ToxSci Advance Access originally published online on October 9, 2007
Toxicological Sciences 2008 101(1):152-158; doi:10.1093/toxsci/kfm252
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Activation of 5-Lipoxygenase and NF-
B in the Action of Acenaphthenequinone by Modulation of Oxidative Stress
,1
* Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa 920-1192, Japan
College of Pharmacy, Pusan National University, Busan 609-735, South Korea
Department of Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229
Faculty of Pharmaceutical Sciences, Doshisha Women's College, Kyoto 610-0395, Japan
1 To whom correspondence should be addressed at Graduate School of Natural Sciences and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. Fax: +81-76-234-4456. E-mail: chungsw{at}p.kanazawa-u.ac.jp; swchung{at}pusan.ac.kr.
Received June 3, 2007; accepted September 18, 2007
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ABSTRACT |
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Quinoid polycyclic aromatic hydrocarbons are potent redox-active compounds that undergo enzymatic and nonenzymatic redox cycling with their semiquinone radical. We previously reported that acenaphthenequinone (AcQ) can damage human lung epithelial A549 cells through the formation of reactive species (RS). However, the biochemical mechanisms by which RS-generating enzymes cause oxidative burst during AcQ exposure remain elusive. Here we examined the biochemical mechanism of AcQ-induced RS generation by using selective metabolic inhibitors in A549 cells. We found that AA861, a 5-lipoxygenase (5-LO)–specific inhibitor significantly decreases RS generation. This inhibition of RS seems to be 5-LO specific because other inhibitors did not suppress AcQ-induced RS generation by nicotinamide adenine nucleotide phosphate (reduced) oxidase and/or xanthine oxidase. In addition, the inhibition of 5-LO by AA861 markedly reduced AcQ-induced nuclear factor kappa B (NF-
B) activation. We further found the activation of 5-LO pathway by exposing cells to AcQ mediates the secretion of inflammatory leukotriene B4, which can be significantly suppressed by a potent RS scavenger, N-acetylcysteine. Thus, based on our findings, we propose that AcQ-induced damage is likely due to increased RS generation and NF-B activity through 5-LO activation.
Key Words: quinoid PAHs; acenaphthenequinone; reactive species; 5-lipoxygenase; NF-B; inflammation.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUPPLEMENTARY DATAFUNDINGREFERENCES |
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In recent years, many studies have focused on the adverse health effects of diesel exhaust particles (DEP), which are composed of a variety of compounds including polycyclic aromatic hydrocarbons (PAHs), oxygen-containing PAHs, nitroaromatic hydrocarbons, and aliphatic hydrocarbons (Bai et al., 2001
; Draper, 1986). They have been shown to produce reactive species (RS) by directly or indirectly enhancing inflammatory processes by inducing the expression of redox-sensitive transcription factors, growth factors, and cytokines (Kaimul et al., 2005; Mundandhara et al., 2006; Takizawa et al., 1999). One of the components of DEP is quinoid PAHs that are potent redox-active compounds producing significant amounts of reactive oxygen species undergoing either enzymatic or nonenzymatic redox cycling (Bolton et al., 2000). Many studies have shown that certain quinoid PAHs can cause oxidative damage, leading to the inflammatory response via RS generation (Chung et al., 2007; Sugimoto et al., 2005).
Several intracellular RS are known to serve in an integral signaling pathway. However, excess intracellular RS cause deleterious oxidative stress through the formation of oxidized cellular macromolecules (Bolton et al., 2000; Moldovan et al., 2006). The prolonged presence of RS as a result of exogenous pro-oxidant factors enhances the endogenous oxidase system. Endogenous cellular RS are produced by different processes, such as mitochondrial respiration, and by several enzymes, such as cyclooxygenase-2, lipoxygenase (LO), xanthine oxidase, nitric oxide synthase-3, and nicotinamide adenine nucleotide phosphate (reduced) (NAD(P)H) oxidase (Leopold and Loscalzo, 2005). One of the major sources of RS is LOs, which are nonheme iron-containing dioxygenases that oxidize arachidonic acid and linoleic acid to arachidonate hydroperoxide and linoleate hydroperoxide, respectively. Mammalian cells have several LOs (e.g., 5-, 12-, 15-, and 12/15-LO), in which the numbers refer to the position that they insert oxygen into arachidonate (Rubbo and O'Donnell, 2005). 5-LO converts arachidonic acid into leukotriene B4 (LTB4), which is a potent lung inflammatory agent. Its effects include idiopathic pulmonary fibrosis, acute lung injury, and chronic obstructive pulmonary disease (Goempertz et al., 2001; Lewis et al., 1990; Romano and Claria, 2003; Woo et al., 2000). In addition, arachidonate 5-LO acts as a pro-oxidant enzyme in the cellular redox milieu (Lewis et al., 1990; Werz and Steinhilber, 2005). 5-LO enzyme contributes to the generation of RS, leading to the activation of nuclear factor kappa B (NF-B) (Bonizzi et al., 1999; Jatana et al., 2006).
The redox-sensitive transcription factor NF-B is comprised of two subunits, p65 and p50. NF-B is present in the cytoplasm in an inactive form but enters the nucleus in response to various stimuli including oxidants and certain environmental stresses. On activation with oxidants, NF-B regulates the expression of proinflammatory proteins like tumor necrosis factor-
, interleukins, like IL-1, IL-2, and IL-6; chemokines, adhesion molecules, like intercellular adhesion molecule-1, vascular adhesion molecule, and E-selectin; enzymes like inducicle nitric oxide synthase and COX-2 (Ahn and Aggarwal, 2005; Yu and Chung, 2006). In addition, inhibition of 5-LO protects against ischemia-reperfusion injury in rats via downregulation of the inflammatory mediators NF-B and inducicle nitric oxide synthase (Jatana et al., 2006).
Although the molecular signaling pathways of PAHs have been extensively studied, relatively little attention has been paid to the effects of quinoid PAHs on the cellular regulation. Acenaphthenequinone (AcQ), a quinoid PAH is present in the atmosphere at concentrations up to 7.1 ng/m3 (California Regional Particulate Air Quality Study [CRPAQS], 2006), and recently, we reported that AcQ significantly increased intracellular RS levels in a concentration-dependent manner (Chung et al., 2007). However, the biochemical mechanisms by which RS-generating enzymes cause oxidative burst are poorly understood. The objective of the present study was to study the involvement of 5-LO and NF-B in the action of AcQ by modulating oxidative stress. Our results suggest that exposure to AcQ plays a role in cellular activation leading to the inflammatory response through the 5-LO–mediated LTB4 secretion and NF-B activation.
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MATERIALS AND METHODS |
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Chemicals and reagents.
AcQ was purchased from Sigma-Aldrich (St Louis, MO). The stock solutions of the test compounds were maintained in dimethylsulfoxide (DMSO) solutions and were added directly to the cell culture medium as 1000 x stocks to give the desired final concentration. N-acetylcysteine (NAC, RS scavenger), diphenylene iodonium (DPI) (NADPH oxidase inhibitor), allopurinol (xanthine oxidase inhibitor), rotenone (NADH dehydrogenase complex I inhibitor), tranylcypromine (monoamine oxidases inhibitor), indomethacin (cyclooxygenase inhibitor), AA861 (5-LO inhibitor), and sodium azide (partially myeloperoxidase inhibitor) were purchased from Sigma-Aldrich.
Cells and culture conditions.
A549, human lung carcinoma cells were obtained from Riken Gene Bank (Tsukuba, Japan). Cells were grown in Dulbecco's Modified Eagle Medium Media (DMEM) supplemented with 10% fetal bovine serum (FBS) (Sigma-Aldrich) in a humidified 5% CO2 at 37°C containing 100 IU/ml penicillin, 100 mg/ml streptomycin (Wako Pure Chemical, Osaka, Japan), and 2.5 mg/l amphotericin B (Sigma-Aldrich). For all experiments, cells were used at the exponential phase and plated in 100-mm culture dishes, and cultures at 70–80% confluence were used for the exposures. Cells were allowed to adhere to the dish overnight, and then the culture medium was replaced with fresh DMEM (serum free) with or without test compounds as indicated.
Determination of RS activity.
Cells were inoculated at a density of 1 x 104 cells per well in 96-well plate and allowed to adhere overnight. Cells were then incubated in serum-free DMEM containing chemicals and 10µM 2',7'-dichlorofluorescein diacetate (DCFDA, Sigma-Aldrich) at 37°C. The change in fluorescence intensity was measured using a Fluoroskan Ascent FL (Thermo Electron, Waltham, MA) at excitation and emission wavelengths of 485 and 530 nm, respectively. A fluorometric assay was performed to determine the relative levels of RS, such as superoxide radical, hydroxyl radical, and hydrogen peroxide. This assay measures the oxidative conversion of stable, nonfluorescent DCFDA to the highly fluorescent DCF in the presence of esterases (Je et al., 2004).
Protein preparation for western blot analysis.
Cells were harvested and washed twice with phosphate-buffered saline (PBS) at 4°C. Total cell lysates were lysed in lysis buffer (20mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid-NaOH [pH 7.5], 60mM β-glycerol phosphate, 20mM NaF, 150mM NaCl, 5mM ethylene glycol tetraacetic acid, 1mM Na2-ethylenediaminetetraacetic acid, 0.5% Tween-20, 0.5% NP-40, 0.5% sodium deoxycholate, 1mM dithiotreitol, 2 µg/ml leupeptin). The supernatant was collected and protein concentration was then measured with protein assay reagents (Bio-Rad, Hercules, CA). Cytosolic and nuclear extracts were prepared by CelLytic NuCLEAR Extraction kit (Sigma-Aldrich). Equal amounts of proteins were boiled for 2 min and chilled on ice, subjected to 8–12% sodium dodecyl sulfate polyacrylamide gel electrophoresis, and electrophoretically transferred onto Immobilon-P transfer membrane (Millipore, Billerica, MA). Monoclonal antibody β-actin was purchased from Sigma-Aldrich. Monoclonal antibody phosphorylate ERK and polyclonal antibody NF-B (p65 and p50), cPLA2 and TFIIB were purchased from Santa Cruz Biotechnologym, Inc. (Santa Cruz, CA). Polyclonal antibody 5-LO was purchased from Cayman Chemicals. (Ann Arbor, MI). Peroxidase-labeled donkey anti-rabbit immunoglobulin and peroxidase-labeled sheep anti-mouse immunoglobulin were purchased from Amersham Life Science (Arlington, IL). The proteins were visualized with the enhanced chemiluminescence detection system (Pierce, Rockford, IL).
Luciferase reporter gene assay.
Cells were harvested and washed with PBS. The cells were suspended in 5 ml of transfection medium of FBS-free Opti-modified eagle's medium I medium (GIBCO, Grand Island, NY) containing 20 µg of luciferase reporter vector and 50 µl of LipofectAMINE (GIBCO) and transiently transfected for 30 min at 37°C. The reporter vectors transfected to cells were NF-B promoter-driven luciferase expressing plasmid pTAL-NF-B, Then, 25 ml of assay medium was added to the cell suspension and the cells were plated on 48-well plates at a cell density of 5 x 104 cells (500 µl of diluted cell suspension solution) per well. After 24 h, the cells washed with a fresh assay FBS-free medium were treated with DMSO and each test compound. The final DMSO concentration in the assay medium was adjusted to 0.1% (vol/vol). After the treatment, the cells were harvested in 50 µl of PicaGene cell lysis buffer LUC (Toyo Ink, Tokyo, Japan). Luciferase activity in the cell lysate was assayed using a PicaGene luciferase kit (Toyo Ink) according to the manufacturer's protocol and normalized to protein concentration measured by a protein assay kit (Bio-Rad).
Enzyme immunoassay for LTB4.
Cells were transferred to a 48-well plate and allowed to adhere overnight. Cells were incubated for each time in FBS-free medium in the presence of 10µM of AcQ, and the level of LTB4 present in the media was analyzed using an enzyme immunoassay kit (R&D Systems, Minneapolis, MN), and the measurement was made according to the manufacturer's instructions.
Statistics.
The results are presented as means ± SD. The statistical significance of the difference between the groups was determined by one-factor ANOVA followed by the Fischer's protected least significance difference post hoc test. A value of p < 0.05 was considered to be significant.
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RESULTS |
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RS Generation by AcQ
Data in Table 1 show that incubation of A549 cells with 1–10µM AcQ for 1 h significantly increased the RS level in a concentration-dependent manner. To probe the source of AcQ-induced RS generation, we used several inhibitors known to block both mitochondrial and/or nonmitochondrial RS-generating enzymes. As shown in Table 2, only specific 5-LO inhibitor AA861 (50µM) significantly suppressed AcQ-induced RS production, whereas no other inhibitors had suppressive effect on AcQ-induced RS production. These results suggest that the 5-LO pathway is likely the major site source for the AcQ-induced RS generation in A549 cells, not the mitochondrial RS-generating enzyme system. We confirmed that the suppression of AcQ-induced RS generation by AA861 is dose dependent (Fig. 1A), which was compared with NAC (Fig. 1B). We also found that AA861 and/or NAC did not affect the generation of RS by oneself (Supplementary Data, Fig. S1A). Taken together, these results indicate that the RS generated by AcQ in A549 cells involves the 5-LO pathway.
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Activation of 5-LO Pathway by AcQ
To investigate the effect of AcQ on the induction of 5-LO expression, the cells were incubated with 10µM AcQ for each time. Exposure of A549 cells to AcQ caused the 5-LO protein level in nuclear extracts to significantly increase in a time-dependent manner, but caused the level of 5-LO in the cytosol to decrease (Fig. 2A). AcQ also caused an increase in cytosolic phospholipases 2 (cPLA2), phosphorylated ERK (p-ERK) (Fig. 2A) and LTB4 formation (Fig. 2B). These results are consistent with a previous report that transport of 5-LO to the nucleus is associated with increases in cPLA2 and p-ERK, which in turn cause increased production of LTB4 (Brock, 2005
).
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Effect of NAC and AA861 on AcQ-Induced 5-LO Activation
To determine whether AcQ-mediated RS generation correlates with 5-LO pathway activation, we preincubated cells with specific 5-LO inhibitor, AA861 (50µM) and RS scavenger, NAC (4mM) for 30 min, and found that AcQ-induced 5-LO activation, that is, translocation was not significantly affected by NAC. By contrast, AA861 suppressed the activation of 5-LO pathway, such as 5-LO translocation, cPLA2 activation, and ERK phosphorylation (Fig. 3A). We ascertained that NAC and AA861 did not activate the 5-LO pathway (Supplementary Data, Fig. S1B). These data strongly indicate that the suppression of RS generation by NAC did not interfere with 5-LO activation (i.e., nuclear translocation) by AcQ.
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To determine whether 5-LO translocation is involved in LTB4 secretion induced by AcQ, LTB4 level was determined by an enzyme immunoassay kit. The LTB4 level was increased by the exposure to 10µM AcQ alone but significantly suppressed by the addition of 4mM NAC and/or 50µM AA861 (Fig. 3B). These results together with those obtained with specific inhibitors imply that 5-LO pathway serves as a major site of AcQ-induced RS generation in A549 cells.
NF-B Upregulation with 5-LO Activation
Treatment of A549 cells transformed with a NF-B promoter–luciferase fusion gene with 10µM AcQ for 2 h markedly enhanced the NF-B luciferase activity (Fig. 4A), suggesting that in A549 cells AcQ upregulates NF-B expression. However, preincubation of cells with 10–50µM AA861 for 30 min diminished the NF-B activity. Next, to determine whether NF-B activation by AcQ is involved in 5-LO–related RS generation, cells were preincubated with 4mM NAC and/or 50µM AA861 for 30 min. Both NAC and AA861 strongly suppressed AcQ-induced NF-B activity as well as control (Fig. 4C). As control, we checked whether NAC and AA861 can induce NF-B activity and confirmed that they cannot (Supplementary Data, Figs. S1C and S1D). The expression was quantified by western blotting using the p65 and p50 antibodies in nuclear cellular fractions. These results suggest that 5-LO–related RS generation is required for upregulation of the inflammatory-related transcription factor NF-B.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUPPLEMENTARY DATAFUNDINGREFERENCES |
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Recently, we found that AcQ causes more oxidative stress-related damage to A549 cells compared with other quinoid PAHs tested (Chung et al., 2007
). Intracellular RS are generated by many subcellular systems, such as xanthine oxidase, NAD(P)H oxidase, cyclooxygenase-2, LO, and nitric oxide synthase-3 (Rojkind et al., 2002). Of all the enzyme systems, the 5-LO pathway is unique because it produces not only RS but also proinflammatory leukotrienes (LTs). Other studies have demonstrated a link between 5-LO and RS generation. For example, RS generated by the 5-LO pathway was found to arrest growth of fibroblasts by activating p53 (Catalano et al., 2005). Also, 5-LO activity is required for RS generation by CD28 stimulation in T lymphocytes (Los et al., 1995). However, the detailed mechanisms by which quinone PAHs, especially AcQ, directly regulate the potential site of cytosolic RS-generating enzymes are not understood. The present results suggest that 5-LO is involved in the generation of RS by various RS-generating enzymes following exposure to AcQ treatment.
Quinones, which have been identified as DEP components, reportedly have several toxic properties (Hiyoshi et al., 2005). Consequently, the perpetual exposure of these chemicals threatens human health gradually and causes several chronic diseases, including inflammation, allergy, and cancer. The toxic effects of quinones depend mainly on the generation of RS (Oginuma et al., 2005). In redox cycling of quinones, the results of two mechanisms were presented: (1) their direct actions as electrophiles, leading to covalent modification of nucleophilic functions, and (2) their ability to act as catalysts in the generation of RS. Like these enzymatic and nonenzymatic redox cycling pathways, quinone-mediated generation of RS including superoxide and hydrogen peroxide can lead to cellular oxidative stress (O'Brien, 1991; Rodriguez et al., 2005). AcQ, one of the listed quinoid PAHs, is found in particulate matter extracts (Chung et al., 2006). Although we recently suggested that AcQ plays a pivotal role in the inflammation process (Chung et al., 2007), it is very poor information of AcQ.
Because 5-LO catalyzes the early steps in the conversion of LTs, including LTB4, from arachidonic acid, it plays a key role in LT synthesis within the nucleus (Harizi et al., 2003; Woo et al., 2000). Therefore, nuclear import of 5-LO is essential for increased LT biosynthesis (Hsieh et al., 2001). To determine the possible involvement of AcQ-promoted RS on LTB4 formation, we preincubated A549 cells with the antioxidant NAC and the 5-LO–specific inhibitor AA861. We found that LTB4 formation was inhibited and that 5-LO is crucial for AcQ-mediated stasis. These data strongly indicate that AcQ-promoted RS generation causally involved in activation of 5-LO pathway and the formation of LTB4.
Oxidant stress due to RS has a profound effect on the gene transcription process as evidenced by the activation of redox-sensitive transcription factor NF-B, resulting in the translocation of the p65/p50 dimer into the nucleus where it activates mainly proinflammatory genes (Chung et al., 2002). NF-B, a major transcription factor involved in the cellular signal pathways, has been studied because of its key role in the inflammatory process (Ye et al., 2004). Several environmental pollutants including PAHs are known to transactivate NF-B (Burdick et al., 2003; Cho et al., 2005). Activation of 5-LO can generate LTB4 intermediates capable of activating NF-B (Aoki et al., 1998; Brach et al., 1992; Brock, 2005). The data presented here indicate that upregulation of NF-B by AcQ is attributable to the 5-LO pathway in A549 cells, likely mediates through RS because NAC significantly inhibited NF-B activity. Data showing the inhibition of NF-B by AA861 strongly suggest involvement of 5-LO in the activation of NF-B pathway.
In conclusion, our current findings suggest that 5-LO likely plays an important role in the AcQ-induced RS generation and NF-B activation. To establish unequivocally, further investigations are needed to see whether RS scavengers, like catalase or superoxide dismutase would prevent the translocation of 5-LO or the activation of NF-B by AcQ. The significance of our study is the proposed action of AcQ that may contribute greatly to the inflammatory processes in human pulmonary lung diseases by activating proinflammatory NF-B transcription factor and LTB4 formation through 5-LO–derived oxidative stress.
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SUPPLEMENTARY DATA |
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Supplementary data are available online at http://toxsci.oxfordjournals.org/.
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FUNDING |
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21st Century Center of Excellence program and a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUPPLEMENTARY DATAFUNDINGREFERENCES |
|---|
Ahn KS, Aggarwal BB. Transcription factor NF-
B: A sensor for smoke and stress signals. Ann. N.Y. Acad. Sci. (2005) 1056:218–233.[CrossRef][Web of Science][Medline]Aoki Y, Qiu D, Zhao GH, Kao PN. Leukotriene B4 mediates histamine induction of NF-kappaB and IL-8 in human bronchial epithelial cells. Am. J. Physiol. (1998) 274:1030–1039.
Bai Y, Suzuki AK, Sagai M. The cytotoxic effects of diesel exhaust particles on human pulmonary artery endothelial cells in vitro: Role of active oxygen species. Free Radic. Biol. Med. (2001) 30:555–562.[CrossRef][Web of Science][Medline]
Bolton JL, Trush MA, Penning TM, Dryhurst G, Monks TJ. Role of quinones in toxicology. Chem. Res. Toxicol. (2000) 13:135–160.[CrossRef][Web of Science][Medline]
Bonizzi G, Piette J, Schoonbroodt S, Greimers R, Havard L, Merville MP, Bours V. Reactive oxygen intermediate-dependent NF-kappaB activation by interleukin-1beta requires 5-lipoxygenase or NADPH oxidase activity. Mol. Cell. Biol. (1999) 19:1950–1960.
Brach MA, de Vos S, Arnold C, Gruss HJ, Mertelsmann R, Herrmann F. Leukotriene B4 transcriptionally activates interleukin-6 expression involving NK-chi B and NF-IL6. Eur. J. Immunol. (1992) 22:2705–2711.[Web of Science][Medline]
Brock TG. Regulating leukotriene synthesis: The role of nuclear 5-lipoxygenase. J. Cell. Biochem. (2005) 96:1203–1211.[CrossRef][Web of Science][Medline]
Burdick AD, Davis JW 2nd, Liu KJ, Hudson LG, Shi H, Monske ML, Burchiel SW. Benzo(a)pyrene quinones increase cell proliferation, generate reactive oxygen species, and transactivate the epidermal growth factor receptor in breast epithelial cells. Cancer Res. (2003) 63:7825–7833.
Catalano A, Rodilossi S, Caprari P, Coppola V, Procopio A. 5-Lipoxygenase regulates senescence-like growth arrest by promoting ROS-dependent p53 activation. EMBO J. (2005) 24:170–179.[CrossRef][Web of Science][Medline]
Cho AK, Sioutas C, Miguel AH, Kumagai Y, Schmitz DA, Singh M, Eiguren-Fernandez A, Froines JR. Redox activity of airborne particulate matter at different sites in the Los Angeles Basin. Environ. Res. (2005) 99:40–47.[Medline]
Chung HY, Kim HJ, Kim KW, Choi JS, Yu BP. Molecular inflammation hypothesis of aging based on the anti-aging mechanism of calorie restriction. Microsc. Res. Tech. (2002) 59:264–272.[CrossRef][Web of Science][Medline]
Chung MY, Lazaro RA, Lim D, Jackson J, Lyon J, Rendulic D, Hasson AS. Aerosol-borne quinones and reactive oxygen species generation by particulate matter extracts. Environ. Sci. Technol. (2006) 40:4880–4886.[Medline]
Chung SW, Chung HY, Toriba A, Kameda T, Tang N, Kizu R, Hayakawa K. An environmental quinoid polycyclic aromatic hydrocarbon, acenaphthenequinone (AcQ), modulates COX-2 expression through ROS generation and NF-{kappa}B activation in A549 cells. Toxicol. Sci. (2007) 95:348–355.
CRPAQS (California Regional Particulate Air Quality Study). California Air Resources Board, Central California Air Quality Studies Data Access, Sacrament. CA (2006) Available at http://www.arb.ca.gov/airways/datamaintenance/default.asp. Accessed July 4, 2006.
Draper WM. Quantification of nitro and dinitropolycyclic aromatic hydrocarbons in diesel exhaust particulate matter. Chemosphere (1986) 15:437–447.
Goempertz S, O'Brien C, Bayley DL, Hill SL, Stockley RA. Changes in bronchial inflammation during acute exacerbations of chronic bronchitis. Eur. Respir. J. (2001) 17:1112–1119.
Harizi H, Juzan M, Moreau JF, Gualde N. Prostaglandins inhibit 5-lipoxygenase-activating protein expression and leukotriene B4 production from dendritic cells via an IL-10-dependent mechanism. J. Immunol. (2003) 170:139–146.
Hiyoshi K, Takano H, Inoue KI, Ichinose T, Yanagisawa R, Tomura S, Kumagai Y. Effects of phenanthraquinone on allergic airway inflammation in mice. Clin. Exp. Allergy (2005) 35:1243–1248.[CrossRef][Web of Science][Medline]
Hsieh FH, Lam BK, Penrose JF, Austen KF, Boyce JA. T helper cell type 2 cytokines coordinately regulate immunoglobulin E-dependent cysteinyl leukotriene production by human cord blood-derived mast cells: Profound induction of leukotriene C(4) synthase expression by interleukin 4. J. Exp. Med. (2001) 193:123–133.
Jatana M, Giri S, Ansari MA, Elango C, Singh AK, Singh I, Khan M. Inhibition of NF-kB activation by 5-lipoxygenase inhibitors protects brain against injury in a rat model of focal cerebral ischemia. J. Neuroinflamm. (2006) 3:12.[CrossRef]
Je JH, Lee JY, Jung KJ, Sung B, Go EK, Yu BP, Chung HY. NF-kappaB activation mechanism of 4-hydroxyhexenal via NIK/IKK and p38 MAPK pathway. FEBS Lett. (2004) 566:183–189.[CrossRef][Web of Science][Medline]
Kaimul AM, Nakamura H, Tanito M, Yamada K, Utsumi H, Yodoi J. Thioredoxin-1 suppresses lung injury and apoptosis induced by diesel exhaust particles (DEP) by scavenging reactive oxygen species and by inhibiting DEP-induced downregulation of Akt. Free Radic. Biol. Med. (2005) 39:1549–1559.[CrossRef][Web of Science][Medline]
Leopold JA, Loscalzo J. Oxidative enzymopathies and vascular disease. Arterioscler. Thromb. Vasc. Biol. (2005) 25:1332–1340.
Lewis RA, Austen KF, Soberman RJ. Leukotrienes and other products of the 5-lipoxygenase pathway: Biochemistry and relation to pathobiology in human disease. N. Engl. J. Med. (1990) 323:645–655.[Web of Science][Medline]
Los M, Schenk H, Hexel K, Baeuerle PA, Droge W, Schulze-Osthoff K. IL-2 gene expression and NF-B activation through CD28 requires reactive oxygen production by 5-lipoxygenase. EMBO J. (1995) 14:3731–3740.[Web of Science][Medline]
Moldovan L, Mythreye K, Goldschmidt-Clermont PJ, Satterwhite LL. Reactive oxygen species in vascular endothelial cell motility. Roles of NAD(P)H oxidase and Rac1. Cardiovasc. Res. (2006) 15:236–246.
Mundandhara SD, Becker S, Madden MC. Effects of diesel exhaust particles on human alveolar macrophage ability to secrete inflammatory mediators in response to lipopolysaccharide. Toxicol. In Vitro (2006) 20:614–624.[CrossRef][Web of Science][Medline]
O'Brien PJ. Molecular mechanisms of quinone cytotoxicity. Chem. Biol. Interact. (1991) 80:1–41.[CrossRef][Web of Science][Medline]
Oginuma M, Shimada H, Imamura Y. Involvement of carbonyl reductase in superoxide formation through redox cycling of adrenochrome and 9,10-phenanthrenequinone in pig heart. Chem. Biol. Interact. (2005) 155:148–154.[CrossRef][Web of Science][Medline]
Rodriguez CE, Fukuto JM, Taguchi K, Froines J, Cho AK. The interactions of 9,10-phenanthrenequinone with glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a potential site for toxic actions. Chem. Biol. Interact. (2005) 155:97–110.[CrossRef][Web of Science][Medline]
Rojkind M, Dominguez-Rosales JA, Nieto N, Greenwel P. Role of hydrogen peroxide and oxidative stress in healing responses. Cell. Mol. Life Sci. (2002) 59:1872–1891.[CrossRef][Web of Science][Medline]
Romano M, Claria J. Cyclooxygenase-2 and 5-lipoxygenase converging functions on cell proliferation and tumor angiogenesis: Implications for cancer therapy. FASEB J. (2003) 14:1986–1995.
Rubbo H, O'Donnell V. Nitric oxide, peroxynitrite and lipoxygenase in atherogenesis: Mechanistic insights. Toxicology (2005) 208:305–317.[CrossRef][Web of Science][Medline]
Sugimoto R, Kumagai Y, Nakai Y, Ishii T. 9,10-Phenanthraquinone in diesel exhaust particles downregulates Cu,Zn-SOD and HO-1 in human pulmonary epithelial cells: Intracellular iron scavenger 1,10-phenanthroline affords protection against apoptosis. Free Radic. Biol. Med. (2005) 38:388–395.[CrossRef][Web of Science][Medline]
Takizawa H, Ohtoshi T, Kawasaki S, Kohyama T, Desaki M, Kasama T, Kobayashi K, Nakahara K, Yamamoto K, Matsushima K, et al. Diesel exhaust particles induce NF-kappa B activation in human bronchial epithelial cells in vitro: Importance in cytokine transcription. J. Immunol. (1999) 162:4705–4711.
Werz O, Steinhilber D. Development of 5-lipoxygenase inhibitors—Lessons from cellular enzyme regulation. Biochem. Pharmacol. (2005) 70:327–333.[CrossRef][Web of Science][Medline]
Woo CH, Eom YW, Yoo MH, You HJ, Han HJ, Song WK, Yoo YJ, Chun JS, Kim JH. Tumor necrosis factor-á generates reactive oxygen species via a cytosolic phospholipase A2-linked cascade. J. Biol. Chem. (2000) 275:32357–32362.
Ye YN, Liu ES, Shin VY, Wu WK, Cho CH. The modulating role of nuclear factor-kappaB in the action of alpha7-nicotinic acetylcholine receptor and cross-talk between 5-lipoxygenase and cyclooxygenase-2 in colon cancer growth induced by 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone. J. Pharmacol. Exp. Ther. (2004) 311:123–130.
Yu BP, Chung HY. Adaptive mechanisms to oxidative stress during aging. Mech. Ageing Dev. (2006) 127:436–443.[Web of Science][Medline]
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