RESUMO
Platelet-endothelial cell adhesion molecule-1 (PECAM-1, CD31) plays an active role in the process of leukocyte migration through cultured endothelial cells in vitro and anti-PECAM-1 antibodies (Abs) inhibit accumulation of leukocytes into sites of inflammation in vivo. Despite the latter, it is still not clear at which stage of leukocyte emigration in vivo PECAM-1 is involved. To address this point directly, we studied the effect of an anti-PECAM-1 Ab, recognizing rat PECAM-1, on leukocyte responses within rat mesenteric microvessels using intravital microscopy. In mesenteric preparations activated by interleukin (IL)-1 beta, the anti-PECAM-1 Ab had no significant effect on the rolling or adhesion of leukocytes, but inhibited their migration into the surrounding extravascular tissue in a dose-dependent manner. Although in some vessel segments these leukocytes had come to a halt within the vascular lumen, often the leukocytes appeared to be trapped within the vessel wall. Analysis of these sections by electron microscopy revealed that the leukocytes had passed through endothelial cell junctions but not the basement membrane. In contrast to the effect of the Ab in mesenteric preparations treated with IL-1 beta, leukocyte extravasation induced by topical or intraperitoneal administration of the chemotactic peptide formyl-methionyl-leucyl-phenylalanine was not inhibited by the anti-PECAM-1 Ab. These results directly demonstrate a role for PECAM-1 in leukocyte extravasation in vivo and indicate that this involvement is selective for leukocyte extravasation elicited by certain inflammatory mediators. Further, our findings provide the first in vivo indication that PECAM-1 may have an important role in triggering the passage of leukocytes through the perivascular basement membrane.
Assuntos
Antígenos de Diferenciação Mielomonocítica/fisiologia , Membrana Basal/fisiologia , Moléculas de Adesão Celular/fisiologia , Endotélio Vascular/fisiologia , Inflamação/patologia , Leucócitos/citologia , Animais , Anticorpos Monoclonais , Adesão Celular , Interleucina-1/farmacologia , Masculino , Mesentério/citologia , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas , Ratos , Ratos Sprague-Dawley , Gravação em VídeoRESUMO
1. The role of leukotriene B4 (LTB4) and LTC4 as mediators of gastric mucosal damage following ethanol challenge in vivo has been investigated using two selective 5-lipoxygenase inhibitors, BW A4C and BW A137C. 2. Oral administration of ethanol to rats in vivo, induced macroscopic damage to the gastric mucosa and markedly increased the formation of the 5-lipoxygenase products, LTB4 and LTC4, from the mucosa ex vivo. 3. Pretreatment with the acetohydroxamic acids BW A4C and BW A137C (5-50 mg kg-1 p.o.) dose-dependently reduced ethanol-stimulated LTB4 and LTC4 formation by the gastric mucosa, with an ID50 of approximately 5 mg kg-1 p.o. 4. A single oral dose of BW A4C (20 mg kg-1) induced near-maximal inhibition of mucosal LTB4 formation within 30 min, which was well maintained for 5 h, whereas BW A137C (20 mg kg-1 p.o.) induced maximal inhibition between 30 and 60 min after administration, which then diminished over the subsequent 5 h. 5. The mucosal formation of the cyclo-oxygenase product, 6-keto-prostaglandin F1 alpha, which was unaltered following ethanol challenge, was not inhibited by the acetohydroxamic acids. Likewise, the small increase in mucosal thromboxane B2 formation following challenge was not inhibited by BW A4C. 6. Neither BW A4C nor BW A137C, at doses that almost completely inhibited the mucosal synthesis of LTB4 or LTC4, reduced the macroscopic gastric mucosal damage induced by ethanol. 7. Pretreatment with the lipoxygenase inhibitor BW 755C (5-50 mg kg-1 p.o.) did reduce mucosal damage, but there was a dissociation between the degree of protection and the inhibition of leukotriene biosynthesis. 8. Oral administration of high doses of either BW A4C or BW A137C (300mgkg-1) did not induce macroscopic gastric damage over a 3 h period. 9. These findings suggest that the leukotrienes, LTB4 and LTC4 are not the primary mediators of ethanol-induced acute mucosal damage, but do not exclude their role in more chronic gastric damage and inflammation.
Assuntos
Araquidonato Lipoxigenases/antagonistas & inibidores , Benzenoacetamidas , Mucosa Gástrica/enzimologia , Ácidos Hidroxâmicos/farmacologia , Inibidores de Lipoxigenase , Úlcera Gástrica/prevenção & controle , 4,5-Di-Hidro-1-(3-(Trifluormetil)Fenil)-1H-Pirazol-3-Amina , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Etanol , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Masculino , Pirazóis/farmacologia , Radioimunoensaio , Ratos , Ratos Endogâmicos , Úlcera Gástrica/induzido quimicamente , Fatores de TempoRESUMO
Inflammation of the guinea-pig colon was produced by skin sensitization and subsequent intracolonic challenge with the chemical hapten, dinitrochlorobenzene. Metabolism of [14C]-arachidonic acid by homogenates of control colon was very low, although metabolites co-migrating on thin layer chromatography (t.l.c.) with prostaglandin E2 (PGE2), PGF2 alpha, PGD2, 6-keto-PGF1 alpha, thromboxane B2 (TXB2), HHT and 11-, 12-, 15-HETE were formed. There was an overall 3 fold increase in metabolism of [14C]-arachidonic acid by homogenates of inflamed mucosa. The greatest increase in metabolite formation was of PGE2, with smaller increases in HHT, 11-, 12-, 15-HETE, PGD2, TXB2, PGF2 alpha and 6-keto-PGF1 alpha. The formation of these metabolites was inhibited both by indomethacin and the dual pathway inhibitor, BW755C. The formation of immunoreactive PGE2, TXB2 and 6-keto-PGF1 alpha was also increased in homogenates of inflamed guinea-pig colon. The small level of immunoreactive LTB4 detected in control colon was not changed in inflamed colonic tissue. The dinitrochlorobenzene model of colitis offers a means of studying arachidonic acid metabolism in an immune-mediated inflammatory response in intestinal tissue.
Assuntos
Ácidos Araquidônicos/metabolismo , Colite Ulcerativa/metabolismo , 4,5-Di-Hidro-1-(3-(Trifluormetil)Fenil)-1H-Pirazol-3-Amina , Animais , Ácido Araquidônico , Cromatografia em Camada Fina , Colite Ulcerativa/imunologia , Dinitroclorobenzeno , Modelos Animais de Doenças , Cobaias , Imunização , Indometacina/farmacologia , Masculino , Prostaglandinas/metabolismo , Pirazóis/farmacologia , RadioimunoensaioRESUMO
1 Homogenates of rat gastric mucosa, forestomach and ileum and dog gastric mucosa reproducibly generated prostacyclin from endogenous substrate.2 Prostacyclin formation was inhibited by pre-incubation with indomethacin, flurbiprofen, naproxen, ketoprofen or meclofenamate (0.1-10 muM).3 BW755C (3-amino-1[m-(trifluoromethyl)-phenyl]-2-pyrazoline) stimulated prostacyclin production in the rat gastric mucosa and ileum with inhibition occurring only at high concentrations (> 200 muM). The stimulation of prostacyclin production by BW755C in rat forestomach homogenates was less pronounced, with inhibition at concentrations > 20 muM.4 BW755C thus exhibits differential activity on prostacyclin production from different gastric tissues in vitro.5 The antioxidant-lipoxygenase inhibitor, nordihydroguiaretic acid (NDGA, 3-15 muM) likewise augmented rat mucosal prostacyclin formation.6 Paracetamol stimulated and, at higher concentrations, inhibited prostacyclin formation (> 1 mM), and had comparable activity in both rat gastric tissues.7 The ability of NDGA and BW755C to enhance prostacyclin generation may reflect the removal of a modulating influence of lipoxygenase products on prostacyclin formation, the diversion of substrate to the cyclo-oxygenase pathway, or free-radical scavenging.
Assuntos
Anti-Inflamatórios/farmacologia , Epoprostenol/biossíntese , Mucosa Gástrica/metabolismo , Íleo/metabolismo , Prostaglandinas/biossíntese , 4,5-Di-Hidro-1-(3-(Trifluormetil)Fenil)-1H-Pirazol-3-Amina , Acetaminofen/farmacologia , Animais , Catecóis/farmacologia , Técnicas In Vitro , Masculino , Masoprocol , Pirazóis/farmacologia , Ratos , Ratos EndogâmicosRESUMO
1 The characteristics of the antisecretory actions of prostaglandin E2 (PGE2) and two stable prostacyclin analogues during different rates of acid stimulation have been evaluated in the lumen-perfused isolated whole stomach of the rat and mouse. 2 In the rat isolated stomach, histamine induced a dose-dependent increase in acid output. Preincubation with PGE2 caused a dose-related and surmountable inhibition. 3 The stable prostacyclin analogues, 6 beta-PGI1 and a 16-phenoxy derivative likewise caused a surmountable inhibition of histamine-stimulated acid output from rat stomach. 4 PGE2 had inconsistent actions on the acid secretion stimulated by pentagastrin, methacholine or dibutyryl cyclic adenosine 3',5'-monophosphate. 5 In the mouse isolated stomach, acid secretion was stimulated by low concentrations of histamine, pentagastrin or methacholine. 6 PGE2 failed to inhibit histamine-stimulated acid output from mouse stomach, but high concentrations of the potent 15-phenoxy analogue did show anti-secretory activity. 7 The results indicate the usefulness of the rat isolated stomach for studying the interaction of prostaglandins with the acid secretory process in mammalian gastric mucosa.
Assuntos
Epoprostenol/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Prostaglandinas E/farmacologia , Prostaglandinas/farmacologia , Animais , Bucladesina/farmacologia , Mucosa Gástrica/metabolismo , Histamina/farmacologia , Técnicas In Vitro , Compostos de Metacolina/farmacologia , Camundongos , Pentagastrina/farmacologia , RatosRESUMO
1. The role of endogenous nitric oxide (NO) in maintaining intestinal vascular integrity following acute endotoxin (E. coli. lipopolysaccharide) challenge was investigated in the anaesthetized rat by use of NG-monomethyl-L-arginine (L-NMMA), a selective inhibitor of NO synthesis. 2. L-NMMA (10-50 mg kg-1, i.v.) pretreatment enhanced both the macroscopic and histological intestinal damage and the increases in vascular permeability, measured as the leakage of [125I]-labelled human serum albumen, induced after 15 min by endotoxin (50 mg kg-1, i.v.). 3. The effects of L-NMMA (50 mg kg-1, i.v.) were enantiomer specific, as D-NMMA had no effect. Furthermore, these effects were reversed by L-arginine (300 mg kg-1, i.v.), the precursor of NO synthesis but not by D-arginine (300 mg kg-1, i.v.). 4. L-NMMA (10-50 mg kg-1, i.v.) increased mean systemic arterial blood pressure but this does not appear to be the mechanism by which endotoxin-induced intestinal damage was enhanced, since similar systemic pressor responses induced by phenylephrine (10 micrograms kg-1 min-1, i.v.), had no such effect. 5. The results suggest that synthesis of NO from L-arginine has a role in maintaining the microvascular integrity of the intestinal mucosa following acute endotoxin challenge.
Assuntos
Arginina/análogos & derivados , Vasos Sanguíneos/efeitos dos fármacos , Endotoxinas/toxicidade , Enteropatias/induzido quimicamente , Óxido Nítrico/metabolismo , Animais , Arginina/farmacologia , Contagem de Células Sanguíneas , Pressão Sanguínea/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Hemorragia/induzido quimicamente , Hemorragia/fisiopatologia , Enteropatias/metabolismo , Enteropatias/patologia , Enteropatias/fisiopatologia , Radioisótopos do Iodo , Jejuno/patologia , Lipopolissacarídeos/farmacologia , Masculino , Fenilefrina/farmacologia , Ratos , Ratos Endogâmicos , ômega-N-MetilargininaRESUMO
1. The role of arachidonic acid metabolites and oxygen radicals in carrageenin-induced rat paw oedema and dermal reverse passive Arthus reaction (RPA) have been investigated. 2. Indomethacin (10 mg kg-1, p.o.) inhibited carrageenin paw oedema when administered 30 min before, but not 2 h after carrageenin. BWB70C (10 mg kg-1, p.o.), a selective inhibitor of 5-lipoxygenase, had no effect whether administered before or after carrageenin. Administration of both indomethacin and BWB70C had no greater anti-inflammatory effect than indomethacin alone. 3. BW755C (20 mg kg-1, p.o.), which inhibits the cyclo-oxygenase and lipoxygenase pathways of arachidonic acid metabolism, or superoxide dismutase-polyethylene glycol conjugate (SOD-PEG, 3000 u, i.v.) inhibited carrageenin paw oedema whether administered either 30 min before, or 2 h after carrageenin. 4. Pretreatment with dexamethasone (0.1 mg kg-1) or colchicine (2 mg kg-1), likewise suppressed carrageenin paw oedema. 5. BW755C (25-100 mg kg-1, p.o.) dose-dependently reduced plasma leakage in the RPA, whereas indomethacin (5 mg kg-1, p.o.) or BWB70C either alone or in combination, did not. 6. SOD-PEG (300-3000 u, i.v.) dose-dependently inhibited plasma leakage in the RPA. In addition, the iron chelator and peroxyl radical scavenger, desferrioxamine (200 mg kg-1, s.c.) also inhibited plasma leakage. 7. Pretreatment with dexamethasone (0.1 mg kg-1) or colchicine (1 mg kg-1) reduced the plasma leakage in RPA, whereas MK-886 (10 mg kg-1) had no effect. 8. These results indicate an important role for oxygen radicals but not arachidonic acid metabolites in the maintenance of carrageenin paw oedema and the plasma leakage in RPA. Furthermore, the results suggest that the anti-inflammatory actions of BW755C can be dissociated from its effects on arachidonic acid metabolism and are attributed to its anti-oxidant activity.
Assuntos
Antioxidantes/farmacologia , Ácido Araquidônico/fisiologia , Reação de Arthus/fisiopatologia , Edema/fisiopatologia , Espécies Reativas de Oxigênio/metabolismo , 4,5-Di-Hidro-1-(3-(Trifluormetil)Fenil)-1H-Pirazol-3-Amina/farmacologia , Animais , Carragenina , Colchicina/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Desferroxamina/farmacologia , Dexametasona/farmacologia , Edema/induzido quimicamente , Inibidores de Lipoxigenase/farmacologia , Masculino , Peroxidase/metabolismo , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismoRESUMO
Platelet-activating factor (Paf) has been proposed as a mediator of the gastrointestinal damage in endotoxic shock. The formation of Paf in rat jejunal tissue, determined following extraction and bioassay on rabbit washed platelets has therefore been correlated with the induction of damage following endotoxin administration. Intravenous injection of E. coli endotoxin led to a time-dependent increase in the jejunal formation of Paf, which after 20 min was twenty fold greater than the control level. There was a significant correlation between elevated Paf release and intestinal hyperaemia and haemorrhage, thus supporting a role for Paf as a mediator of such damage.
Assuntos
Endotoxinas/toxicidade , Mucosa Intestinal/metabolismo , Fator de Ativação de Plaquetas/metabolismo , Animais , Intestinos/efeitos dos fármacos , Masculino , Ratos , Ratos EndogâmicosRESUMO
1. The effects of anti-inflammatory drugs on eicosanoid formation and colonic damage in a chronic model of inflammatory bowel disease (IBD) in the rat were investigated. 2. A single colonic instillation of the hapten, trinitrobenzene sulphonic acid (TNB) resulted in ulceration and inflammation which persisted for 3 weeks. 3. The macroscopic colonic damage, present 3 weeks after TNB, was correlated with an increase in immunoreactive 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and leukotriene B4 (LTB4) synthesis by the rat colon. 4. Anti-inflammatory drugs were administered 2 weeks after TNB, when there was substantial colonic damage, and continued for a week. The experimental drug BW755C inhibited the increased formation of 6-keto-PGF1 alpha and LTB4 by the inflamed colon. Indomethacin and aspirin markedly inhibited prostanoid formation in both inflamed and control colon. Sulphasalazine or prednisolone also inhibited the formation of 6-keto-PGF1 alpha but the effects were less marked. 5. None of the anti-inflammatory drugs significantly reduced the colonic damage induced by TNB. 6. The results suggest that eicosanoids, including LTB4, have only a minor role in maintaining the chronic macroscopic damage induced in the rat colon by TNB. The role of such eicosanoids in the underlying infiltration and activity of inflammatory cells in this model of IBD, however, is not known.
Assuntos
Anti-Inflamatórios/farmacologia , Colite/metabolismo , Ácidos Eicosanoicos/biossíntese , 6-Cetoprostaglandina F1 alfa/metabolismo , Animais , Técnicas In Vitro , Leucotrieno B4/biossíntese , Masculino , Radioimunoensaio , Ratos , Ratos EndogâmicosRESUMO
1. The effect of endotoxin (E. coli lipopolysaccharide) on the induction of nitric oxide synthase (NOS) and the changes in vascular permeability in the colon and jejunum over a 5 h period have been investigated in the rat. 2. Under resting conditions, a calcium-dependent constitutive NOS, determined by the conversion of radiolabelled L-arginine to citrulline, was detected in homogenates of both colonic and jejunal tissue. 3. Administration of endotoxin (3 mg kg-1, i.v.) led, after a 2 h lag period, to the appearance of calcium-independent NOS activity in the colon and jejunum ex vivo, characteristic of the inducible NOS enzyme. 4. Administration of endotoxin led to an increase in colonic and jejunal vascular permeability after a lag period of 3 h, determined by the leakage of radiolabelled albumin. 5. Pretreatment with dexamethasone (1 mg kg-1 s.c., 2 h prior to challenge) inhibited both the induction of NOS and the vascular leakage induced by endotoxin. 6. Administration of the NO synthase inhibitor NG-monomethyl-L-arginine (12.5-50 mg kg-1, s.c.) 3 h after endotoxin injection, dose-dependently reduced the subsequent increase in vascular permeability in jejunum and colon, an effect reversed by L-arginine (300 mg kg-1, s.c.). 7. These findings suggest that induction of NOS is associated with the vascular injury induced by endotoxin in the rat colon and jejunum.
Assuntos
Aminoácido Oxirredutases/biossíntese , Permeabilidade Capilar/efeitos dos fármacos , Colo/irrigação sanguínea , Colo/enzimologia , Endotoxinas/farmacologia , Escherichia coli , Jejuno/irrigação sanguínea , Jejuno/enzimologia , Lipopolissacarídeos/toxicidade , Aminoácido Oxirredutases/metabolismo , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Colo/efeitos dos fármacos , Dexametasona/farmacologia , Indução Enzimática/efeitos dos fármacos , Jejuno/efeitos dos fármacos , Masculino , Óxido Nítrico Sintase , Ratos , Ratos Wistar , ômega-N-MetilargininaRESUMO
In conclusion, we have described a novel series of acetohydroxamic acids that are potent and selective inhibitors of arachidonate 5-lipoxygenase in vitro and in vivo. In addition, we have shown that these compounds attenuate "leukotriene-dependent" anaphylactic bronchospasm, the accumulation of inflammatory leukocytes, and the development of fever in experimental models. It now remains to be determined if these compounds have any therapeutic value in man.
Assuntos
Anafilaxia/metabolismo , Araquidonato Lipoxigenases/antagonistas & inibidores , Ácidos Araquidônicos/metabolismo , Ácidos Hidroxâmicos/farmacologia , Inibidores de Lipoxigenase , Ácido 5,8,11,14-Eicosatetrainoico/farmacologia , Anafilaxia/fisiopatologia , Animais , Araquidonato 5-Lipoxigenase/metabolismo , Ácido Araquidônico , Testes de Provocação Brônquica , Espasmo Brônquico/fisiopatologia , Febre/fisiopatologia , Mucosa Gástrica/efeitos dos fármacos , Cobaias , Humanos , Inflamação , Leucócitos/enzimologia , Leucotrieno B4/fisiologia , Masoprocol/farmacologia , Ratos , SRS-A/fisiologiaRESUMO
The stimulation of gastric alkaline secretion in vivo following topical mucosal application of four stable anti-ulcer analogues of prostacyclin has been investigated in the rat and in the dog using intragastric pH-stat techniques. In the rat, basal alkaline secretion was significantly stimulated by the prostacyclin analogues 16-phenoxy-(5 alpha)-5,9-epoxy-PGF1 (16-phenoxy) and its methyl ester, when administered in the luminal perfusion fluid. The 16-phenoxy analogue (25 and 50 micrograms ml-1) increased basal alkaline secretion with its methyl ester being more potent. The methyl ester of 16,16-dimethyl PGI1 (25 and 50 micrograms ml-1) likewise stimulated alkaline secretion whereas its corresponding free acid was inactive at these concentrations. In further studies in the conscious dog with a Heidenhain gastric pouch, these four prostacyclin analogues administered intraluminally (1.25 micrograms ml-1) significantly increased gastric alkaline secretion. The present findings indicate that the stable 16-phenoxy and 16, 16-dimethyl analogues of prostacyclin, can stimulate gastric alkaline secretion in the dog and rat in vivo. As with the previously reported 16,16-dimethyl PGE2 analogue, this property of stimulating alkaline secretion may therefore contribute to the antiulcer activity of these prostacyclin analogues.
Assuntos
Epoprostenol/farmacologia , Suco Gástrico/metabolismo , Álcalis/metabolismo , Animais , Cães , Suco Gástrico/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Masculino , Ratos , Ratos Endogâmicos , Especificidade da EspécieRESUMO
Macroscopic jejunal damage and plasma leakage induced within 15 min by E. coli lipopolysaccharide (LPS 50 mg kg-1 i.v.) in the rat was enhanced by the inhibitor of nitric oxide (NO) formation, NG-monomethyl-L-arginine (L-NMMA 50 mg kg-1 i.v.). The nitro-vasodilator, S-nitroso-N-acetyl-penicillamine (SNAP; 10 micrograms kg-1 min-1 i.v.), which generates NO, attenuated both LPS-induced intestinal damage and the enhancement of such damage and plasma leakage produced by L-NMMA. Endogenous NO may thus have a protective role in the intestinal vasculature that can be mimicked by generators of NO.
Assuntos
Endotoxinas/toxicidade , Enteropatias/prevenção & controle , Penicilamina/análogos & derivados , Vasodilatadores/farmacologia , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Endotoxinas/antagonistas & inibidores , Escherichia coli , Enteropatias/induzido quimicamente , Enteropatias/fisiopatologia , Jejuno/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Masculino , Penicilamina/farmacologia , Ratos , Ratos Endogâmicos , S-Nitroso-N-Acetilpenicilamina , Soroalbumina Radioiodada , ômega-N-MetilargininaRESUMO
There is considerable evidence that excessive nitric oxide (NO) synthesized from L-arginine by inducible nitric oxide synthase (iNOS) plays an important pathological role in inflammatory arthritis. Since NO synthesized by constitutive isoforms of NOS has a physiological role, a great deal of activity has been directed at identifying inhibitors of NOS that are selective for the induced isoform. The major chemical areas that have been described so far in the search for such selective iNOS inhibitors and the activity of some of these compounds in animal models of arthritis are reviewed.
RESUMO
The leukotrienes have potent inflammatory actions which could be of importance in gastric mucosal integrity. In animals, LTC4 produces vasoconstriction in the gastric mucosa. Furthermore, acute gastric damage produced by ethanol is accompanied by marked increases in the mucosal formation of LTC4 and LTB4. Depending on the extent of protection, prostaglandins either have no effect or prevent the increases in leukotriene formation which accompany ethanol-induced damage. Various non-specific inhibitors of leukotriene synthesis prevent ethanol and indomethacin-induced damage to the gastric mucosa. However, a novel selective 5-lipoxygenase inhibitor (BW A4C) had no effect on these models of acute gastric damage at doses which completely inhibited gastric mucosal leukotriene synthesis. These studies cast doubt on the role of the leukotrienes in these models of acute gastric damage. However, the potent biological actions of the leukotrienes may be of importance in the pathogenesis of other forms of gastric damage, or as mediators of chronic gastric ulceration or inflammation.