Mucosal Inflammation Research Group, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The ability of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors to exacerbate inflammatory bowel disease suggests that prostaglandins are important anti-inflammatory mediators in this context. Prostaglandin D2 has been suggested to exert anti-inflammatory effects. We investigated the possibility that prostaglandin D2 derived from cyclooxygenase-2 plays an important role in downregulating colonic inflammation in rats. Colitis was induced by intracolonic administration of trinitrobenzene sulfonic acid. At various times thereafter (from 1 h to 7 days), colonic prostaglandin synthesis and myeloperoxidase activity (index of granulocyte infiltration) were measured. Prostaglandin D2 synthesis was elevated >4-fold above controls within 1-3 h of induction of colitis, preceding significant granulocyte infiltration. Treatment with a selective cyclooxygenase-2 inhibitor abolished the increase in prostaglandin D2 synthesis and caused a doubling of granulocyte infiltration. Colonic granulocyte infiltration was significantly reduced by administration of prostaglandin D2 or a DP receptor agonist (BW-245C). These results demonstrate that induction of colitis results in a rapid increase in prostaglandin D2 synthesis via cyclooxygenase-2. Prostaglandin D2 downregulates granulocyte infiltration into the colonic mucosa, probably through the DP receptor.
inflammation; inflammatory bowel disease; neutrophil; DP receptor
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
THE NOTION THAT PROSTAGLANDINS (PGs) contribute to the pathogenesis of inflammatory bowel disease (IBD) stems from a series of studies published more than two decades ago, in which rectal biopsies from patients with active ulcerative colitis were found to produce high levels of PG (8, 10, 27). However, a number of subsequent clinical and animal studies have shown that the increase in PG levels that accompanied colonic inflammation may have been beneficial, assisting in protecting the mucosa from insult and/or promoting repair. The evidence for this includes 1) nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit PG synthesis, have been reported to exacerbate IBD or cause a reactivation of quiescent IBD (14, 23); 2) NSAIDs were similarly shown to exacerbate experimental colitis (24, 31), but structurally similar compounds that lack inhibitory activity on PG synthesis did not (25); and 3) intracolonic administration of PGE2 or PGE2 analogs reduced the severity of experimental colitis (1, 4, 33).
The confirmation of the existence of at least two isoforms of cyclooxygenase (COX-1 and COX-2) (15, 35) and the availability of selective COX-2 inhibitors made it possible to determine which isoform is responsible for PG synthesis in colitis. Reuter and colleagues (24) demonstrated that most of the PGs produced in inflamed rat colon are derived from COX-2. In addition, an increase in the severity of colitis was observed when rats with colitis were treated with selective COX-2 inhibitors (24). COX-2 has also recently been shown to be the primary source of PG synthesis in colitis in humans (19).
PGD2 is the major PG produced by mucosal mast cells and has
also been shown to be produced by cultured human enterocytes
(18). PGD2 has been shown to suppress the
infiltration of leukocytes into the inflamed pleural cavity of the rat
(6). In that study, the PGD2 appeared to be
produced primarily by COX-2. It is possible, therefore, that
PGD2 may similarly act in an anti-inflammatory capacity in
colitis and that it may be derived predominantly from COX-2. In this
study, therefore, we have used a rat model of experimental colitis to
examine 1) changes in the production of PGD2
during colitis, 2) the contribution of COX-2 to colonic
PGD2 synthesis, and 3) the possible
anti-inflammatory effects of PGD2 in colitis. We have
also attempted to determine whether anti-inflammatory effects of
PGD2 are mediated via the DP prostanoid receptor or via the
peroxisome-proliferator activated receptor- (PPAR-
).
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Animals. Male Wistar rats (175-200 g) were purchased from Charles River Breeding Farms (Montreal, Canada). The animals were fed a standard chow pellet diet, had free access to water, and were maintained on a 12:12-h light-dark cycle. All procedures in this study were approved by the Animal Care Committee of the University of Calgary and were in compliance with the guidelines of the Canadian Council on Animal Care.
Induction of colitis. Colitis was induced as described previously (21). Briefly, rats were lightly anesthetized with halothane, and the hapten trinitrobenzene sulfonic acid (TNBS; 30 mg in 0.5 ml of 50% ethanol) was administered into the distal colon via a cannula. Untreated rats served as controls. At several time points thereafter (from 1 h to 7 days), groups of rats were euthanized by cervical dislocation. The colon was excised and pinned out on a wax platform. Tissue samples were taken for determination of PG synthesis, for measurement of myeloperoxidase (MPO) activity, and for histological assessment. MPO is an enzyme found primarily in the azurophilic granules of neutrophils and in other cells of myeloid origin. We have previously used MPO activity as a quantitative measure of the number of granulocytes in intestinal tissue and have shown that it correlates well with histological quantification of granulocyte numbers. Thus tissue MPO activity served as an index of granulocyte infiltration into the colon.
PG synthesis and COX-2 mRNA expression.
Samples of distal colonic tissue were weighed and placed in an
Eppendorf tube containing 1 ml of 10 mM sodium phosphate buffer (pH
7.4). The samples were minced with a scissors for 15 s, then incubated for 20 min in a shaking water bath (37°C). The samples were
centrifuged (9,000 g for 1 min), and the supernatants were stored at 20°C. PGD2 and PGE2
concentrations in the supernatants were determined using ELISA. Samples
of colonic tissue were taken from control rats and from rats 1 and
3 h after TNBS administration. These samples were processed for
determination of COX-2 mRNA expression by RT-PCR, as described in
detail previously (5).
Effects of selective COX-2 inhibition. To determine which isoform of COX was responsible for PGD2 synthesis in the early phase of colitis, rats were treated orally with celecoxib (a selective COX-2 inhibitor; 10 mg/kg) or indomethacin (a nonselective COX inhibitor; 10 mg/kg) immediately after instillation of TNBS and were killed 3 h later. Control rats received the vehicle of 0.5% carboxymethylcellulose. The dose of celecoxib used in this study has been shown to selectively inhibit COX-2 activity, and the dose of indomethacin used has been shown to inhibit COX-1 and COX-2 activity (22, 30).
Effects of DP and PPAR- receptor agonists.
To further examine the potential role for PGD2 in
TNBS-induced colitis, rats were treated intracolonically with
PGD2 (10-100 µg/kg) 1 and 4 h after TNBS
administration. Control rats received an equal volume of saline in
place of PGD2. The doses of PGD2 used were
recently shown to significantly reduce inflammation in a rat model of
pleurisy (6). Other rats were treated with either a DP
receptor agonist (BW-245C; 10-50 µg/kg) or a PPAR-
agonist
that is also a metabolite of PGD2
(15-deoxy-
12-14PGJ2, subsequently
abbreviated as
PGJ2; 10-100 µg/kg) 1 and 4 h
after TNBS administration. All rats were killed 8 h after TNBS administration for assessment of tissue MPO activity and for histology.
MPO activity. Tissue samples were homogenized in hexadecyltrimethylammonium bromide buffer (50 mg/ml). The homogenates were centrifuged (9,000 g for 1 min), and the supernatants were assayed for MPO activity, as described previously (31).
Histology. Colonic tissues were fixed in 10% neutral-buffered formalin, dehydrated through graded concentrations of ethanol, embedded in paraffin, and sectioned. Sections (5 µm thick) were stained with hematoxylin and eosin according to standard protocols, and the slides were coded to prevent observer bias during evaluation. In some experiments, the degree of infiltration of granulocytes into the colonic tissue was semiquantitatively scored with the use of the following criteria: 0 = normal; 1 = mild infiltration; 2 = modest infiltration; 3 = dense infiltration. It should be noted that in the early stages of colitis, the degree of infiltration by granulocytes is so dense that it is virtually impossible to accurately quantify. This is one of the reasons that we utilized a biochemical marker of granulocyte numbers (MPO activity) in most studies.
Expression of PGD synthase and PPAR-.
Colonic tissue was homogenized in 1.5 ml of lysis buffer consisting of
0.1% Triton X-100, 500 mM NaCl, 50 mM HEPES, 0.1 mg/ml leupeptin, and
10 mg/ml phenylmethylsulfonyl fluoride. The homogenates were incubated
on ice for 30 min, then centrifuged at 400 g for 10 min. The
supernatants were collected, and protein concentrations were determined
with a Bio-Rad protein colorimetric assay (Bio-Rad, Hercules, CA). An
aliquot (50 µg) of total protein lysate was separated on a 10%
(PPAR-
) or 12.5% (PGD synthase) polyacrylamide gel and transferred
onto a nitrocellulose membrane (Pall, Ann Arbor, MI). The membrane was
incubated overnight at 4°C in blocking buffer (20 mM Tris, 100 mM
NaCl, 0.5% Tween 20, and 5% nonfat dried milk), then incubated with
either rabbit anti-mouse polyclonal PPAR-
antibody (1:1,000
dilution; Biomol Research Laboratories, Plymouth Meeting, PA) or rabbit
anti-rat PGD synthase antibody (1:800 dilution; Cedarlane Laboratories,
Hornby, ON, Canada) for 2 h at room temperature. The
membrane was next incubated with horseradish peroxidase-conjugated
donkey anti-rabbit IgG (Jackson ImmunoResearch Laboratories, West
Grove, PA) for 1 h at room temperature. Antibody labeling was then
visualized by addition of enhanced chemiluminescence reagent according
to the manufacturer's instructions (Amersham, Little Chalfont, UK).
Materials.
TNBS was obtained from Fluka Chimica (Buchs, Switzerland).
PGD2 ELISA kits, PGJ2, and PGD2
were obtained from Cayman Chemical (Ann Arbor, MI). BW-245C
[5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropylhydantoin)] was a generous gift from Glaxo-Wellcome (Stevenage, UK). Celecoxib was
obtained from Monsanto (St. Louis, MO). Indomethacin and other chemicals were obtained from Sigma Chemical (St. Louis, MO) or VWR
Scientific (Edmonton, AB, Canada).
Statistical analysis. All data are shown as means ± SE. Comparisons between two groups of data were performed using a Student's unpaired t-test. Comparisons among three or more groups were performed using a one-way analysis of variance followed by a Dunnett's multiple-comparison test or a Bonferroni post hoc test. Values of probability <5% (P < 0.05) were considered significant.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
MPO activity and PG synthesis.
As reported previously (32), intracolonic administration
of TNBS caused severe ulceration and damage to the distal colon of the
rats. Figure 1 shows the time course of
changes in colonic MPO following TNBS administration. A significant
increase in MPO activity was first observed at the 8-h time
point, and the greatest increase in MPO activity was seen at
day 3. Administration of TNBS resulted in significant
increases in PGD2 synthesis 1 h (4.3-fold) and 3 h (3.6-fold) after TNBS but not thereafter (Fig. 1). Thus increases in
PGD2 synthesis occurred before a significant increase in
granulocyte infiltration. In contrast, a significant increase in
PGE2 synthesis was not observed until three days after the administration of TNBS. Thus increased PGE2 synthesis
(32-fold) occurred at the same time as the greatest increase in MPO
activity (Fig. 1).
|
Effect of COX inhibitors.
Treatment with celecoxib (10 mg/kg) reduced colonic PGD2
synthesis at 3 h to the levels seen in rats without colitis.
Indomethacin caused an even greater suppression of PGD2
synthesis. Both celecoxib and indomethacin caused a more than doubling
of colonic MPO activity (Fig. 2). In
contrast, celecoxib and indomethacin did not alter PGE2
synthesis in colitic rats (data not shown). The increase in
PGD2 synthesis observed at 1 and 3 h after TNBS
administration occurred in parallel with significant (P < 0.01) increases in COX-2 mRNA expression (control: 0.4 ± 0.1 densitometry units; 1 h post-TNBS: 1.7 ± 0.3 densitometry
units; 3 h post-TNBS: 1.3 ± 0.2 densitometry units;
n = 4 per group).
|
Expression of PGD synthase.
Since a significant increase in PGD2 synthesis was observed
at the 3 h time point, we investigated whether the expression of
PGD synthase (the enzyme that catalyzes the conversion of
PGH2 to PGD2) was altered following induction
of colitis. As depicted in Fig. 3, PGD
synthase expression in colonic tissue at 3 h after TNBS was
similar to that in rats without colitis. Moreover, PGD synthase
expression was significantly reduced from 24 h to 7 days after
induction of colitis.
|
Effect of exogenous PGD2 on colonic granulocyte
infiltration.
Because inhibition of PGD2 synthesis with COX inhibitors
resulted in a significant increase in granulocyte infiltration, we next
examined whether administration of PGD2 would reduce
TNBS-induced granulocyte infiltration. As shown in Fig.
4, the highest dose of PGD2
(100 µg/kg) significantly reduced colonic MPO activity, but the lower
doses had no effect. Histologically, the colonic tissue from rats that
received intracolonic TNBS but were then treated with vehicle exhibited
widespread epithelial injury and marked submucosal edema (Fig.
5). Granulocyte infiltration (mainly neutrophils) was evident in the submucosa and mucosa. The density of
the granulocyte infiltrate was blindly scored on a 0 (normal) to 3 (dense infiltrate) scale. In rats that received PGD2 after TNBS administration, the colonic tissue exhibited greater preservation of the epithelium and reduced levels of submucosal edema. Again, granulocyte infiltration was evident (mean histological score of
1.0 ± 0.3 with the highest dose) but was not as extensive as in
the vehicle-treated group (mean histological score of 2.5 ± 0.3;
P < 0.05).
|
|
Expression of PPAR-.
Western blot analysis showed the presence of a 50-kDa band
corresponding to PPAR-
in the colon of naïve rats.
Expression of this protein was significantly higher in rats with
colitis at 3 and 24 h (Fig. 6).
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Although PGE2 and PGI2 can contribute to inflammatory reactions by virtue of their vasodilator properties (promoting edema formation) and through effects on sensory afferent nerves (promoting pain), it is also clear that these PGs and other members of this family of lipid mediators can exert many anti-inflammatory actions. For example, PGs can inhibit leukocyte adherence (2), inhibit the release of reactive oxygen metabolites from neutrophils (34), prevent mast cell degranulation (12), and inhibit the generation of a number of other inflammatory mediators and cytokines from various cells (9, 11, 16). A recent study of experimental pleuritis highlighted the anti-inflammatory properties of PGD2 (6). Production of this prostanoid was markedly elevated during the resolution of acute inflammation in that model, and exogenous PGD2 was found to significantly reduce neutrophil levels in the inflammatory exudate. Moreover, the increase in PGD2 production paralleled changes in COX-2 expression and was suppressed by a selective COX-2 inhibitor. In the present study, we attempted to determine whether PGD2 might similarly be an important anti-inflammatory mediator in experimental colitis, where it has already been shown that NSAIDs and selective COX-2 inhibitors exacerbate the inflammatory response and the tissue injury (24, 31). Interestingly, PGD2 production was elevated very early after induction of colitis (1-3 h) but not thereafter. The increase in PGD2 synthesis preceded significant changes in PGE2 synthesis, as well as preceding significant granulocyte infiltration. This suggested to us that PGD2 may play a role in modulating the initial granulocyte infiltration in this model. Indeed, we observed that exogenous PGD2 could significantly reduce granulocyte infiltration into the colon, supporting this hypothesis. Moreover, selective inhibition of COX-2 (with celecoxib) resulted in a complete blockade of the increase in colonic PGD2 synthesis, and this was accompanied by a more than doubling of granulocyte infiltration, as measured by MPO activity. Together, these results strongly suggest that PGD2 derived from COX-2 is an important early signal in colitis that acts to downregulate granulocyte infiltration.
It is not clear why the increase in PGD2 synthesis occurred in such a narrow window of time. PGE2 synthesis was not significantly increased at the same time as PGD2 synthesis, and we know from previous studies (24) that, at least at 72 h after TNBS administration, PGE2 is produced primarily via COX-2. Moreover, the initial increase in PGD2 synthesis occurred in parallel with an increase in COX-2 expression, but it declined despite the continued elevation of COX-2 expression, as we have previously demonstrated (24). This suggests that secondary enzymes in the synthesis of PGD2 and PGE2 may have been more important in regulating their production during acute colitis than COX-2. Indeed, our observation that the expression of PGD synthase significantly decreased at 24 h after induction of colitis is consistent with the diminution of PGD2 synthesis. The factors responsible for the downregulation of PGD synthase expression remain to be identified.
PGD2 can interact with both cell surface receptors, such as
the DP prostanoid receptor, and nuclear receptors, such as PPAR- (20). We attempted to determine whether actions at one of
these receptors accounted for the ability of PGD2 to reduce
granulocyte infiltration in acute colitis by assessing the effects of a
DP receptor agonist (BW-245C) and a PPAR-
agonist
(
PGJ2). BW-245C was found to significantly diminish
colonic MPO activity, whereas
PGJ2 significantly
increased colonic MPO activity (each at the highest dose tested). Thus
it seems likely that the anti-inflammatory activity of PGD2
was mediated via the DP receptor. It is interesting, however, that
expression of the PPAR-
receptor was markedly upregulated in the
inflamed colon. Several anti-inflammatory activities of PPAR-
agonists (such as
PGJ2) have been demonstrated,
including inhibition of cytokine expression (13,
29), suppression of expression of inducible nitric oxide
synthase (3, 26), and inhibition of cell
migration (7). Moreover, Su and colleagues (29) recently demonstrated that agonists of the PPAR-
receptor diminished the severity of injury in a mouse model of colitis. It is possible, therefore, that treatment with a PPAR-
agonist over
a more prolonged period of time, or at a different time point after
induction of colitis, might have a significant anti-inflammatory effect.
In summary, the results of the present study demonstrate that COX-2-derived PGD2, most probably acting via the DP receptor, acts to downregulate granulocyte infiltration into colonic mucosa during the early stages of the inflammatory response induced by TNBS. The ability of selective COX-2 inhibitors to exacerbate colitis may be due, at least in part, to suppression of the synthesis of PGD2.
![]() |
ACKNOWLEDGEMENTS |
---|
We are grateful to Webb McKnight and Michael Dicay for their assistance in performing these studies.
![]() |
FOOTNOTES |
---|
This work was supported by a grant from the Medical Research Council of Canada (MRC). M. N. Ajuebor is supported by an Alberta Heritage Foundation for Medical Research (AHFMR) Fellowship. J. L. Wallace is a MRC Senior Scientist and an AHFMR Senior Scientist.
Address for reprint requests and other correspondence: J. L. Wallace, Dept. of Pharmacology and Therapeutics, Univ. of Calgary, 3330 Hospital Dr. NW, Calgary, AB, T2N 4N1, Canada (E-mail: wallacej{at}ucalgary.ca).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Received 14 February 2000; accepted in final form 7 April 2000.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Allgayer, H,
Deschryver K,
and
Stenson WF.
Treatment with 16,16'-dimethylprostaglandin E2 before and after induction of colitis with trinitrobenzenesulfonic acid in rats decreases inflammation.
Gastroenterology
96:
1290-1300,
1989[ISI][Medline].
2.
Asako, H,
Kubes P,
Wallace JL,
Gaginella T,
Wolf RE,
and
Granger DN.
Indomethacin-induced leukocyte adhesion in postcapillary venules: role of lipoxygenase products.
Am J Physiol Gastrointest Liver Physiol
262:
G903-G908,
1992
3.
Colville-Nash, PR,
Qureshi SS,
Willis D,
and
Willoughby DA.
Inhibition of inducible nitric oxide synthase by PPAR agonist: correlation with induction of heme oxygenase 1.
J Immunol
161:
978-984,
1998
4.
Fedorak, RN,
Empey LR,
MacArthur C,
and
Jewell LD.
Misoprostol provides a colonic mucosal protective effect during acetic-induced colitis in rats.
Gastroenterology
98:
615-625,
1990[ISI][Medline].
5.
Ferraz, JGP,
Sharkey KA,
Reuter BK,
Asfaha S,
Tigley AW,
Brown ML,
McKnight W,
and
Wallace JL.
Induction of cyclooxygenase-1 and -2 in the rat stomach during endotoxemia: role in resistance to damage.
Gastroenterology
113:
195-204,
1997[ISI][Medline].
6.
Gilroy, D,
Colville-Nash PR,
Willis D,
Chivers J,
Paul-Clark MJ,
and
Willoughby DA.
Inducible cyclooxygenase may have anti-inflammatory properties.
Nat Med
5:
698-701,
1999[ISI][Medline].
7.
Goetze, S,
Xi X-P,
Kawano H,
Gotlibowski T,
Fleck E,
Hsueh WA,
and
Law RE.
PPAR- ligands inhibit migration mediated by multiple chemoattractants in vascular smooth muscle cells.
J Cardiovasc Pharmacol
33:
798-806,
1999[ISI][Medline].
8.
Gould, SR,
Brash AR,
and
Conolly ME.
Increased prostaglandin production in ulcerative colitis.
Lancet
2:
98,
1977[ISI][Medline].
9.
Ham, EA,
Soderman DD,
Zanetti ME,
Dougherty HW,
McCauley E,
and
Kuehl FA.
Inhibition by prostaglandins of leukotriene B4 release from activated neutrophils.
Proc Natl Acad Sci USA
80:
4349-4353,
1983[Abstract].
10.
Harris, DW,
Smith PR,
and
Swan CHJ
Determination of prostaglandin synthetase activity in rectal biopsy material and its significance in colonic disease.
Gut
19:
875-877,
1978[Abstract].
11.
Hogaboam, CM,
Befus AD,
and
Wallace JL.
Modulation of rat mast cell reactivity by IL-1. Divergent effects on nitric oxide and platelet-activating factor release.
J Immunol
151:
3767-3774,
1993
12.
Hogaboam, CM,
Bissonnette EY,
Chin BC,
Befus AD,
and
Wallace JL.
Prostaglandins inhibit inflammatory mediator release from rat mast cells.
Gastroenterology
104:
122-129,
1993[ISI][Medline].
13.
Jiang, C,
Ting AT,
and
Seed B.
PPAR- agonists inhibit production of monocyte inflammatory cytokines.
Nature
391:
82-86,
1998[ISI][Medline].
14.
Kaufmann, HJ,
and
Taubin HL.
Nonsteroidal anti-inflammatory drugs activate quiescent inflammatory bowel disease.
Ann Intern Med
107:
513-516,
1987[ISI][Medline].
15.
Kujubu, DA,
Fletcher BS,
Varnum BC,
Lim RW,
and
Herschman HR.
TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells encodes a novel prostaglandin synthase/cyclooxygenase homologue.
J Biol Chem
266:
12866-12872,
1991
16.
Kunkel, SL,
Wiggins RC,
Chensue SW,
and
Larrick J.
Regulation of macrophage tumour necrosis factor production by prostaglandin E2.
Biochem Biophys Res Commun
137:
404-410,
1986[ISI][Medline].
17.
Lehamn, JM,
Lenhard JM,
Oliver BB,
Ringold GM,
and
Kliewer SA.
PPAR- and
are activated by indomethacin and other NSAIDs.
J Biol Chem
272:
3406-3410,
1997
18.
Longo, WE,
Panesar N,
Mazuski J,
and
Kaminski DL.
Contribution of cyclooxygenase-1 and cyclooxygenase-2 to prostanoid formation by human enterocytes stimulated by calcium ionophore and inflammatory agents.
Prostaglandins Other Lipid Med
56:
325-339,
1998[Medline].
19.
McCartney, SA,
Mitchell JA,
Fairclough PD,
Farthing MJG,
and
Warner TD.
Selective COX-2 inhibitors and human inflammatory bowel disease.
Aliment Pharmacol Ther
13:
1115-1117,
1999[ISI][Medline].
20.
Mitchell, JA,
and
Warner TD.
Cyclooxygenase-2: pharmacology, physiology, biochemistry and relevance to NSAID therapy.
Br J Pharmacol
128:
1121-1132,
1999
21.
Morris, GP,
Beck PL,
Herridge MS,
Depew WT,
Szewczuk MR,
and
Wallace JL.
Hapten-induced model of chronic inflammation and ulceration in the rat colon.
Gastroenterology
96:
795-803,
1989[ISI][Medline].
22.
Muscara, MN,
Vergnolle N,
Lovren F,
Triggle CR,
Elliot SN,
Asfaha S,
and
Wallace JL.
Selective cyclooxygenase-2 inhibition with celecoxib elevates blood pressure and promotes leukocyte adherence.
Br J Pharmacol.
129:
1423-1430,
2000
23.
Rampton, DS,
McNeil NI,
and
Sarner M.
Analgesic ingestion and other factors preceding relapse in ulcerative colitis.
Gut
24:
187-189,
1983[Abstract].
24.
Reuter, BK,
Asfaha S,
Buret A,
Sharkey KA,
and
Wallace JL.
Exacerbation of inflammation-associated colonic injury in rat through inhibition of cyclooxygenase-2.
J Clin Invest
98:
2076-2085,
1996
25.
Reuter, BK,
Mauleon D,
and
Wallace JL.
Mechanisms underlying colonic damage caused by chiral NSAIDs.
J Clin Gastroenterol
13:
S266-S269,
1998.
26.
Ricote, M,
Li AC,
Wilson TM,
Kelly CJ,
and
Glass CK.
The peroxisome-proliferator activated receptor- is a negative regulator of macrophage activation.
Nature
391:
79-82,
1998[ISI][Medline].
27.
Sharon, P,
Ligumsky M,
Rachmilewitz D,
and
Zor U.
Role of prostaglandins in ulcerative colitis: enhanced production during active disease and inhibition by sulfasalazine.
Gastroenterology
75:
638-640,
1978[ISI][Medline].
29.
Su, CG,
Wen X,
Bailey ST,
Jiang W,
Rangwala SM,
Keilbaugh SA,
Flanigan A,
Murthy S,
Lazar MA,
and
Wu GD.
A novel therapy for colitis utilizing PPAR-gamma ligands to inhibit the epithelial inflammatory response.
J Clin Invest
104:
383-389,
1999
30.
Wallace, JL,
Chapman K,
and
McKnight W.
Limited anti-inflammatory efficacy of cyclooxygenase-2 inhibition in carrageenan-airpouch inflammation.
Br J Pharmacol
126:
1200-1204,
1999
31.
Wallace, JL,
Keenan CM,
Gale D,
and
Shoupe TS.
Exacerbation of experimental colitis by nonsteroidal anti-inflammatory drugs is not related to elevated leukotriene B4 synthesis.
Gastroenterology
102:
18-27,
1992[ISI][Medline].
32.
Wallace, JL,
MacNaughton WK,
Morris GP,
and
Beck PL.
Inhibition of leukotriene synthesis markedly accelerates healing in a rat model of inflammatory bowel disease.
Gastroenterology
96:
29-36,
1989[ISI][Medline].
33.
Wallace, JL,
Whittle BJR,
and
Boughton-Smith NK.
Prostaglandin protection of rat colonic mucosa from damage induced by ethanol.
Dig Dis Sci
30:
866-876,
1985[ISI][Medline].
34.
Wong, K,
and
Freund F.
Inhibition of n-formylmethionyl-leucylphenylalanine induced respiratory burst in human neutrophils by adrenergic agonists and prostaglandins of the E series.
Can J Physiol Pharmacol
59:
915-920,
1981[ISI][Medline].
35.
Xie, W,
Chipman JG,
Robertson DL,
Erikson RL,
and
Simmons DL.
Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing.
Proc Natl Acad Sci USA
88:
2692-2696,
1991[Abstract].