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Vol. 286, Issue 3, 1383-1390, September 1998
Department of Applied Pharmacology, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan
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Abstract |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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To elucidate the role of cyclooxygenase (COX)-2 in ulcer healing, we compared the effects of NS-398 (COX-2-selective inhibitor) and indomethacin (nonselective COX inhibitor) on the healing of acetic acid-induced gastric ulcers in rats. Prostaglandin E2 (PGE2) production was elevated in ulcerated tissue, but remained unaffected in intact tissue. COX-2 mRNA was only detected in the ulcerated tissue, in which the COX-2 protein was found in fibroblasts, macrophages/monocytes and granulocytes. In contrast, COX-1 mRNA expression was not affected by ulceration. In an in vitro study, the increased PGE2 production was inhibited by NS-398; this had no effect on PGE2 production in the intact tissue. When NS-398 and indomethacin were administered to rats, 3 and 6 mg/kg NS-398 only reduced PGE2 production in the ulcerated tissue, but 10 mg/kg NS-398 and 0.5 to 2 mg/kg indomethacin inhibited the production in both the ulcerated and intact tissues. The healing of gastric ulcers was significantly impaired by 3 to 10 mg/kg NS-398 and 1 and 2 mg/kg indomethacin. The delay in ulcer healing was associated with the inhibition of PGE2 production in the ulcerated tissue. As observed upon histological analysis, regeneration of the mucosa, maturation of the ulcer base and angiogenesis in the base were significantly prevented by 6 mg/kg NS-398 and 2 mg/kg indomethacin, although the inhibitory effect of NS-398 was weaker than that of indomethacin. These results clearly indicate that COX-2 plays an important role in the healing of gastric ulcers in rats.
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Introduction |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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NSAIDs inhibit the
activity of COX, the key enzyme in PG production (Vane, 1971
). COX
exists in two isoforms, of which COX-1 is a constitutive enzyme
expressed in many tissues including the stomach, and COX-2 is normally
undetectable in most tissues, its expression being induced at
inflammatory sites (Mitchell et al., 1995; Herschman, 1996).
Conventional NSAIDs such as indomethacin inhibit both COX-1 and COX-2
activities, although COX-2 selective inhibitors such as NS-398 have
been developed as new NSAIDs (Arai et al., 1993; Futaki
et al., 1993, 1994; Vane, 1994; Pairet and Engelhardt,
1996). It is well known that treatment with conventional NSAIDs causes
a delay in the healing of gastric ulcers; this delay is associated with
a reduction of the increased PG production in ulcerated tissues in rats
and humans (Szelenyi et al., 1982; Wang et al.,
1989; Levi et al., 1990; Lancaster-Smith et al., 1991). It follows that exogenous PGE2 prevents the
indomethacin-induced delay in ulcer healing in rats (Wang et
al., 1989).
Recently, Mizuno et al. (1997) reported that COX-2 is
induced by gastric ulceration in mice, resulting in an increase in PG production. Consequently, it is thought that COXs and PGs play important roles in gastric ulcer healing. In addition, Mizuno et
al. (1997) claimed that COX-2 may play an important role in ulcer
healing, based on the finding that the ulcerated area is larger in
NS-398-treated mice than controls. However, in their study, it was
impossible to distinguish between the roles of COX-2 in ulcer
development and ulcer healing, because NS-398 was administered from the
day of ulcer induction. Furthermore, they only examined the effect of
NS-398 at a single dose (10 mg/kg, i.p.), and did not determine PG
production in the gastric tissue after the administration of NS-398.
Futaki et al. (1993) reported that orally administered NS-398 at 10 mg/kg significantly reduces PGE2 production in
the gastric mucosa to about 40% of the control level, suggesting that NS-398 administered at >10 mg/kg may also inhibit COX-1 activity in
the gastric tissue, as do conventional NSAIDs. Accordingly, it remains
unknown whether or not the impairment of ulcer healing can be caused by
the inhibition of COX-2 activity alone. Therefore, we closely examined
the effect of NS-398 on PGE2 production in gastric tissues
and the healing of acetic acid ulcers in rats, obtained corresponding
data for indomethacin, and analyzed the dissimilarities to elucidate
the role of COX-2 in gastric ulcer healing.
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Materials and Methods |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Production of gastric ulcers.
Male Donryu rats (Nihon SLC,
Hamamatsu, Japan), weighing 250 to 300 g, were used. Under ether
anesthesia, gastric ulcers were induced by submucosal injection of 20%
acetic acid (0.04 ml) into the border between the antrum and the fundus
on the anterior wall of the stomach (Takagi et al., 1969).
After closure of the abdomen, the rats were maintained in the usual
manner. Because deep, well-defined ulcers were observed 5 days after
the acid injection, we defined the 5th day as the day of ulceration
(day 0). At the indicated times, rats were killed and their stomachs
were excised. Subsequently, the stomachs were incised along the greater
curvature and the ulcerated area (mm2) was determined under
a dissecting microscope (×10; Olympus, Tokyo, Japan). The investigator
(S.O.) determining the ulcer size was unaware of the treatment given
the animals. The preventive rates for ulcer healing with COX inhibitors
were calculated as follows: Preventive rate (%) = {[(ulcerated area
on day X in the drug group) 
(ulcerated area on day X in the control
group)]/[(ulcerated area on day 0 in the control group) (ulcerated
area on day X in the control group)]} × 100.
Northern blot analysis of COX mRNA expression.
Rat COX-1 and
COX-2 cDNA probes were prepared by means of the reverse transcription
polymerase chain reaction, as described previously (Feng et
al., 1993). Total RNA for amplification of these cDNAs was
isolated from the spleen of a lipopolysaccharide-infused rat. The
primers used were as follows: 5'-AACCGTGTGTGTGACTTGCTGAA-3' and
5'-AGAAGGAGCCCCTCAGAGCTCAGTG-3' for COX-1 and
5'-TGATGACTGCCCAACTCCCATG-3' and 5'-AATGTTGAAGGTGTCCGGCAGC-3' for
COX-2. The products corresponding to COX-1 (887 base pairs) and COX-2
(702 base pairs) were purified from polyacrylamide gels, and used after
their sequences had been confirmed to be completely identical to known
ones (with reference to the databases of GenBank and EMBL). The cDNA
probes were 32P-labeled by the random primer method
(Ready-To-Go; Pharmacia Biotec, Uppsala, Sweden). Gastric specimens
were taken from both intact (posterior side) and ulcerated tissues of
stomachs with ulcers and from stomachs without ulcers. Total RNAs were
extracted by means of the acid-guanidinium
thiocyanate-phenol-chloroform method (Chomczynski and Sacchi, 1987),
using TRIZOL (GIBCO BRL, Gaithersburg, MD). Poly (A)+ RNAs
were purified with Oligotex dT30 (TaKaRa, Kyoto, Japan). Poly
(A)+ RNAs (0.2 µg) were separated by electrophoresis on
1.2% agarose gels, transferred to nylon membranes (Gene Screen Plus;
New England Nuclear, Boston, MA), and then hybridized with
32P-labeled cDNA probes (Sambrook et al., 1989).
The detection and quantification of hybridized mRNAs were carried out
with an imaging analyzer (BAS-5000Mac; Fuji Film, Tokyo, Japan). The
levels of the mRNAs were expressed as the ratio to
glyceraldehyde-3-phosphate dehydrogenase mRNA.
Immunohistochemical detection of the COX-2 protein. Gastric specimens were taken from the ulcerated tissue. After they had been fixed with 4% paraformaldehyde in phosphate-buffered saline, frozen sections (14-µm thick) were prepared. The sections were incubated with anti-COX-2 antibody (Cayman Chemicals, Ann Arbor, MI) after deactivation of endogenous peroxidase with 0.3% H2O2 and blockage of nonspecific binding sites. The COX-2 protein was visualized by the avidin-biotin-peroxidase complex method using a Vectastain ABC-peroxidase kit (Vector Laboratories, Burlingame, CA) and 3, 3'-diaminobenzidine tetrahydrochloride (Dojindo Laboratories, Kumamoto, Japan). The sections were successively stained with hematoxylin. Macrophages/monocytes and granulocytes were identified by staining with macrophage-specific and granulocyte-specific esterase activities (Sigma Chemical Co., St. Louis, MO), respectively.
Determination of PGE2 production in gastric
tissues.
PGE2 production was assayed according to the
method of Lee and Feldman (1994). Unless otherwise stated, 3 hr after
the administration of the drugs, gastric specimens were taken from both
intact (posterior side) and ulcerated tissues of stomachs with ulcers,
and from stomachs without ulcers. The specimens were placed in 50 mM
Tris-HCl (pH 8.4) buffer and then finely minced. After the tissues had been washed and resuspended in 1 ml of buffer, they were subjected to
vortex mixing at room temperature for 1 min to stimulate
PGE2 production, followed by centrifugation at 10,000 × g for 15 sec. To examine the in vitro effects
of COX inhibitors, the tissues were preincubated with the drugs or the
vehicle on ice for 10 min before stimulation. The amounts of
PGE2 in the resulting supernatants were determined by
enzyme-immunoassaying (PGE2 EIA kit; Cayman Chemicals).
PGE2 production was expressed as pg PGE2/mg
tissue/min.
Histological evaluation of ulcer healing.
Gastric specimens
were taken from ulcerated tissues, and then fixed in 10% formalin and
embedded in paraffin. Six-µm sections were prepared, and then stained
with hematoxylin and eosin. As described previously by our group
(Tsukimi et al., 1996), the length of the regenerated mucosa
on the ulcer base and the thickness of the base were measured under a
light microscope. These measurements are presented, respectively, as
regeneration of the mucosa and maturation of the ulcer base.
Drugs. NS-398 (kindly provided by Taisho Pharmaceutical Co., Tokyo, Japan) and indomethacin (Sigma) were suspended in a trace of Tween 80 and saline. The drugs were administered s.c. in a volume of 5 ml/kg body weight. In the case of repeated administration, the drugs were administered once daily for the indicated periods starting from day 0. Control animals received the vehicle alone.
Statistical analysis. The data are presented as means ± S.E. Statistical differences were evaluated using Student's t test or Dunnett's multiple comparison test, with P < .05 being regarded as significant.
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Results |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Expression of COX-2 in ulcerated gastric tissue. We examined the expression of COX-1 and COX-2 mRNAs in gastric tissues by Northern blotting (fig. 1). The gastric mucosa of normal stomachs contained COX-1 mRNA, but not COX-2 mRNA. However, COX-2 mRNA expression was found in ulcerated tissue. In the ulcerated tissue, the expression of COX-2 mRNA was already detectable on day 0, and its level remained constant to day 7. Thereafter, COX-2 mRNA expression decreased with time. This change in COX-2 mRNA expression was well associated with those in the ulcerated area and PGE2 production in the ulcerated tissue, as shown in figure 8. Despite the presence of ulcers, COX-2 mRNA was not expressed in the intact tissue of stomachs with ulcers. However, COX-1 mRNA was found in both the ulcerated and intact tissues. The levels of COX-1 mRNA in both tissues were similar to that in the gastric mucosa of normal stomachs, and these levels did not change throughout the course of the experiment.
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PGE2 production in gastric tissues after single administration of NS-398 and indomethacin. To properly assess the in vivo effects of NS-398 and indomethacin on PGE2 production in gastric tissues, we first considered the strength of their effects over time (fig. 4, inset). After 6 mg/kg NS-398 and 2 mg/kg indomethacin had been administered to rats with ulcers, their maximal effects were observed at 3 hr. Based on this finding, we examined the in vivo effects of NS-398 and indomethacin on PGE2 production at 3 hr after their administration.
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Effects of NS-398 and indomethacin on the healing of gastric ulcers. We examined the effects of repeated administration of NS-398 and indomethacin on the healing of gastric ulcers (fig. 5). On day 0, gastric ulcers had clearly developed. There were round and well-defined ulcers in all animals, the ulcerated area of 46.9 ± 3.8 mm2. Thereafter, the ulcer size spontaneously decreased. NS-398 and indomethacin were administered at daily intervals from day 0. On day 3, ulcer healing was not affected by NS-398 or indomethacin. NS-398 at 3 and 6 mg/kg had no effect to day 7, but significant impairment of ulcer healing was noted on day 10. On day 14, NS-398 at 3 mg/kg continued to delay the healing, although the inhibitory effect of the drug at 6 mg/kg was still significant. At 10 mg/kg, NS-398 significantly prevented ulcer healing from day 7 to 14. The preventive rates with NS-398 were 15.0, 21.9 and 32.6% with 3, 6 and 10 mg/kg on day 10, and 12.1 and 29.3% with 6 and 10 mg/kg on day 14, respectively.
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Discussion |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Our results indicate that COX-2 expression is induced by gastric
ulceration in rats and that the level of COX-2 mRNA decreases with
ulcer healing. In contrast, COX-1 mRNA was expressed in both intact and
ulcerated tissues, the levels remaining constant during ulcer healing.
These findings are consistent with those of Mizuno et al.
(1997) concerning mice. Furthermore, we found that COX-2 is only
localized in ulcerated tissue. Immunohistochemical staining showed that
the COX-2 protein is expressed in fibroblasts, macrophages/monocytes and granulocytes in the upper portion of the ulcer base. Several in vitro studies have revealed the expression of COX-2 in
these cell types in response to various stimuli (Mitchell et
al., 1995; Herschman, 1996). In ulcerated tissue, PGE2
production was significantly elevated when compared with that in normal
tissue, and this increased production returned to the normal level in
parallel with ulcer healing. This change in PGE2 production
was well correlated with COX-2 mRNA expression. The increased
PGE2 production in the ulcerated tissue was
dose-dependently inhibited by NS-398, but the production in other
tissues was unaffected. These results indicate that COX-2 contributes
to the elevation of PGE2 production in the ulcerated tissue. In addition, NS-398 administered at 6 mg/kg reduced the increased PGE2 production to near the normal level, without
affecting PGE2 production in the intact tissue throughout
the experiment. This finding also suggests that the increased
PGE2 in the ulcerated tissue might be predominantly due to
COX-2.
We clearly demonstrate that COX-2 plays a crucial role in the healing of gastric ulcers. The inhibition of only COX-2 activity by NS-398 at 3 and 6 mg/kg caused a significant delay in the ulcer healing in rats. The healing was also impaired by indomethacin and 10 mg/kg NS-398, which inhibited both COX-1 and COX-2 activities. Furthermore, we histologically confirmed that regeneration of the mucosa is prevented by 6 mg/kg NS-398 and 2 mg/kg indomethacin. The delay was well associated with the inhibition of PGE2 production in the ulcerated tissue. But, neither NS-398 nor indomethacin affected ulcer healing on day 3. It is probable that the duration from day 0 to day 6 is a lag period in which the delay in ulcer healing had not yet become manifest. The persistent impairment of healing responses caused by the inhibition of PG production leads to visible healing impairment after day 6. In contrast, when both NS-398 and indomethacin were administered starting from day 10, no delay in ulcer healing was observed. These results suggest that the persistent inhibition of increased PG production in the early phase of the healing process leads to impairment of ulcer healing.
Furthermore, we examined the delayed ulcer healing mechanism through
the selective inhibition of COX-2 activity. Schmassmann et
al. (1995) reported that, in addition to a decrease in the ulcerated area, maturation of the ulcer base (reduction of the ulcer
base size) and angiogenesis in the ulcer base are also important factors for efficient healing of gastric ulcers. In fact, the maturation and angiogenesis were reported to be suppressed in the
indomethacin-induced delay of ulcer healing in rats (Schmassmann et al., 1995; Tsukimi et al., 1996). We describe
that maturation of the ulcer base and angiogenesis are significantly
prevented on inhibition of COX-2 activity by NS-398 alone. This finding also indicates the important role of COX-2 in ulcer healing. It should
be noted that NS-398 at 6 mg/kg also prevented maturation of the base,
and the preventive rates were similar in the 6 mg/kg NS-398-treated and
2 mg/kg indomethacin-treated groups. However, both regeneration of the
mucosa and angiogenesis were more strongly inhibited by 2 mg/kg
indomethacin than by 6 mg/kg NS-398. These results suggest that COX-2
might play a predominant role in maturation of the ulcer base, and that
COX-1 as well as COX-2 might be involved in both regeneration of the
mucosa and angiogenesis in the ulcer base.
Our results further suggest that NS-398 administered at 3 and 6 mg/kg
only inhibits COX-2 activity, but the drug at 10 mg/kg is able to
inhibit COX-1 activity as well as COX-2 activity in stomachs with
ulcers. Namely, NS-398 at less than 6 mg/kg reduced the stimulated
PGE2 production in the ulcerated tissue without inhibiting
PGE2 production in the intact tissue of an ulcerated stomach. However, NS-398 at 10 mg/kg inhibited the production by both
tissues in the same way that indomethacin did. In addition, NS-398 at 3 and 6 mg/kg failed to affect PGE2 production by the gastric
mucosa of normal rats, but at 10 mg/kg it significantly reduced this
production. It is evident that the intact tissue of stomachs with
ulcers and the gastric tissue of normal rats only possess COX-1, as
found in this study. Arai et al. (1993) and Masferrer
et al. (1994) reported that NS-398, administered orally at
10 mg/kg to rats, only slightly inhibits PGE2 production in
the stomach. The PGE2 production assay was carried out at
30 min and 6 hr after drug administration by Arai et al.
(1993) and Masferrer et al. (1994), respectively. In
contrast, in the study by Futaki et al. (1993), when gastric
PGE2 production was measured 3 hr after the administration
of 10 mg/kg NS-398, it was significantly reduced (60% inhibition),
compared with in the control. Therefore, we examined the time courses
of the effects of these drugs on PGE2 production in
ulcerated gastric tissue after their administration. We confirmed that
the maximal effects of COX inhibitors were observed at 3 hr after drug
administration. We speculated that the evaluation of the in
vivo effect of NS-398 on gastric PGE2 production may have been insufficient in the studies by Arai's and Masferrer's groups. Thus, proper evaluation of the role of COX-2 in the stomach using NS-398 at high doses such as 10 mg/kg is unlikely. At present, it
is unknown why there is only a slight difference in the doses of NS-398
between COX-2 selective inhibition (6 mg/kg) and dual COX inhibition
(10 mg/kg), despite the fact that NS-398 is highly selective for COX-2
in in vitro experiments (Futaki et al., 1994; Panara et al., 1995; Chulada and Langenbach, 1997). To our
knowledge, there have been no reports concerning the metabolism of
NS-398 in rats, yet it seems possible that a metabolite of NS-398
having the ability to inhibit COX-1 activity may be produced in a large quantity with concentrations of more than 10 mg/kg. Alternatively, a
considerable amount of NS-398 may accumulate in the gastric mucosa with
10 mg/kg NS-398 administration.
Overall, we conclude that COX-2 plays an important role in the healing of gastric ulcers in rats. COX-2-selective inhibitors are expected to be new NSAIDs without ulcerogenic effects, but they are likely to impair gastric ulcer healing if used in the early phase of the healing process.
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Acknowledgments |
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The authors thank N. J. Halewood for critical reading of the manuscript, and M. Ishikawa, M. Shimose, M. Yoshida, S. Kitazawa and K. Matsuno for their technical assistance.
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Footnotes |
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Accepted for publication May 21, 1998.
Received for publication April 6, 1998.
Send reprint requests to: Dr. Satoru Takahashi, Department of Applied Pharmacology, Kyoto Pharmaceutical University, Missasagi, Yamashina, Kyoto 607-8414, Japan.
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Abbreviations |
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COX, cyclooxygenase; PG, prostaglandin; NSAID, nonsteroidal antiinflammatory drug.
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References |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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