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INFLAMMATION AND IMMUNOPHARMACOLOGY
KEIO Research Park 2N4, Keio University School of Medicine, Tokyo, Japan
Received for publication
September 30, 2004
Accepted
December 1, 2004.
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Abstract |
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Cyclooxygenase (COX) is a key enzyme in inflammation. COX catalyzes the conversion of arachidonic acid to eicosanoids, including prostaglandins (PGs) and thromboxanes, and these COX-derived eicosanoids (especially PGE2) are heavily involved in inflammatory diseases. Prostaglandins have also been implicated in adhesion formation, because tissue PGE2 levels are elevated in bowels traumatized by mechanical stimuli (Celebioglu et al., 1999
). There are two COX isozymes: COX-1 is constitutively expressed in most tissues and plays various basic "house-keeping" roles; in contrast, COX-2 is induced in response to various stimuli and is involved in the pathogenesis of various diseases, including inflammation and tumors. Recent reports suggest a significant role for COX-2 in adhesion formation in the uterine horn (Guvenal et al., 2001; Saed et al., 2003), whereas the contribution of COX-1 to abdominal adhesion is not fully understood. A role for COX-1 in inflammation was confirmed by studies using mice in which the Ptgs1 gene encoding COX-1 was disrupted (Langenbach et al., 1995). Involvement of COX-1 in the development of inflammation has been also demonstrated in a rat model of collagen-induced arthritis (Ochi and Goto, 2002). Because COX-1 is constitutively expressed throughout the gastrointestinal tract in several species, including humans (Kargman et al., 1996), the roles of COX-1 in abdominal adhesion formation require closer investigation.
COX-2 is an inducible isozyme and several proinflammatory stimuli increase the expression level of COX-2 at inflammatory sites. The molecular mechanisms that regulate COX-2 expression have been extensively studied, and involvement of several factors, including mitogen-activated protein (MAP) kinases (Guan et al., 1998; Ridley et al., 1998; Scherle et al., 1998), peroxisome proliferator-activated receptors, and nuclear factor-
B (Plummer et al., 1999; Charalambous et al., 2003), has been suggested (Pang et al., 2003). Accumulating evidence suggests that the major signaling pathway responsible for COX-2 induction differs, depending on the stimulus and the cell type. Hence, it has been shown that p38 MAP kinase can be activated by mechanical stimuli (Dieckgraefe et al., 1997; Pyles et al., 1997), and mechanical stimuli-induced COX-2 expression is mediated by activation of p38 MAPK in podocytes (Martineau et al., 2004). Based on these reports, we were interested in determining whether the p38 MAPK pathway plays a significant role in COX-2 expression in the mechanically stimulated cecum.
The aims of the present study were to elucidate the contribution of COX-1 and COX-2 in adhesion formation and to determine the signaling pathways implicated in the induction of COX-2 in the traumatized cecum, with a particular focus on the involvement of p38 MAP kinase.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Mofezolac (Mitsubishi Pharma, Tokyo, Japan) is a highly selective COX-1 inhibitor (Goto et al., 1998), and NS-398 (N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide) and CAY10404[3-(4-methylsulphonylphenyl)-4-phenyl-5-trifluoromethylisoxazole], purchased from Cayman Chemical (Ann Arbor, MI), were used as specific COX-2 inhibitors (Habeeb et al., 2000). PGE2 and (R)-butaprost, an analog of PGE2 with good selectivity for the EP2 receptor subtype (Kiriyama et al., 1997), and AH6809 (6-isopropoxy-9-oxoxanthene-2-carboxylic acid) and SC-19220 (8-chloro-dibenz[b,f][1,4]-oxazepine-10(11H)-carboxy-(2-acetyl)hydrazide) were also obtained from Cayman Chemical. SB202190 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole], which is a widely used pyridinyl imidazole inhibitor of p38
and p38
, but not p38
and p38
(Jiang et al., 1996, 1997; Kumar et al., 1997; Stein et al., 1997; Wang et al., 1997), was obtained from Calbiochem (San Diego, CA). Antibodies for p38 and phosphorylated p38 (Thy180/Tyr182) were obtained from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA). Antibodies for COX-1 or COX-2 for use in Western blotting were also obtained from Santa Cruz Biotechnology, Inc.
Formation of Experimental Adhesion. Mice were anesthetized with a subcutaneous injection of sodium pentobarbital (40 mg/kg). After treatment of the abdomen with a povidone iodine solution, a vertical midline incision was made and the cecum was exteriorized. Both surfaces of the cecum were scraped 40 times with a swab, without injuring the mesenteric arteries and veins. The cecum was returned to its original position, and the abdominal wall facing the treated cecum was also scraped with a swab. The abdomen was closed in two layers with a silk suture. All procedures were conducted under sterile conditions. Sham-operated mice were prepared in the same manner, but no scraping was performed.
Mofezolac, NS-398, and CAY10404were orally administered to the mice once daily for 7 days. Vehicle control mice were given 0.5% methylcellulose solution orally. AH-6809, SC-19220, and SB202190 were dissolved in dimethyl sulfoxide and diluted 1000-fold with sterile phosphate-buffered saline (PBS) to obtain the desired concentrations. Then, 0.5 ml of each solution was administered to the mice by intraperitoneal (i.p.) injections. Although SB202190 is known to be toxic, no signs of toxicity (including no decrease in body weight) were observed in SB202190-treated mice at the doses used, compared with vehicle-treated mice. Administration of 0.5 ml of a 15 µM SB202190 solution results in a systemic dose of 82.5 µg/kg, which gives little or no toxicity in mice in a 7-day experiment (Zhang et al., 2003).
Antisense Treatment. An antisense phosphorothioate oligonucleotide for murine COX-2 (5'-GCAGAGCAGCACCGA-3') and a randomized control oligonucleotide were synthesized as described previously (Kage et al., 1999). An aqueous solution of each oligonucleotide was intraperitoneally administered daily at a dose of 3 mg/kg, starting 2 h before mechanical stimulation (Khan et al., 2002).
Assessment of Adhesion. One week after the surgery, the mice were anesthetized with sodium pentobarbital (40 mg/kg i.p.), and intraperitoneal adhesion formation was assessed using three different methods. Assessment was performed by a single research worker throughout the study, and this person was blinded to the treatment. First, the severity of adhesion was evaluated by macroscopic observation, using a modified Mazuji classification system (Mazuji et al., 1964). Scores of 0 to 4 (with 4 being the most severe) were assigned based on the severity of adhesion, as follows: 0, no adhesion; 1, mild adhesion (localized and easy to separate); 2, moderate adhesion; and 3, severe adhesion (very widespread and difficult to separate). Cecum-cecum adhesion, cecum-abdominal wall adhesion, and cecum adhesion to other tissues, including the small intestine and liver, were evaluated independently. Therefore, the severest adhesion formation could receive a score of 12. Second, the maximum force required to detach the adhered cecum completely was determined using a piezo-electrical device, as described in a previous report (Wiseman et al., 2004). Finally, the cecum and intestine were opened along the mesenteric attachment for performance of planimetry (Muller et al., 2003). Tension-free specimens were placed on a glass plate and photographed, and the adhesion area was computed by analyzing the images using NIH Image software.
RT-PCR Study. After evaluation of adhesion formation, the cecum was excised, washed thoroughly with ice-cold PBS, and quickly frozen with liquid nitrogen. Total RNA was extracted with ISOGEN reagent (Nippon Gene, Tokyo, Japan), according to the manufacturer's instructions. Real-time PCR was conducted as described previously (Paliege et al., 2004). Oligonucleotides for primers and probes were designed using Primer Express 1.0 (Applied Biosystems, Foster City, CA). COX-1 sense, 5'-GCTGAAGGAGGAGC ATCCC-3', antisense, 5'-AGGCGAGTGGTCTGGAAGAG-3', and probe, 5'-CGTGGGATGATGAGC-3'; and COX-2 sense, 5'-CCCTGAAGCCGTACACATCA-3', antisense, 5'-TGTCACTGTAGAGGGCTTTCAATT-3', and probe, 5'-TGCAGCCATTTCCTTCTCTCCTGTAAGTTCT-3'. Real-time PCR amplification was performed using TaqMan Universal PCR Master Mix and the ABI Prism 7700 sequence detection system (Applied Biosystems). Relative amounts of mRNA, normalized against -actin mRNA, were calculated from the threshold cycle numbers.
Determination of PGE2 Levels in the Cecal Tissue and Peritoneal Fluid. The PGE2 level in the cecal tissue was determined as described previously (Futaki et al., 1994; Tanaka et al., 2002). Briefly, the cecum was excised on day 7, washed quickly with ice-cold PBS, weighed, and placed in a tube containing 100% methanol plus 0.1 M indomethacin. The tissues were homogenized using a Polytron homogenizer, followed by centrifugation at 10,000 rpm for 10 min at 4°C. The supernatant of each sample was evaporated under a vacuum, the residue was redissolved in the assay buffer, and the PGE2 concentration was determined using a PGE2 enzyme immunoassay (EIA) kit (Amersham Biosciences, Inc., Piscataway, NJ). For determination of PGE2 contents in peritoneal fluid, the peritoneal cavity was washed with 1 ml of PBS, and the solution collected was directly used in the EIA.
Western Blot Analyses. To investigate the protein expression levels of COX-1 and COX-2 in the cecum upon adhesion, Western blot analyses were conducted as described previously (Qiu et al., 2003). Band intensity was quantified by densitometry and all protein levels were normalized against those at day 0.
Immunoprecipitation. Immunoprecipitation was conducted as described previously (de Alvaro et al., 2004). Briefly, a part of the cecum (about 100 mg) was homogenized with a Polytron homogenizer and lyzed in 1 ml of lysis buffer (50 mM HEPES, pH 7.5, 100 mM NaCl, 1 mM EDTA, 10% glycerol, 0.5% Nonidet P-40, leupeptin, aprotinin, phenylmethylsulfonyl fluoride, benzamidine sodium vanadate, and -glycerophosphate). The cell extract was normalized for protein content and incubated for 2 h at 4°C with anti-p38 antibody precoupled with protein G-Sepharose beads. The beads were subsequently washed three times with lysis buffer. The protein was released from the beads by boiling the samples for 5 min in sample buffer. The supernatants were run on SDS-polyacrylamide gel electrophoresis and transferred to nitrocellulose membranes. Western blotting was conducted using an anti-p38 antibody or an antibody specific for the phosphorylated form of p38 and a secondary peroxidase-conjugated anti-rabbit IgG diluted to 1:1000. The Western blots were quantified by densitometry, and phosphorylated p38 MAP kinase levels are presented as relative values normalized against the total p38 MAP kinase levels.
Statistics. All data are expressed as mean ± S.E.M. Adhesion scores were statistically analyzed by a nonparametric Mann-Whitney U test. Other numeric data were statistically evaluated using an unpaired Student's t test or by using one-way analysis of variance with Bonferroni's correction (for multiple comparison). A p value less than 0.05 was considered to be statistically significant.
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Results |
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COX-1 and COX-2 Gene and Protein Expression. COX-1 and COX-2 mRNA expression levels were determined in the intact and traumatized cecum by real-time RT-PCR. In the intact cecum, constitutive expression of COX-1 mRNA was observed, whereas only marginal levels of COX-2 mRNA expression were detected. After mechanical stimulation, expression of COX-2 mRNA increased on day 1 and thereafter, with maximum expression observed from day 3 to day 7 (Fig. 2A). The expression level of COX-1 mRNA did not change after mechanical stimulation, based on measurements made until day 7.
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As shown in Fig. 2B, expression of COX-1 and COX-2 proteins showed a similar trend. COX-2 expression increased in the traumatized cecum, whereas COX-1 expression did not change, even after mechanical stimulation.
Effects of COX-1 and COX-2 Inhibitors on Adhesion Formation. To examine the respective roles of COX-1 and COX-2 on peritoneal adhesion formation, specific inhibitors for each cyclooxygenase isozyme were administered to mice that had undergone mechanical stimulation. As shown in Fig. 3, A and B, mofezolac, a selective COX-1 inhibitor, had no effect on adhesion score and adhesion area, even at 30 mg kg/day, the highest dose examined. On the other hand, NS-398 and CAY10404 highly selective COX-2 inhibitors, attenuated adhesion formation in a dose-dependent manner and led to a significant reduction in adhesion score and adhesion area at doses of more than 3 mg/kg (Fig. 3, A and B). No side effects, such as ulcer formation in the gastrointestinal tract, were observed in any experimental groups (data not shown). As shown in Fig. 3, C and D, the PGE2 levels in cecum tissues and in the peritoneal fluid were significantly increased on day 7 after mechanical stimulation. NS-398 and CAY10404inhibited PGE2 elevation at doses of more than 3 mg/kg, and the PGE2 concentration returned to its basal level at doses of 30 mg/kg (Fig. 3, C and D). In contrast, mofezolac inhibited PGE2 formation only at 30 mg/kg in traumatized mice and to a much lesser extent than the COX-2 inhibitors.
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Effects of an EP Receptor Agonist and an EP Receptor Antagonist. To confirm that COX-2 inhibitors attenuated peritoneal adhesion by inhibiting PGE2 formation in the traumatized cecum, we examined the effects of exogenously administered PGE2 in mice treated with COX-2 inhibitors. As shown in Fig. 4A, PGE2 (107 M solution i.p.) eliminated the inhibitory effect of NS-398 on peritoneal adhesion, whereas PGE2 alone did not induce adhesion in sham-operated mice. Similar results were obtained when the mice were treated with (R)-butaprost (10-6 M i.p.).
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As shown in Fig. 4B, AH 6809, an EP receptor antagonist, also attenuated peritoneal adhesion. In contrast, SC-19220, a selective antagonist of PGE2 at EP1 receptors, had no effect.
Effect of a COX-2 Antisense Oligonucleotide. To further examine the significance of the role of COX-2 in adhesion formation, an antisense oligonucleotide for COX-2 mRNA was administered to mice that had received mechanical stimulation. As shown in Fig. 5A, expression of COX-2 was largely attenuated in antisense oligonucleotide-treated mice, compared with vehicle-treated or control oligonucleotide-treated mice. Administration of the antisense oligonucleotide significantly (p < 0.01 versus vehicle control) reduced the adhesion score and the adhesion area, whereas a randomized control oligonucleotide had no effect (Fig. 5, B and C).
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Peritoneal Adhesion in COX-2-Deficient Mice. To further investigate the significance of the role of COX-2 in peritoneal adhesion in the traumatized cecum, we used mice lacking the COX-2 gene (COX-2 KO mice). As shown in Fig. 6, peritoneal adhesion was significantly attenuated in COX-2 KO mice, based on both the adhesion score and the adhesion area. Exogenous administration of PGE2 to the peritoneal cavity of these mice produced severity of adhesion at an almost wild-type level, whereas this procedure resulted in no additional effect in wild-type littermates.
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Involvement of p38 Kinase in COX-2 Induction. We next investigated the molecular signals responsible for up-regulation of COX-2 mRNA in the cecum. When the mice were treated with an inhibitor of p38 MAP kinase, SB202190 (3 and 15 µM), adhesion scores were significantly reduced (54% inhibition at 15 µM) (Fig. 7A), and the adhesion area was also reduced by treatment with SB202190 (Fig. 7B). PGE2 elevation in the traumatized cecum was dose dependently decreased by treatment with SB202190, and COX-2 mRNA expression levels in the cecum were also significantly lower in SB202190-treated mice. The dose-response profiles of the adhesion scores, PGE2 contents and COX-2 mRNA expression were almost the same.
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Activation of p38 MAP kinase in the traumatized cecum was examined by immunoprecipitation with a phosphorylated p38 MAP kinase-selective antibody. As shown in Fig. 8, only a faint level of phosphorylated p38 MAP kinase was detected in the cecum in sham-operated mice. In the traumatized cecum, the level of the phosphorylated form of p38 significantly increased on day 1 and thereafter, suggesting activation of p38 MAP kinase in the traumatized cecum.
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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The major findings of the present study are as follows: first, COX-2 is induced extensively after trauma, whereas COX-1 is constitutively expressed and its expression level does not change after mechanical stimulation. Second, COX-2, but not COX-1, plays a significant role in adhesion formation, because treatment with selective inhibitors for COX-2 and with an antisense oligonucleotide for COX-2 mRNA attenuated adhesion; the COX-1 isoform had only a marginal effect, if any, on adhesion. Third, peritoneal adhesion was much less severe in COX-2 knockout mice, compared with wild-type littermates. Fourth, PGE2 is one of the primary COX-2-derived mediators responsible for adhesion formation, and fifth, the p38 MAP kinase pathway is involved in COX-2 induction in the traumatized cecum. Together, these results suggest that a mechanical stimulus can activate the p38 MAP kinase-dependent signaling pathway, resulting in COX-2 induction, which then promotes adhesion formation via increased PGE2 production.
As shown in Fig. 2, COX-1 is constitutively expressed in the intact cecum and its expression level is not changed after tissue trauma. In spite of the presence of COX-1 in the cecum, mofezolac, a selective COX-1 inhibitor, did not exert any effects on adhesion formation, even at a dose of 30 mg/kg. This dose is thought to be sufficient for COX-1 inhibition in rodents, because mofezolac inhibits COX-1-dependent acute pain in mice, even at 10 mg/kg (Goto et al., 1998; Kusuhara et al., 1998). In a preliminary experiment, we also confirmed that platelet aggregation is inhibited upon administration of mofezolac at 30 mg/kg in mice (85.3 ± 10.8% inhibition 60 min after drug administration). Therefore, our present results suggest that the contribution of COX-1 to peritoneal adhesion formation is marginal, at most. In contrast, selective inhibition of COX-2 by NS-398 or CAY10404significantly reduced the severity of peritoneal adhesion, suggesting that COX-2 plays an important role in adhesion formation. We note that COX-independent actions of COX inhibitors have recently been reported by several investigators (Tegeder et al., 2001). However, here we have used three structurally distinct COX inhibitors (Mofezolac, NS-398, and CAY10404 and found that the two COX-2-selective inhibitors attenuated adhesion formation. Importantly, the COX-2 inhibitor-induced reduction in adhesion formation was reversed by simultaneous treatment of the traumatized cecum with exogenous PGE2 (Fig. 4A). Furthermore, an antisense oligonucleotide for COX-2 mRNA significantly attenuated adhesion (Fig. 5). These results, together, strongly suggest a primary role of COX-2 in adhesion formation induced by mechanical stimuli.
As shown in Fig. 3, C and D, mechanical stimuli elevate the PGE2 contents in the traumatized cecum over those in the intact cecum and also increase the PGE2 concentration in the peritoneal fluid. Administration of NS-398 or CAY10404significantly inhibited PGE2 elevation, and the PGE2 concentration was decreased to its basal level at a dose of 30 mg/kg, the highest dose examined. These results suggest that the primary enzyme responsible for elevated PGE2 production in the traumatized cecum is COX-2. Because the decreased PGE2 level in the COX-2 inhibitor-treated cecum is clearly correlated with decreased adhesion formation, it is highly plausible that COX-2-derived PGE2 is involved in the pathogenesis of peritoneal adhesion. This hypothesis is supported by the reversal of the effect of the COX-2 inhibitors by exogenous PGE2 or a PGE2 analog, (R)-butaprost (Fig. 4A), and attenuation of adhesion formation by an EP receptor antagonist (AH6809) equipotent for the EP1 and EP2 subtypes (Fig. 4B). Because (R)-butaprost is relatively highly selective for the EP2 receptor subtype, a significant part of the PGE2 activity may be mediated via EP2 receptor. However, the EP receptor subtypes involved in adhesion formation in the traumatized cecum need to be more closely investigated, using subtype-specific antagonists or mice that are genetically devoid of each subtype.
As shown in Figs. 7 and 8, p38 MAP kinase was activated after mechanical stimulation, and pharmacological blockade of the p38 MAP kinase-dependent pathway with SB202190 resulted in reduced expression of COX-2 mRNA, with this change showing a strong correlation with attenuation of adhesion formation. These results suggest that p38 MAP kinase is directly involved in mechanical stimulus-induced adhesion formation, via COX-2 induction. Several previous reports have also shown that p38 MAP kinase can mediate COX-2 expression induced by mechanical stimuli (Dieckgraefe et al., 1997; Pyles et al., 1997; Martineau et al., 2004), and it is possible that the p38 MAP kinase-dependent pathway may be the primary common pathway responsible for mechanical stimulus-induced COX-2 expression in various cells. Involvement of other pathways, such as the nuclear factor-B-dependent pathway, should also be investigated in this respect. In the traumatized cecum in SB202190-treated mice, we observed that phosphorylation of p38 MAP kinase itself was attenuated compared with that in vehicle-treated mice (data not shown). The reason for the reduced level of phosphorylated p38 is unclear, because SB202190 is not known to inhibit phosphorylation of p38. It is likely that downstream factors (for example, COX-2-derived eicosanoids) are involved in the prolonged activation of p38 through a feedback mechanism.
In conclusion, selective inhibitors of COX-2 and an antisense oligonucleotide for COX-2 mRNA significantly attenuated peritoneal adhesion formation in the mechanically stimulated cecum, whereas a COX-1 inhibitor had no effect, suggesting that COX-2, but not COX-1, is implicated in adhesion formation. Up-regulation of COX-2 mRNA expression was observed after mechanical stimulation and this elevated expression was inhibited by treatment with inhibitors of the p38 MAP kinase pathway. Exogenously administered PGE2 or an EP2-selective PGE2 analog reversed the inhibitory effect of the COX-2 inhibitors. These results suggest that induction of COX-2 occurs through activation of the p38 MAPK pathway in the mechanically stimulated cecum, leading to elevation of PGE2, which then facilitates adhesion formation.
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Footnotes |
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ABBREVIATIONS: COX, cyclooxygenase; PG, prostaglandin; MAP, mitogen-activated protein; MAPK, MAP kinase; WT, wild-type; PBS, phosphate-buffered saline; RT-PCR, reverse transcription-polymerase chain reaction; EIA, enzyme immunoassay; EP, E-prostanoid.
Address correspondence to: Dr. Jun Katada, KEIO Research Park 2N4, Keio University School of Medicine, Shinanomachi 35, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail: katada{at}kt.rim.or.jp
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