce tumor growth by altering angiogenesis; a process requiring associated angiogenic factors such as vascular endothelial growth factor (VEGF). In this study, we determined whether CLA could modulate the expression of VEGF in murine mammary tumor cells and adipocytes. The c9, t11-CLA isomer reduced VEGF transcripts and protein when mammary tumor cells were stimulated with PMA. That isomer also reduced VEGF expression in un stimulated mouse 3T3-L1 adipocytes. Since VEGF can be regulated by cyclooxygenase-2 (COX-2), we determined whether CLA could alter COX-2 enzyme expression and $PGE_2$ production. The c9, t11-CLA isomer reduced not only COX-2 enzyme expression but also $PGE_2$ production. Thus, c9, t11-CLA could modulate neovascularization by alteration of VEGF expression from mammary tumor cells and adipocytes by reducing COX-2 metabolites.

Dose-response assessment of the anti-cancer efficacy of soy isoflavones in dimethylhydrazine-treated rats fed 6% fructooligosaccharide

  • Sung, Rye-Young;Choi, Young-Sun
    • Nutrition Research and Practice
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    • v.2 no.2
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    • pp.55-61
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    • 2008
  • We investigated the combinatorial effects of different doses of dietary soy isoflavones (SI) and fructooligosaccharide (FOS) in a rat model of colon cancer. We hypothesized that increased bioavailability of SI metabolites due to dietary FOS may increase production of bioactive equol and affect colon carcinogenesis in a dose-dependent manner. Sprague-Dawley male rats were injected with 12-dimethylhydrazine (DMH) and were providec experimental diets that contained 0, 10, 50, 150, or 500 mg SI per kg of diet and 6% FOS for 12 weeks. The number of aberrant crypt foci (ACF) and the expression of cyclooxygenase-2 (COX-2) in colonic tissues were significantly decreased in the 6% FOS-fed groups compared to the control group. Gut transit time and fecal pH were significantly lower, and fecal concentrations of bifidobacteria were increased with 6% FOS. However, dietary SI supplementation in combination with 6% dietary FOS did not affect ACF formation or COX-2 expression. Plasma equol concentrations were dose-dependently increased by supplementation of SI up to 500 mg/kg of diet. In conclusion, SI supplementation up to 500 mg/kg of diet appeared to have no additive beneficial effects in rats with chemically-induced colon cancer that were fed 6% FOS, although plasma equol was dose-dependently increased.

Arachidonic Acid Ingibits Norepinephrine Release through Blocking of Voltage-sensitive $Ca^{2+}$ Channels in PC12 Cells

  • Choi, Se-Young;Park, Tae-Ju;Choi, Jun-Ho;Kim, Kyong-Tai
    • Animal cells and systems
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    • v.1 no.1
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    • pp.81-86
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    • 1997
  • We studied the mechanism of arachidonic acid on the secretion of a neurotransmitter in rat pheochromocytoma PC12 cells. Arachidonic acid inhibited the 70 mM $K^+$-induced secretion of norepinephrine. Arachidonic acid also inhibited the 70 mM $K^+$-induced $Ca^{2+}$ mobilization which is due to the opening of the voltage-sensitive $Ca^{2+}$ channels (VSCC). Both the half maximal inhibitory concentration ($IC_{50}$) of the norepinephrine secretion and VSCC coincided at 30 uM. The major oxidized metabolites of arachidonic acid, prostaglandins did not mimic the inhibitory effect of arachidonic acid. Nordihydroguaiaretic acid (NDGA) and indomethacin which are inhibitors of lipoxygenase and cyclooxygenase, respectively, did not block the inhibitory effect of arachidonic acid. The results suggest that arachidonic acid serves as a signal itself, not in the form of metabolites. The pretreatment of various $K^+$ channel blockers such as 4-aminopyridine, tetraethylarnmonium, glipizide, or glibenclamide also did not show any effect on the inhibitory effect of arachidonic acid. Through these results we suggest that arachidonic acid regulates VSCC directly and affects the secretion of neurotransmitters.

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