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CELLULAR AND MOLECULAR
GSF-National Research Center for Environment and Health, Institute for Inhalation Biology, Neuherberg/Munich, Germany (I.B.-S., N.D., E.K., K.L.M., G.S., M.S.); and Merck Selbstmedikation GmbH, Darmstadt, Germany (S.M.K.)
Received July 27, 2005; accepted October 11, 2005.
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Abstract |
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; Van Cauwenberge et al., 2000; Gwaltney, 2002). Studies in both naturally and experimentally induced rhinovirus infections demonstrate that nasal secretions become enriched in proinflammatory mediators such as cytokines and arachidonic acid-derived lipid mediators including leukotrienes and prostaglandins (Gwaltney, 1995, 2002; Winther et al., 1998; Van Cauwenberge et al., 2000; Gentile and Skoner, 2001). This is usually accompanied by an infiltration of neutrophils in the nasal mucosa (Winther et al., 1998; Van Cauwenberge et al., 2000). Among the lipid mediators, leukotriene B4 (LTB4) is the most potent chemoattractant for neutrophils and might be responsible for the neutrophilic infiltrate in rhinitis patients (Denzlinger, 1996; Gentile and Skoner, 2001). LTB4, together with cysteinyl leukotrienes, enhance mucus secretion (Gentile and Skoner, 2001). Levels of nasal cysteinyl leukotrienes such as leukotriene C4 increase during an experimentally induced URTI and are temporally associated with the development of symptoms (Gentile et al., 2003). 5-Lipoxygenase (5-LO), the initial enzyme for leukotriene synthesis, is induced in epithelial cells by respiratory syncytial virus infection and catalyzes formation of LTB4 and cysteinyl leukotrienes (Behera et al., 1998).
Because nasal decongestants, e.g., oxymetazoline, effectively reduce rhinitis symptoms (e.g., obstruction, rhinorrhea), a few studies also dealt with their possible anti-inflammatory activities. Bjerknes and Steinsvag (1993) reported that compounds such as oxymetazoline chloride and xylometazoline chloride inhibit human neutrophil functions including actin polymerization, phagocytosis, and oxidative burst. Furthermore, Westerveld et al. (2000) showed that oxymetazoline strongly inhibits the expression of the inducible form of nitric oxide synthase and speculated that nasal decongestants might offer a new tool to reduce inflammatory mechanisms. Westerveld et al. (1995) also referred to anti-oxidant actions of oxymetazoline by showing that this compound is a potent inhibitor of microsomal lipid peroxidation and an excellent hydroxyl radical scavenger.
Based on these findings, we hypothesized that oxymetazoline inhibits proinflammatory reactions and prevents oxidative stress focusing on arachidonic acid-derived metabolites. We tested this hypothesis with both cell-free and cellular systems. Cytosolic phospholipase A2 (cPLA2) plays a central role in lipid mediator synthesis during inflammation by releasing arachidonic acid from membrane phospholipids. Arachidonic acid is further metabolized by cyclooxygenases (COXs) to immune-modulating prostaglandin E2 (PGE2) among other prostanoids, by 5-LO to proinflammatory LTB4, and by 15-lipoxygenase (15-LO) to anti-inflammatory 15(S)-hydroxy-eicosatetraenoic acid (15-HETE). Arachidonic acid can also be oxidized by free radical-induced peroxidation to 8-isoprostane, a marker for oxidative stress in vivo (Roberts and Morrow 2000). Because 5-LO is involved in the pathogenesis of URTI (Behera et al., 1998), oxymetazoline's putative inhibitory effect on the activity of 5-LO was directly assessed in a cell-free system. In addition, 15-LO contributing to resolution of inflammation (Serhan et al., 2003) was also tested for its response to oxymetazoline. Another cell-free system covered oxymetazoline's antioxidative potency to prevent the oxidation of methionine by agglomerates of ultrafine carbon particles (UCPs). For the cellular system to study oxymetazoline's effect, alveolar macrophages (AMs) were selected, which are competent immune cells with regard to eicosanoid metabolism (Denzlinger 1996). Particulate stimulants such as UCP and zymosan were recently shown to activate lipid mediator synthesis and to induce oxidative stress in macrophages (Girotti et al., 2004; Beck-Speier et al., 2005). It is noteworthy that the tissue eicosanoid metabolism seems to be enhanced in upper airway diseases (Perez-Novo et al., 2005), and increased numbers of macrophages in the nasal mucosa during URTI (van Benten et al., 2001, 2005) might trigger this change. Therefore, canine AMs stimulated by UCP or opsonized zymosan were used as a model for activated lipid mediator synthesis and oxidative stress. They were analyzed for cPLA2 activity and formation of PGE2, 15-HETE, LTB4, and 8-isoprostane. In addition, cPLA2-dependent stimulation of respiratory burst activity was assessed to evaluate the microbicidal defense capacity of AMs.
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Materials and Methods |
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Solutions of Oxymetazoline and Suspensions of Ultrafine Carbon Particles and Opsonized Zymosan
Oxymetazoline (Merck Biosciences, Darmstadt, Germany) was dissolved and diluted in PBS with Ca2+/Mg2+, pH 7, containing 0.1% glucose. Ultrafine carbon particles were generated by spark discharging according to Roth et al. (2004). The particles consisted of individual primary particles with a diameter of 5 to 10 nm and a specific surface area of 750 ± 150 m2/g (n = 50). During aerosol generation, the primary particles aggregated to agglomerates of a size of about 70 nm. These agglomerates of UCPs were suspended in distilled water by repeated vortexing and sonification as described previously (Beck-Speier et al., 2005). In suspension, UCP formed even larger agglomerates with a size distribution of 70% being <100 nm and 30% being >100 nm (S. Takenaka, unpublished data). The specific surface area of these agglomerates is very similar to the sum of the surface areas of the primary particles. In the incubations, the cells were exposed to UCP at a mass concentration of 32 µg/ml, which corresponded to a surface area of 240 cm2/ml. This concentration of UCP was chosen to achieve optimal cellular responses of the arachidonic acid-derived metabolites and respiratory burst activity (Beck-Speier et al., 2005).
Opsonized zymosan was prepared from zymosan A with a diameter of 2 to 3 µm (Sherwood and Richardson, 1988; Dewitt et al., 2003). The zymosan A was purified by boiling for 30 min at 90°C in PBS and incubated with fresh-frozen canine serum in equal volume portions for 30 min at room temperature according to Allen (1986). The opsonized zymosan was washed twice, suspended in PBS, pH 7, containing 0.1% glucose, and aliquots were frozen until use. The cells were exposed to opsonized zymosan at 100 µg/ml, which represents a mass concentration to achieve optimal functional responses (Maier et al., 1992; Beck-Speier et al., 2005). In comparison with UCP, the zymosan particles with their larger diameter (2-3 µm) possess a smaller surface area per mass (estimated below 10 m2/g) than UCP. The specific surface area is a decisive parameter for particles to elicit biologic responses (Beck-Speier et al., 2005).
Cell-Free Systems with Oxymetazoline
Lipoxygenase Inhibitor Activity. The lipoxygenase inhibitor activity of oxymetazoline was determined by a lipoxygenase inhibitor screening assay (Cayman Chemical) in a cell-free system consisting of 5-LO with linoleic acid as substrate or 15-LO with arachidonic acid as substrate, respectively. Oxymetazoline in concentrations ranging from 0.001 to 1 mM was added to 5-LO or 15-LO in the screening assay buffer, respectively, and the lipoxygenase inhibitor screening assay was immediately started by addition of the corresponding substrates and running for 5 min according to the instructions of the manufacturer.
Influence on the Oxidative Capacity of UCP. The influence of oxymetazoline on the oxidative capacity of UCP was studied by preincubating UCP (2 mg/ml H2O) with various concentrations of oxymetazoline (0.1, 1, and 10 mM) for 60 min at room temperature in parallel with the controls. To assay the oxidative capacity of UCP, aliquots of 50 µl (100 µg UCP) of particle suspension taken from the preincubations were suspended in 1 ml H2O and incubated in the presence of 100 µM methionine for 2 h at 25°C. Formation of methionine sulfoxide was measured fluorometrically after precolumn derivatization with o-phthaldialdehyde and high-performance liquid chromatography separation as described recently (Beck-Speier et al., 2005).
Alveolar Macrophages
Canine AMs were isolated by bronchoalveolar lavage of healthy beagle dogs, centrifuged at 400g for 20 min and resuspended in PBS without Ca2+/Mg2+ as previously described by Beck-Speier et al. (2005).
Incubation of Alveolar Macrophages with Oxymetazoline
To assess the effect of oxymetazoline on AMs in the absence and presence of UCP or opsonized zymosan as stimulatory agents, respectively, the following treatments were performed: AMs (1 x 106 cells/ml) were incubated with various oxymetazoline concentrations in PBS with Ca2+/Mg2+, pH 7, containing 0.1% glucose, for 80 min at 37°C; AMs (1 x 106 cells/ml) were preincubated with various oxymetazoline concentrations in PBS, pH 7, with Ca2+/Mg2+ and 0.1% glucose for 20 min at 37°C, subsequently stimulated by UCP (32 µg/ml), and incubated for further 60 min at 37°C; and AMs (1 x 106 cells/ml) were preincubated with various oxymetazoline concentrations in PBS, pH 7, with Ca2+/Mg2+ and 0.1% glucose for 20 min at 37°C, subsequently stimulated by opsonized zymosan (100 µg/ml), and incubated for further 60 min at 37°C. The incubation procedures were terminated by centrifugation at 400g for 10 min at room temperature. The cells were resuspended in HEPES buffer, pH 7.4, containing 1 mM EDTA. Aliquots were examined for cell viability as determined by trypan blue exclusion. The residual cells were homogenized by sonification (3 x 15 s) and centrifuged at 10,000g for 15 min at 4°C. The supernatants were taken for determination of protein, cPLA2 activity, and lipid mediators.
Cytosolic Phospholipase A2 Activity of Alveolar Macrophages
The supernatants of the cell homogenates were analyzed for cPLA2 activity by performing a cPLA2 activity assay (Cayman Chemical) according to the instructions of the manufacturer. Protein was measured at 595 nm in a microtiter plate format by using 5 µl of homogenate and 200 µl of 1:5 diluted Biorad solution (Bio-Rad, Munich, Germany) with bovine serum albumin as standard.
Lipid Mediators of Alveolar Macrophages
For analysis of lipid mediators, the supernatants of the cell homogenates were deproteinized by adding 8-fold volume of 90% methanol containing 0.5 mM EDTA and 1 mM 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl, pH 7.4 (Beck-Speier et al., 2005). These methanol suspensions were stored at -40°C for 24 h followed by two centrifugation steps at 10,000g for 20 min at 4°C with a 24-h interval to remove the proteins. Aliquots of the obtained supernatants were dried in a vacuum centrifuge, dissolved in assay buffer, and used for quantification of PGE2, LTB4, 15-HETE, and 8-isoprostane by their specific enzyme immunoassays (Cayman Chemical) according to the instructions of the manufacturer.
Respiratory Burst Activity of Alveolar Macrophages
The respiratory burst activity of AMs was determined by lucigenin-dependent chemiluminescence (CL) (Allen, 1986; Li et al., 1998). Canine AMs (1 x 105 cells/250 µl) were preincubated in PBS with Ca2+/Mg2+, pH 7, containing 0.1% glucose and 0.8 mM lucigenin, for 10 min at 37°C in a chemiluminescence analyzer (Autolumat LB 953; Berthold Technologies, Bad Wildbad, Germany). CL signals of AMs in the absence and presence of various oxymetazoline concentrations were recorded for 20 min at 37°C. Thereafter, UCP or opsonized zymosan, respectively, was added, and the CL signals of the cells were monitored for further 20 min at 37°C.
Statistical Analysis
Statistical significance was determined by analysis of variance and two-sample Student's t test (STAT-SAK, version 2.12, by G.E. Dallal, 1986; Malden, MA). Changes with p 
0.05 were considered as significant.
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Results |
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Evaluation of the Inhibitor Activity of Oxymetazoline against 5-Lipoxygenase and 15-Lipoxygenase. The inhibitory capacity of oxymetazoline against lipoxygenases was studied in a cell-free system consisting of oxymetazoline and 5-LO or 15-LO together with appropriate substrates, respectively. Figure 1 shows that oxymetazoline at concentrations from 0.4 to 1 mM strongly inhibited the activity of 5-LO, whereas that of 15-LO was only marginally affected. A 50% inhibition of 5-LO was achieved by 0.4 mM oxymetazoline.
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Cellular System with Alveolar Macrophages: Effect of Oxymetazoline on Generation of Arachidonic Acid-Derived Metabolites and Respiratory Burst Activity
The effect of oxymetazoline on AMs in the absence and presence of stimulators was studied in view of the following endpoints: activation of cPLA2, including formation of PGE2 and 15-HETE; and formation of LTB4, CL as respiratory burst activity, and 8-isoprostane as marker for lipid peroxidation. These cellular responses were studied under three different conditions.
Oxymetazoline in the Absence of Stimulatory Agents. As shown in Fig. 2A, oxymetazoline exerted a mild but significant stimulatory effect on cPLA2 activity and formation of 15-HETE at 1 mM concentration and on synthesis of PGE2 at concentrations ranging from 0.1 to 1 mM. However, as demonstrated in Fig. 2B, LTB4 formation was significantly inhibited by oxymetazoline at concentrations from 0.4 to 1 mM, and CL was decreased by oxymetazoline concentrations from 0.1 to 1 mM. Formation of 8-isoprostane was not altered by oxymetazoline (Fig. 2B). Cell viability remained stable in the presence of oxymetazoline (mean ± S.D. resulting from four different experiments): 93 ± 1% viability for control cells, 90 ± 2% for 0.001 mM oxymetazoline-treated cells, 91 ± 3% for 0.01 mM oxymetazoline-treated cells, 89 ± 5% for 0.1 mM oxymetazoline-treated cells, 89 ± 4% for 0.4 mM oxymetazoline-treated cells, and 85 ± 6% for 1.0 mM oxymetazoline-treated cells. Similar findings were obtained when the cells were stimulated in the presence of oxymetazoline by UCP or opsonized zymosan (data not shown), indicating that oxymetazoline in concentrations up to 1.0 mM did not remarkably impair cell viability.
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Oxymetazoline in the Presence of Ultrafine Carbon Particles. To study the effect of oxymetazoline on UCP-stimulated AMs, a particle concentration of 32 µg/ml was selected to induce significant effects on arachidonic acid-derived metabolites and respiratory burst activity (Beck-Speier et al., 2005). As shown in Fig. 3, A and B, UCP in the absence of oxymetazoline stimulated AMs for a strong increase in the levels of cPLA2 activity, PGE2, 15-HETE, LTB4, CL, and 8-isoprostane (p < 0.01). However, the presence of oxymetazoline exerted various effects on these UCP-induced responses. Oxymetazoline did not essentially change the UCP-induced levels of cPLA2 activity and 15-HETE (Fig. 3A). The UCP-induced increase of PGE2 formation was reduced by low oxymetazoline concentrations (0.001 and 0.01 mM) but not by higher oxymetazoline concentrations (0.1 and 1 mM). The UCP-induced levels of LTB4 synthesis and CL were not affected by the low oxymetazoline concentrations (0.001 and 0.01 mM) but inhibited by higher oxymetazoline concentrations (Fig. 3B). The particle-induced formation of 8-isoprostane was strongly reduced by all concentrations of oxymetazoline (Fig. 3B).
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; Beck-Speier et al., 2005). In the presence of oxymetazoline, the levels of both parameters decreased drastically at higher oxymetazoline concentrations (0.1-1.0 mM).
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Discussion |
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) and as it is known for zymosan (Girotti et al., 2004). Phagocytosis is accompanied by respiratory burst (Root and Metcalf, 1977). According to our observation, opsonized zymosan elicits a much higher respiratory burst activity in AMs than nonopsonized UCP due to receptor-mediated versus nonreceptor-mediated phagocytosis (Beck-Speier et al., 2005).
In the cell-free system, oxymetazoline strongly inhibited 5-LO activity with an effective concentration of 0.4 mM for 50% inhibition but did not affect 15-LO activity (Fig. 1). This difference of oxymetazoline's influence on 5-LO and 15-LO was also found in the cellular system. Likewise, oxymetazoline strongly inhibited the synthesis of proinflammatory LTB4 and respiratory burst activity in AMs, whereas cPLA2 activity with production of PGE2 and 15-HETE was enhanced (Fig. 2). In AMs stimulated by UCP, oxymetazoline (0.1 mM) did not alter UCP-induced cPLA2 activity and formation of PGE2 plus 15-HETE but again inhibited UCP-induced LTB4 formation and respiratory burst activity (Fig. 3). However, at lower oxymetazoline concentrations (0.001 and 0.01 mM), PGE2 production of UCP-treated AMs was reduced. The underlying mechanism needs to be clarified. After stimulating AMs with opsonized zymosan, oxymetazoline also inhibited the enhanced LTB4 formation and respiratory burst activity (Fig. 4). Concerning the effective oxymetazoline concentration for 50% inhibition of the 5-LO pathway with LTB4 formation, the cellular system with 0.1 mM oxymetazoline responded even more sensitive as the cell-free system.
As reported recently, UCP showed a pronounced electron paramagnetic resonance signal indicating unpaired electrons within the carbon matrix of the particles contributing to a highly reactive surface area (Beck-Speier et al., 2005). This electron paramagnetic resonance signal corresponded with a high oxidative capacity of UCP to oxidize methionine in a cell-free system and to induce oxidative stress in a cellular system with canine AMs, indicated by 8-isoprostane formation (Beck-Speier et al., 2005). Because oxymetazoline failed to reduce the oxidative potential of UCP in the cell-free system, we exclude a pronounced interaction of oxymetazoline with particle-associated radicals. However, in our cellular system, oxymetazoline did not induce 8-isoprostane formation by itself (Fig. 2B) but stopped very efficiently the particle-induced oxidative stress at the lowest concentration (0.001 mM) (Fig. 3B). This antioxidative and radical scavenger effect of oxymetazoline might result from its interference with the UCP-induced peroxidation of arachidonic acid.
Oxymetazoline was shown to reduce functions of human neutrophils including actin polymerization, phagocytosis, and oxidative burst at concentrations of about 1 mM as described by Bjerknes and Steinsvag (1993). Furthermore, Westerveld et al. (2000) referred that 0.3 mM oxymetazoline inhibited inducible nitric oxide synthase in a cellular system with rat alveolar macrophage cell line NR 8383, whereas the constitutive nitric oxide synthase was not affected. Oxymetazoline was also a potent inhibitor of lipid peroxidation and excellent hydroxyl radical scavenger (Westerveld et al., 1995). In a cell-free model of microsomal lipid peroxidation, consisting of Fe2+/ascorbic acid and liver microsomes, oxymetazoline inhibited lipid peroxidation completely at concentrations between 0.015 and 0.02 mM (Westerveld et al., 1995). With regard to these earlier studies, it must be noted that relatively high concentrations of oxymetazoline (
0.3 mM to reduce proinflammatory responses of neutrophils and macrophages and 0.02 mM to inhibit lipid peroxidation) were necessary to induce the observed effects. In comparison with these findings, our cellular model with AMs was significantly more sensitive because oxymetazoline concentrations as low as 0.1 mM suppressed proinflammatory reactions and as low as 0.001 mM inhibited UCP-induced lipid peroxidation. Nasal application of decongestants results in the development of a concentration gradient. Assuming a total nasal epithelial lining fluid volume of 800 µl/nostril (Kaulbach et al., 1993), oxymetazoline used in its current product concentration of 1.6 mM (nose sprays for adults and school children) at a dosage volume of 45 µl/puff will be diluted to form a concentration gradient that refers to levels of the active substance used in our experiments (estimated mean value 
0.1 mM). Therefore, the obtained results are of relevance in situ.
Various studies demonstrated strong correlations between rises of inflammatory mediators, mainly cytokines and leukotrienes, and the expression of rhinitis symptoms (Gwaltney, 1995, 2002). Particularly leukotrienes such as LTB4 and leukotriene C4, which rise in the nasal fluid of rhinitis patients, are generated and released by virus-infected cells of the respiratory tract (Ananaba and Anderson, 1991; van Schaik et al., 1999; Gentile and Skoner, 2001; Gentile et al., 2003). Leukotrienes such as LTD4 applied directly to the nasal mucosa of noninfected individuals reproduced symptoms of nasal congestion and rhinorrhea (Bisgaard et al., 1986). Treatments with 5-LO enzyme inhibitors or cysteinyl leukotriene receptor antagonists have been shown to induce a significant clinical benefit because these compounds reduces nasal congestion in allergic rhinitis (Naclerio et al., 1991; Liu et al., 1998; Meltzer et al., 2000). Furthermore, oxidative stress also seems to play a pivotal role in the pathogenesis of viral respiratory infections because reactive oxygen species like nitric oxide have been reported to increase in the exhaled air of patients with allergic rhinitis or URTI (Kharitonov et al., 1995; Martin et al., 1996). The data of our present study reveal oxymetazoline as potent inhibitor of inflammatory and oxidative stress-dependent reactions. This activity resembles the mechanisms described for nonsteroidal anti-inflammatory drugs that act by blocking COX-1 and COX-2, thus inhibiting the conversion of arachidonic acid to prostanoids. Research done over the last few years suggests that drugs inhibiting both the COX enzymes and 5-LO might exert a potent anti-inflammatory effect (Naveau, 2005; Pereg and Lishner, 2005).
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) justifies the extrapolation of our data obtained with canine AMs to the human system. As a consequence, oxymetazoline's anti-inflammatory and antioxidative action is offering additional benefits for the treatment of virus-induced upper respiratory tract inflammation and oxidative stress. The data shown here add significant new information for understanding oxymetazoline's way to modulate and reduce rhinitis symptoms. |
Footnotes |
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ABBREVIATIONS: URTI, upper respiratory tract infection; LTB4, leukotriene B4; 5-LO, 5-lipoxygenase; cPLA2, cytosolic phospholipase A2; COX, cyclooxygenase; PGE2, prostaglandin E2; 15-LO, 15-lipoxygenase; 15-HETE, 15(S)-hydroxy-eicosatetraenoic acid; UCP, ultrafine carbon particle; AM, alveolar macrophage; PBS, phosphate-buffered saline; CL, chemiluminescence.
Address correspondence to: Dr. Ingrid Beck-Speier, GSF-National Research Center for Environment and Health, Institute for Inhalation Biology, Ingolstädter Landstrasse 1, D-85764 Neuherberg/Munich, Germany. E-mail: beck-speier{at}gsf.de
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