leukotriene-b4 and Stomach-Ulcer

Gastric injury is mainly described by inflammation of the gastric epithelium. Recently, our group of work demonstrated that

Topics: Animals; Anti-Ulcer Agents; Antioxidants; Gastric Mucosa; Indomethacin; Leukotriene B4; Nitric Oxide; Plant Extracts; Plant Leaves; Rats; Stomach Ulcer

The co-administration of 3α-hydroxymasticadienoic acid (3α-OH MDA) and diligustilide (DLG) generates a synergist gastroprotective effect on indomethacin-induced gastric damage. However, the related protective activities of the compounds alone (or in combination) remain unclear. In the present study, we evaluated the anti-inflammatory and antioxidative activities, as well as the potential modulation of important gasotransmitters of each compound individually and in combination using the indomethacin-induced gastric damage model. Male Wistar rats were treated orally with the 3α-OH MDA, DLG, or their combination (at a fixed ratio of 1:1, 1:3, and 3:1) 30 min before the generation of gastric mucosal lesions with indomethacin (30 mg/kg, p.o.). Three hours later, the gastric injury (mm

Topics: Animals; Anti-Inflammatory Agents; Anti-Ulcer Agents; Antioxidants; Dinoprostone; Disease Models, Animal; Drug Therapy, Combination; Gastric Mucosa; Hydrogen Sulfide; Indomethacin; Leukotriene B4; Male; Nitric Oxide; Rats, Wistar; Stomach Ulcer; Superoxide Dismutase; Triterpenes; Tumor Necrosis Factor-alpha

To investigate the effects of Clostridium butyricum (C. butyricum) on experimental gastric ulcers (GUs) induced by alcohol, restraint cold stress, or pyloric ligation in mice, respectively.. One hundred and twenty mice were randomly allocated into three types of gastric ulcer models (n = 40 each), induced by alcohol, restraint cold stress, or pyloric ligation. In each GU model, 40 mice were allocated into four groups (n = 10 each): the sham control group; model group (GU induction without pretreatment); C. butyricum group (GU induction with C. butyricum pretreatment); and Omeprazole group (GU induction with Omeprazole pretreatment). The effects of C. butyricum were evaluated by examining the histological changes in the gastric mucosal erosion area, the activities of superoxide dismutase (SOD) and catalase (CAT), the level of malondialdehyde (MDA), and the contents of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, leukotriene B4 (LTB4) and 6-keto-PGF-1α (degradation product of PGI2) in the gastric tissue.. Our data showed that C. butyricum significantly reduced the gastric mucosal injury area and ameliorated the pathological conditions of the gastric mucosa. C. butyricum not only minimized the decreases in activity of SOD and CAT, but also reduced the level of MDA in all three GU models used in this study. The accumulation of IL1-β, TNF-α and LBT4 decreased, while 6-keto-PGF-1α increased with pretreatment by C. butyricum in all three GU models.. Our data demonstrated the protective effects of pretreatment with C. butyricum on anti-oxidation and anti-inflammation in different types of GU models in mice. Further studies are needed to explore its potential clinical benefits.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Catalase; Clostridium butyricum; Cold Temperature; Disease Models, Animal; Ethanol; Gastric Mucosa; Gastritis; Inflammation Mediators; Interleukin-1beta; Leukotriene B4; Ligation; Male; Malondialdehyde; Mice, Inbred ICR; Omeprazole; Oxidative Stress; Probiotics; Proton Pump Inhibitors; Pylorus; Restraint, Physical; Stomach Ulcer; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Salidroside (Sal) is a traditional Chinese medicine with various pharmacological effects. The present study aimed to investigate the protective effect of Sal on ethanol-induced acute gastric ulcer and H2O2-induced gastric epithelial cell damage. 0.2 ml ethanol and 400 μM H2O2 were applied to establish a gastric ulcer model in vivo and in vitro respectively. The production of interleukin (IL)-6, interleukin (IL)-1β and tumor necrosis factor (TNF)-α was analyzed, as well as myeloperoxidase (MPO), malondialdehyde (MDA) and superoxide dismutase (SOD). MTT assay was used to detect cell viability. In addition, MAPK/NF-κB signal pathway-related proteins p-ERK, p-JNK, p-p38, p-IκBα and p-NF-κBp65 were analyzed to determine the underlying protective mechanism. Downstream genes such as cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) and leukotrienes B4 (LTB4) were also measured. Obtained data indicated that Sal inhibited the overproduction of pro-inflammatory cytokines and enhanced antioxidant activity. Collectively, it is assumed that Sal could alleviate ethanol-induced acute gastric ulcer and H2O2-induced gastric epithelial cell damage through the MAPK/NF-κB pathway.

Topics: Animals; Anti-Ulcer Agents; Arachidonate 5-Lipoxygenase; Cell Line; Cell Survival; Cyclooxygenase 2; Cytokines; Ethanol; Glucosides; Humans; Hydrogen Peroxide; Leukotriene B4; Male; Mice, Inbred BALB C; Mitogen-Activated Protein Kinases; NF-kappa B; Phenols; Signal Transduction; Stomach; Stomach Ulcer

KYKZL-1, a newly synthesized compound with COX/5-LOX dual inhibition, was subjected to the anti-inflammatory activity test focusing on its modulation of inflammatory mediators as well as intracellular MAPK and NF-κB signaling pathways. In acute ear edema model, pretreatment with KYKZL-1 (p.o.) dose-dependently inhibited the xylene-induced ear edema in mice with a higher inhibition than diclofenac. In a three-day TPA-induced inflammation, KYKZL-1 also showed significant anti-inflammatory activity with inhibition ranging between 20% and 64%. In gastric lesion test, KYKZL-1 elicited markedly fewer stomach lesions with a low index of ulcer as compared to diclofenac in rats. In further studies, KYKZL-1 was found to significantly inhibit the production of NO, PGE2, LTB4 in LPS challenged RAW264.7, which is parallel to its attenuation of the expression of iNOS, COX-2, 5-LOX mRNAs or proteins and inhibition of phosphorylation of p38 and ERK MAPKs and activation of NF-κB. Taken together, our data indicate that KYKZL-1 comprises dual inhibition of COX and 5-LOX and exerts an obvious anti-inflammatory activity with an enhanced gastric safety profile via simultaneous inhibition of phosphorylation of p38 and ERK MAPKs and activation of NF-κB.

Topics: Animals; Anti-Inflammatory Agents; Blotting, Western; Cell Line; Cyclooxygenase Inhibitors; Dinoprostone; Edema; Indicators and Reagents; Inflammation Mediators; Leukotriene B4; Lipopolysaccharides; Lipoxygenase Inhibitors; Male; MAP Kinase Signaling System; Mice; Mice, Inbred ICR; NF-kappa B; Nitric Oxide; Phenylpropionates; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Stilbenes; Stomach Ulcer; Xylenes

Inflammation and reactive oxygen species are associated with the promotion of various cancers. The use of non-steroidal anti-inflammatory drugs (NSAIDs) in cancer prevention treatments has been promising in numerous cancers. We report the evaluation of NSAIDs chemically modified by the addition of a redox-active nitroxide group. TEMPO-aspirin (TEMPO-ASA) and TEMPO-indomethacin (TEMPO-IND) were synthesized and evaluated in the lung cancer cell line A549.. We evaluated physico-chemical properties of TEMPO-ASA and TEMPO-IND by electron paramagnetic resonance and cyclic voltammetry. Superoxide dismutase-like properties was assayed by measuring cytochrome c reduction and anti-inflammatory effects were assayed by measuring production of prostaglandin E(2) (PGE(2) ) and leukotriene B(4) (LTB(4) ). MTT proliferation assay and clonogenic assay were evaluated in the A549 lung carcinoma cell line. Maximum tolerated doses (MTD) and acute ulcerogenic index were also evaluated in in vivo.. MTD were: TEMPO (140 mg·kg(-1) ), ASA (100 mg·kg(-1) ), indomethacin (5 mg·kg(-1) ), TEMPO-ASA (100 mg·kg(-1) ) and TEMPO-IND (40 mg·kg(-1) ). While TEMPO-ASA was as well tolerated as ASA, TEMPO-IND showed an eightfold improvement over indomethacin. TEMPO-IND showed markedly less gastric toxicity than the parent NSAID. Both TEMPO-ASA and TEMPO-IND inhibited production of PGE(2) and LTB(4) in A549 cells with maximum effects at 100 µg·mL(-1) or 10 µg·mL(-1) respectively.. The nitroxide-NSAIDs retained superoxide scavenging capacity of the parent nitroxide and anti-inflammatory effects, inhibiting cyclooxygenase and 5-lipoxygenase enzymes. These redox-modified NSAIDs might be potential drug candidates, as they exhibit the pharmacological properties of the parent NSAID with antioxidant activity decreasing NSAID-associated toxicity.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Aspirin; Carrageenan; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclic N-Oxides; Dinoprostone; Disease Models, Animal; Edema; Female; Humans; Indomethacin; Leukotriene B4; Mice; Mice, Nude; Rats; Stomach Ulcer; Superoxide Dismutase

Previous studies have shown gastroprotective effect of fish oil in several experimental models. However, the mechanisms and active compounds underlying this effect are not fully understood. Fish oil has several components; among them, one of the most studied is docosahexaenoic acid (DHA), which is an omega-3 long-chain polyunsaturated fatty acid. The aim of this study was to examine the gastroprotective effect of DHA as a pure compound in a rat model of indomethacin-induced gastric injury as well as elucidate some of the mechanism(s) behind DHA's gastroprotective effect. Indomethacin was orally administered to induce an acute gastric injury (3, 10 and 30mg/kg). Omeprazol (a proton pump inhibitor, 30mg/kg, p.o.) and DHA (3, 10, 30mg/kg, p.o.) were gavaged 30 and 120min, respectively, before indomethacin insult (30mg/kg p.o.). Three hours after indomethacin administration, rats were sacrificed, gastric injury was evaluated by determining the total damaged area. A sample of gastric tissue was harvested and processed to quantify prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)) levels by enzyme-linked immunosorbent assay. Indomethacin produced gastric injury in dose-dependent manner. DHA protected against indomethacin-induced gastric damage, and this effect was comparable with omeprazol's gastroprotective effect. DHA did not reverse the indomethacin-induced reduction of PGE(2) gastric levels. In contrast, DHA partially prevented the indomethacin-induced increase in LTB(4) gastric levels. This is the first report demonstrating DHA's gastroprotective effect as a pure compound. Furthermore, the results reveal that the gastroprotective effect is mediated by a decrease in gastric LTB(4) levels in indomethacin-induced gastric damage.

Topics: Administration, Oral; Animals; Anti-Ulcer Agents; Cytoprotection; Dinoprostone; Disease Models, Animal; Docosahexaenoic Acids; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Female; Gastric Mucosa; Indomethacin; Leukotriene B4; Omeprazole; Proton Pump Inhibitors; Rats; Rats, Wistar; Stomach; Stomach Ulcer; Time Factors

Ellagic acid (EA), a plant-derived polyphenol, exhibits antioxidant, anti-inflammatory, and gastroprotective effects. Its gastroprotective mechanisms have not been fully elucidated nor have its effects on chronic ulcer previously been described. Toward these ends, the antiulcer activities of EA were evaluated in acute (ethanol and indomethacin) and chronic (acetic acid) ulcer models in Wistar rats. In this study, oral administration of EA significantly prevented the gastric ulceration caused by ethanol, indomethacin, and acetic acid treatments. Its gastroprotective mechanism in ethanol-induced ulcer were partly due to intensification in the endogenous production of nitric oxide, an antioxidant effect by replenishing depletion of endogenous nonprotein sulfhydryls and attenuation of tumor necrosis factor-α increase, whereas in indomethacin ulcer, it is partly due to a reduction in the plasma level of leukotriene B(4). In acetic acid ulcer, promotion of ulcer-healing effects was partly due to attenuation of the elevated levels of the inflammatory cytokines TNF-α, interferon-γ, and interleukins-4 and -6. These findings suggest that ellagic acid exerts its antiulcer activity by strengthening the defensive factors and attenuating the offensive factors.

Topics: Acetic Acid; Animals; Anti-Ulcer Agents; Cytokines; Dinoprostone; Ellagic Acid; Ethanol; Female; Gastric Mucosa; Indomethacin; Leukotriene B4; Male; Mucus; Rats; Rats, Wistar; Stomach Ulcer

Cochinchina momordica seed extract (SKMS10), which is composed of the major compounds momordica saponins, has been evaluated for its gastroprotective effects in rat models of acute gastric mucosal damage. Ethanol and water immersion restraint stress (WRS) induced gastric damage, including hemorrhages and edema, was significantly attenuated by pretreatment with SK-MS10. In addition, SK-MS10 reduced increases of mucosal myeloperoxidase (MPO), IL-1β, and TNFα levels and the expression of cPLA(2), and 5-LOX induced by ethanol or WRS. SK-MS10 also increased hexosamine, adherent mucus, and the expression of MUC5AC. Furthermore, SK-MS10 enhanced the mucosal expression of the CGRP gene and its serum levels.N(G)-methyl L-arginine (L-NMMA) or capsaicin desensitization reversed the SK-MS10-induced gastroprotection effect. These results suggest that SK-MS10 is a gastroprotective agent against acute gastric mucosal damage by suppressing proinflammatory cytokines, downregulating cPLA(2), 5-LOX, and increasing the synthesis of mucus. Furthermore, CGRP-NO pathway was found to play an important role in these gastroprotective effects of SK-MS10.

Topics: Animals; Arachidonate 5-Lipoxygenase; Calcitonin Gene-Related Peptide; Cyclooxygenase 2; Cytoprotection; Dinoprostone; Disease Models, Animal; Down-Regulation; Ethanol; Gastric Mucosa; Gastrointestinal Agents; Group IV Phospholipases A2; Hexosamines; Inflammation Mediators; Interleukin-1beta; Leukotriene B4; Male; Momordica; Mucin 5AC; Mucin-6; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Peroxidase; Plant Extracts; Rats; Rats, Sprague-Dawley; Restraint, Physical; RNA, Messenger; Seeds; Sensory Receptor Cells; Signal Transduction; Stomach Ulcer; Time Factors; Tumor Necrosis Factor-alpha

Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with a risk of serious adverse events. Now, the development of dual inhibitors of cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) has become a hot area in searching for safer NSAIDs. NNU-hdpa, 2-(4-hydroxylphenyl)-3-(3,5-dihydroxylphenyl) propenoic acid, a newly synthesized compound, is expected to have COX/5-LOX dual inhibition with an improved gastrointestinal profile. In this study, NNU-hdpa was subjected to in vitro and in vivo experiment protocols. In vitro COX/5-LOX inhibition assays showed that NNU-hdpa exhibits a dual inhibitory activity against the COX and 5-LOX enzymes. Anti-inflammatory activity in vivo was evaluated using two animal edema model tests. Pretreatment with NNU-hdpa (p.o.) dose-dependently inhibited the xylene-induced ear edema in mice and carrageenan-induced paw edema in rats respectively. In gastric lesion test, NNU-hdpa was gastric-sparing in that it elicited markedly fewer stomach lesions as compared to the stomach lesions caused by aspirin in rats. In further studies, NNU-hdpa was found to significantly inhibit the productions of PGE(2) and LTB(4) in LPS-challenged RAW 264.7, which is parallel to its prevention of the nuclear translocation of the NF-kappaB p50 and p65 subunits. These data indicate that NNU-hdpa comprises a novel class of dual inhibitors of COX and 5-LOX having therapeutic potential with an enhanced gastric safety profile.

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Cell Line; Cyclooxygenase Inhibitors; Dinoprostone; Drug-Related Side Effects and Adverse Reactions; Edema; Intracellular Space; Leukotriene B4; Lipoxygenase Inhibitors; Macrophages; Male; Mice; NF-kappa B; Phenylpropionates; Propionates; Prostaglandin-Endoperoxide Synthases; Rats; Signal Transduction; Stomach Ulcer; Xylenes

Prostaglandins (PGs) and leukotrienes (LTs) are major factors involved in the defense of the gastric mucosa against ulcer formation. However, little is still known about the gastromucosa-protecting action of proton pump inhibitors (PPIs) and histamine H(2) receptor antagonists (H(2) blockers) in patients with gastric ulcer. We therefore examined the effectiveness of a PPI in protecting the gastric mucosa.. We compared the PGE(2) and LTB(4) levels and the expression levels of cyclooxygenase (COX)-1 and COX-2 mRNA in the gastric mucosa in gastric ulcer patients between the group treated for 8 weeks with a PPI, rabeprazole (PPI group; n=5), and the group treated for 8 weeks with an H(2) blocker, ranitidine (H(2) blocker group; n=6), as well as in nonulcer subjects (control group; n=5).. The mucosal levels of PGE(2) and COX-2 mRNA expression were significantly lower in the ulcer patients than those in the nonulcer patients, whereas the LTB(4) level was significantly higher in the ulcer patients than that in the nonulcer patients, and it was also significantly lower in the ulcerated mucosa than that in the nonulcerated mucosa. The PPI group had a significantly increased PGE(2) and decreased LTB(4) levels in comparison to the H(2) blocker group during the ulcer-healing stage. The COX-1 mRNA expression showed no difference among the PPI and H(2) blocker groups or between before and after the treatment. However, the COX-2 mRNA expression increased in the PPI group more than that in the H(2) blocker group during the ulcer-healing stage.. These findings demonstrated the significant gastric-mucosa-protecting effect of PPI by increasing the PGE(2) production and reducing the LTB(4) production.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; 6-Ketoprostaglandin F1 alpha; Adult; Aged; Cyclooxygenase 2; Dinoprostone; Female; Gastric Mucosa; Humans; Leukotriene B4; Male; Middle Aged; Rabeprazole; Ranitidine; RNA, Messenger; Stomach Ulcer

Acemetacin is regarded as a pro-drug of indomethacin and induces significantly less gastric damage but the reasons for this greater gastric safety of acemetacin are unclear. The anti-inflammatory effects of acemetacin have been attributed, at least in part, to its hepatic biotransformation to indomethacin. The aim of this study was to determine the effects of acemetacin and indomethacin in an in vivo model of acute inflammation and to examine the importance of biotransformation of acemetacin (to indomethacin) to its anti-inflammatory actions.. The zymosan airpouch model was used in rats. Indomethacin or acemetacin (2.7-83.8 micromol kg(-1)) were administered orally or directly into the pouch. Leukocyte infiltration, prostaglandin (PG) E(2) and leukotriene (LT) B(4) levels in exudates, and whole blood thromboxane (TX) B(2) synthesis were measured.. Acemetacin was rapidly converted to indomethacin after its administration. Both acemetacin and indomethacin elicited comparable, dose-dependent reductions of leukocyte infiltration and of PGE(2) and TXB(2) synthesis. However, indomethacin induced more gastric damage than acemetacin and elevated LTB(4) production in the airpouch.. The similar effects of acemetacin and indomethacin on leukocyte infiltration and PG synthesis are consistent with rapid biotransformation of acemetacin to indomethacin. Some of this biotransformation may occur extra-hepatically, for instance in inflammatory exudates. Acemetacin probably exerts actions independent of conversion to indomethacin, given the different effects of these two drugs on LTB(4) production. Such differences may contribute to the relative gastric safety of acemetacin compared to indomethacin.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Area Under Curve; Biotransformation; Chromatography, High Pressure Liquid; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Exudates and Transudates; Indomethacin; Inflammation; Injections, Subcutaneous; Leukotriene B4; Male; Prostaglandins; Rats; Rats, Wistar; Stomach Ulcer; Thromboxanes; Zymosan

The present study was aimed to evaluate the effect of licofelone, a dual inhibitor of cycloxygenase1/2-5-lipoxygenase against indomethacin-induced gastric damage in rats and mice in order to assess the role of leukotrienes if any, in non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastrointestinal inflammation. Acute pretreatment with licofelone reversed the indomethacin-induced gastric ulceration, neutrophil adhesion in mesentery venules, neutrophil count in blood, lipid peroxides and vascularity in the stomachs of mice and rats. Further, chronic pretreatment of licofelone also prevented indomethacin-induced gastric morphological changes and cellular infiltration in mesentery venules. Moreover, acute administration of indomethacin elevated leukotriene B4 levels in gastric mucosa, which was reversed by pretreatment with licofelone The results suggest that licofelone offered gastroprotection against NSAIDs-induced gastropathy through its effect on leukotrienes and by inhibiting extravasation of neutrophils.

Topics: Acetates; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Female; Humans; Indomethacin; Inflammation; Leukotriene B4; Lipid Peroxidation; Male; Mesentery; Mice; Neutrophils; Pyrroles; Rats; Stomach Ulcer; Time Factors

SKI306X compound is a herbal mixture. This plant was in oriental medicine and was clinically approved for the treatment of osteoarthritis (OA) in Korea. SKI306X was previously found to have anti-inflammatory, analgesic and cartilage protective effects in several experimental models. In this study, SKI306X was investigated for its gastro-sparing effects on the gastric mucosa comparing with those of diclofenac, a conventional NSAID, and celecoxib, a cyclooxygenase-2 (COX-2) specific inhibitor. To investigate acute gastric damaging properties of SKI306X, the stomach of the animals was histologically and immuno-histochemically examined after single or repeated administration, and SKI306X demonstrated excellent gastric tolerability. SKI306X did not cause significant gastric irritation, erosion, or ulceration up to the orally administered dose of 2 g/kg and the intraperitoneal (i.p.) dose of 125 mg/kg. In contrast, diclofenac caused mucosal erosion, ulceration and bleeding at clinically effective doses. To determine the mode of gastro-sparing action, eicosanoid synthesis was examined in gastric mucosa and blood. SKI306X significantly decreased gastric and blood leukotriene B(4) (LTB(4)) production. However, SKI306X showed either no effect or a slight increase in levels of prostaglandin E(2) (PGE(2)). In addition, gastro-protective effects of SKI306X were exhibited by suppressing diclofenac-induced erosion and ulceration of gastric mucosa in a rat model and the possible mechanism of these effects were investigated. These studies demonstrated that SKI306X did not produce any significant damage up to dose of 2 g/kg and was effective in significantly protecting the damage associated to diclofenac-induced gastric ulcerations. SKI306X could spare the gastric mucosa through significantly suppressing gastric leukotriene (LT) synthesis.

Topics: Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Depression, Chemical; Diclofenac; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Eicosanoids; Gastric Mucosa; Leukotriene B4; Male; Peroxidase; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rats; Rats, Sprague-Dawley; Stomach Ulcer; Sulfonamides

The anti-inflammatory and ulcerogenic effects of FR188582, 3-chloro-5-[4-(methylsulfonyl) phenyl]-1-phenyl-1H-pyrazole, were investigated. In a recombinant human cyclooxygenase (COX) enzyme activity, FR188582 inhibited COX-2 with an IC50 value of 0.017 microM, and the inhibition of prostaglandin (PG) E2 formation by FR188582 was over 6000 times more selective for COX-2 than COX-1. Oral administration of FR188582 dose-dependently inhibited adjuvant arthritis. This effect was threefold more potent than that of indomethacin. FR188582 and indomethacin dose-dependently suppressed the formation of immunoreactive PGE2, but not immunoreactive leukotriene (LT) B4, in arthritic paw. Unlike indomethacin, FR188582 did not induce visible gastric lesions in rats at doses up to 32 mg/kg, p.o. Furthermore, FR188582 did not inhibit the level of immunoreactive PGE2 and immunoreactive 6-keto PGF1alpha in rat gastric mucosa. These results suggest that FR188582, a highly selective COX-2 inhibitor, has a potent anti-inflammatory effect mediated by inhibition of PGE2 in inflamed tissues. The safety profile of FR188582 appears to be improved over the safety profile of indomethacin.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; CHO Cells; Cricetinae; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Female; Gastric Mucosa; Humans; Indomethacin; Isoenzymes; Leukotriene B4; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rats; Rats, Inbred Lew; Recombinant Proteins; Stomach Ulcer

The roles of neutrophil aggregation, inducible nitric oxide synthase activation and chemoattractant, leukotriene B4, in potentiation of the cigarette smoke effect on ethanol-induced gastric mucosal damage were studied. Smoke exposure markedly increased gastric lesion formation following ethanol administration and this was accompanied by substantial increase in gastric mucosal leukotriene B4 concentration, myeloperoxidase and inducible nitric oxide synthase activities. Antineutrophil serum or aminoguanidine pretreatment significantly attenuated both gastric mucosal lesion formation and inducible nitric oxide synthase activity. The increased myeloperoxidase activity was abolished by antineutrophil serum but not by aminoguanidine. These data indicated that both neutrophil mobilization and inducible nitric oxide synthase activation in the gastric mucosa play an important role in the potentiating action of cigarette smoke on ethanol-induced gastric mucosal lesion formation. Increased synthesis of nitric oxide from inducible nitric oxide synthase during gastric damage may be secondary to neutrophil infiltration in the gastric mucosa. Chemoattractant leukotriene B4 could also contribute to neutrophil recruitment in the tissue.

Topics: Animals; Antibodies; Cell Aggregation; Central Nervous System Depressants; Enzyme Inhibitors; Ethanol; Gastric Mucosa; Leukotriene B4; Male; Neutropenia; Neutrophils; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Peroxidase; Rats; Rats, Sprague-Dawley; Smoking; Stomach Ulcer

On the basis of basic screening for novel, more potent antiarthritics VUFB-16066 (4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid, CAS 112344-S2-2) was chosen as a compound with pronounced anti-inflammatory and immunomodulatory effects, with good gastric tolerance and relatively low toxicity. VUFB-16066 is a dual cyclooxygenase and 5-lipoxygenase inhibitor, and it suppresses alloantigen-driven cellular immune response and phagocytosis of stimulated peritoneal cells. VUFB-16066 exhibits prolonged pharmacological activity connected with its major metabolite having a very long half-life. In the model of adjuvant arthritis VUFB-16066 improves most of disease symptoms including immunopathological disturbances, which indicates possible disease-modifying activity of the drug. The beneficial antiarthritic effect of VUFB-16066 has been also confirmed in patients with rheumatoid arthritis.

Topics: Abdominal Pain; Acetic Acid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Arthritis, Experimental; Butyrates; Carrageenan; Diclofenac; Dinoprostone; Edema; Female; Graft vs Host Reaction; Leukotriene B4; Male; Mice; Mice, Inbred C57BL; Phagocytosis; Phenylbutyrates; Pleurisy; Rats; Rats, Inbred Lew; Stomach Ulcer

Systemic administration of capsaicin aggravates ethanol-induced injury of rat gastric mucosa. We evaluated the effect of subcutaneous administration of capsaicin on the gastric mucosa and on inflammatory mediators in saline- and ethanol-treated rats. Functional ablation of primary afferent C-fibers by capsaicin (total 100 mg/kg subcutaneous) tripled ethanol-induced damage. Pretreatment with ketotifen, a mast cell stabilizer (1 mg/kg) protected rat gastric mucosa from the amplified injury induced by capsaicin and ethanol. Tempol, a selective nontoxic cell-permeable nitroxide, completely prevented the amplified gastric ulceration induced by capsaicin and ethanol. This was accompanied by a significant decrease in leukotriene B4 and C4 generation. It is therefore suggested that mast cells and free radicals contribute to the amplified injury observed in rats pretreated with capsaicin and ethanol and that the pharmacological modulation of mast cell release and scavenging of free radicals may be of therapeutic efficacy in the prevention of gastric injury.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Capsaicin; Cyclic N-Oxides; Ethanol; Free Radical Scavengers; Free Radicals; Gastric Mucosa; Ketotifen; Leukotriene B4; Leukotriene C4; Male; Mast Cells; Nerve Fibers; Platelet Activating Factor; Premedication; Protein Synthesis Inhibitors; Rats; Rats, Sprague-Dawley; Spin Labels; Stomach Ulcer

The potential involvement of leukotrienes in the pathogenesis of indomethacin-induced ulceration of the rat gastric antrum has been studied. Pretreatment with the leukotriene biosynthesis inhibitor, MK886 (30 mg/kg p.o.), inhibited the increases in blood and antral leukotriene B4 release ex vivo associated with the evolution of antral ulceration. Despite this, however, there was no significant reduction in either the area of antral ulceration, or in the associated blood neutrophilia and neutrophil infiltration into the gastric antrum. Similarly, pretreatment with the leukotriene B4 antagonist, SC41930 (50 mg/kg p.o.) or the peptidyl leukotriene antagonist ICI198,615 (50 mg/kg p.o.) did not inhibit the area of antral ulceration induced by indomethacin. Thus, in contrast to published reports studying fundic ulceration, our results suggest that leukotrienes do not play a major role either in the pathogenesis of indomethacin-induced ulceration of the rat gastric antrum or neutrophil infiltration into the damaged antrum.

Topics: Administration, Oral; Animals; Benzopyrans; Female; Indazoles; Indoles; Indomethacin; Injections, Subcutaneous; Leukotriene Antagonists; Leukotriene B4; Microscopy, Electron; Pyloric Antrum; Rats; SRS-A; Stomach Ulcer

The potential involvement of neutrophils in the pathogenesis of indomethacin induced ulceration of the gastric antrum in the re-fed rat was studied. Indomethacin was associated with a time dependent increase in the extent and severity of ulceration, blood neutrophilia, neutrophil infiltration into the gastric antrum, and calcium ionophore induced immunoreactive leukotriene B4 (LTB4) release from the antrum ex vivo. Neutrophil infiltration into the antrum was detectable 1 hour after dosing with indomethacin, at which time damage was apparent microscopically but not macroscopically. Thus, cell infiltration may contribute to the development, if not the initiation, of ulceration. Consistent with this suggestion, oral dexamethasone (5 mg/kg) significantly attenuated indomethacin induced ulceration, the associated neutrophil infiltration, and calcium ionophore induced immunoreactive leukotriene B4 release from the gastric antrum and whole blood ex vivo, although the blood neutrophilia was unaffected. These results suggest that indomethacin induced ulceration of the rat gastric antrum may have a dependence on neutrophil infiltration for its pathogenesis.

Topics: Animals; Cell Movement; Indomethacin; Leukocyte Count; Leukotriene B4; Neutrophils; Pyloric Antrum; Rats; Stomach Ulcer

The effects of longstanding non-steroidal anti-inflammatory drug (NSAID) treatment on gastric mucosal synthesis of leukotriene B4 (LTB4), leukotriene C4 (LTC4), and prostaglandin E2 (PGE2) was studied. Gastric antral biopsies in 65 patients with arthritis taking NSAIDs and 23 control patients were taken and eicosanoid concentrations, stimulated by vortex mixing or calcium ionophore, were measured by radioimmunoassay. Median gastric mucosal synthesis of LTB4 was increased in patients taking NSAIDs compared with non-users: (0.9(0.2-2.5) pg/mg v 0 (0-0.6) pg/mg (p < 0.001)). These differences persisted when subgroups of patients were analysed according to Helicobacter pylori colonisation or degree of mucosal injury. Synthesis of LTB4 was strongly associated with the presence of type C (chemical) gastritis. Increased synthesis of LTC4 was associated with Helicobacter pylori colonisation but not NSAID use. Synthesis of PGE2 was decreased in patients taking NSAIDs compared with control patients (p < 0.001). Enhanced gastric mucosal synthesis of LTB4 in patients taking NSAIDs may represent a primary effect of these drugs and could be implicated in the pathogenesis of gastritis and ulceration associated with NSAIDs.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Arthritis; Dinoprostone; Female; Gastric Mucosa; Gastritis; Humans; Leukotriene B4; Male; Middle Aged; SRS-A; Stomach Ulcer

The role of leukotrienes in the pathogenesis of acute gastric ulceration induced by nonsteroidal antiinflammatory drugs was investigated using a rat model. One part of the study involved oral pretreatment with a leukotriene synthesis inhibitor 1 h prior to administration of indomethacin (20 mg/kg per os). Three hours after indomethacin, the extent of macroscopically visible gastric damage was determined, and gastric LTB4 synthesis was determined. The compounds tested were PF-5901, A-64077, nordihydroguaiaretic acid, and L-698,037. Each compound produced dose-related inhibition of gastric LTB4 synthesis and a parallel reduction in the severity of indomethacin-induced damage. The antioxidant properties of these compounds was assessed using an in vitro assay. There was no correlation between the antioxidant properties of the compounds and their ability to reduce the severity of indomethacin-induced gastric damage. In the second part of the study, the effects of intravenous, administration of LTD4 and LTB4 receptor antagonists on indomethacin-induced gastric epithelial damage (measured by permeability to [51Cr]EDTA) were assessed. The two LTD4 receptor antagonists (MK-571 and ICI-204,219) significantly reduced the permeability changes induced by indomethacin, while the two LTB4 antagonists (SC-41930 and LY-255,283) were without significant effect. Despite the reduction of gastric epithelial injury, blockade of LTD4 receptors did not markedly affect the extent of macroscopically visible injury. These data are consistent with the hypothesis that leukotrienes contribute to the epithelial injury and macroscopically visible damage induced by NSAIDs. However, it remains unclear to what extent leukotrienes are involved in the initiation of the injury, as opposed to its amplification.

Topics: 5-Lipoxygenase-Activating Proteins; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Benzopyrans; Carrier Proteins; Free Radical Scavengers; Gastric Mucosa; Hydroxyurea; Indoles; Indomethacin; Leukotriene Antagonists; Leukotriene B4; Leukotrienes; Lipoxygenase Inhibitors; Male; Masoprocol; Membrane Proteins; Organic Chemicals; Permeability; Phenylcarbamates; Propionates; Quinolines; Rats; Rats, Inbred Strains; Receptors, Immunologic; Receptors, Leukotriene; Receptors, Leukotriene B4; Single-Blind Method; Stomach Ulcer; Sulfonamides; Tetrazoles; Tosyl Compounds

The hypothesis that neutrophils play an important role in the pathogenesis of gastric ulceration induced by nonsteroidal anti-inflammatory drugs (NSAIDs) was tested in rats. Rats made neutropenic by prior treatment with an antibody to rat neutrophils raised in goat were found to be significantly more resistant to the gastric-damaging actions of indomethacin or naproxen than were control rats or rats pretreated with normal goat serum. The reduction of damage in neutropenic rats was not due to effects of the antineutrophil serum on either gastric acid secretion or the ability of indomethacin or naproxen to inhibit prostaglandin synthesis. Gastric cyclooxygenase activity was inhibited by greater than 95% in both normal and neutropenic rats that received indomethacin or naproxen. Reduction of circulating neutrophil numbers by treating rats with methotrexate also resulted in a significant reduction in the susceptibility to gastric damage induced by indomethacin. Since activation of circulating neutrophils appeared to be important in the development of gastric erosions after administration of indomethacin, and in the significant changes in vascular endothelial integrity (Monastral Blue staining) observed within 15 min of indomethacin administration, we investigated the possibility that leukotrienes (LTs) and platelet-activating factor (PAF) might be involved in the pathogenesis of indomethacin-induced ulceration. Changes in gastric LTB4 synthesis were not observed after indomethacin administration. Pretreatment with either an LTD4 antagonist or a PAF antagonist was without significant effect on the extent of gastric damage induced by indomethacin. These results suggest an important role for neutrophils in the pathogenesis of NSAID-induced gastric ulceration. Neutrophils may be important in the vascular injury that occurs early after administration of these compounds.

Topics: Animals; Immune Sera; Indomethacin; Leukotriene B4; Male; Methotrexate; Muscle, Smooth; Neutropenia; Neutrophils; Rats; Rats, Inbred Strains; Reference Values; Stomach; Stomach Ulcer

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonate Lipoxygenases; Arthritis, Experimental; Carrageenan; Cyclooxygenase Inhibitors; Dinoprost; Edema; Inflammation; Leukemia, Basophilic, Acute; Leukotriene B4; Lipoxygenase Inhibitors; Mycobacterium; Phenols; Pyrazoles; Rats; Stomach Ulcer; Tumor Cells, Cultured; Zymosan

We investigated the roles of endogenous leukotrienes (LTs) and prostaglandins (PGs) in the healing of gastric ulcers induced by acetic acid in rats. The mucosal levels of LTB4 and sulfidopeptide LT at the ulcer edge had increased by one day after the induction of ulcers. AA-861, a selective inhibitor of 5-lipoxygenase, did not affect the ulcer healing. Indomethacin delayed the healing. Cimetidine did not affect this delay, but ornoprostil, a PGE1, derivative, prevented it. These results suggest that endogenous LTs are not related to the healing of gastric ulcers and that a deficiency in endogenous PGs may be involved in the persistence of gastric ulcers.

Topics: Acetates; Acetic Acid; Animals; Benzoquinones; Gastric Mucosa; Leukotriene B4; Leukotrienes; Lipoxygenase Inhibitors; Male; Prostaglandins; Quinones; Rats; Rats, Inbred Strains; Stomach Ulcer; Wound Healing

The role of leukotriene synthesis in the gastrointestinal damage induced by platelet-activating factor (PAF) was examined in the rat. The effects of a 20-min infusion of PAF (100 ng/kg per min) on leukotriene B4 (LTB4) and leukotriene C4 (LTC4) synthesis were examined in samples of the stomach, duodenum, jejunum, ileum and colon. Administration of PAF resulted in marked hemoconcentration and extensive hemorrhagic damage which was only observed in the corpus region of the stomach and in the small intestine. However, LTB4 synthesis was increased significantly in all regions studied, while LTC4 synthesis was increased significantly only in the duodenum. Pretreatment of the rats with dexamethasone significantly reduced the PAF-induced increase in LTB4 synthesis in all tissues studied. However, a reduction of PAF-induced damage following dexamethasone treatment was observed in the small intestine, but not the stomach. To further investigate the role of leukotrienes as mediators of PAF-induced gastrointestinal damage, the effects of a 10-min infusion of PAF (100 ng/kg per min i.v.) were compared to those of similar infusions of LTB4, LTC4 or leukotriene D4 (LTD4) (0.3-3 micrograms/kg per min). None of the doses of leukotrienes tested produced hemoconcentration or gastrointestinal damage comparable to that observed with the much lower dose of PAF, with the single exception of significant hemoconcentration observed with the highest dose of LTC4. The results of this study therefore suggest that leukotrienes are unlikely to play a major role as mediators of PAF-induced gastrointestinal damage in the rat.

Topics: Animals; Dexamethasone; Gastrointestinal Diseases; Hemodynamics; Leukotriene B4; Male; Peroxidase; Platelet Activating Factor; Rats; Rats, Inbred Strains; SRS-A; Stomach Ulcer

The antipyretic, analgesic, antinflammatory and antiulcerogenic properties of a new compound 1,4 dihydro-1-ethyl-7-phenylpyrrol (1,2-a)-pyrimidine-4-one (V33) are described. V33 on a mg/kg basis possesses antipyretic and analgesic properties at doses lower than paracetamol and which do not produce hypothermia or motor impairment. V33 possesses antiinflammatory activity and decreases the production of LTB4 from inflammatory exudates without affecting PGE2 content. V33 is not only devoid of gastric ulcerogenic properties but exerts antiulcer activity toward various ulcerogenic stimuli. Lethal dose 50% (LD50) of V33 is higher that of paracetamol.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzoquinones; Dose-Response Relationship, Drug; Fever; Humans; In Vitro Techniques; Leukotriene B4; Male; Mice; Oxygen Consumption; Pyrimidinones; Quinones; Rats; Rats, Inbred Strains; Reaction Time; Stomach Ulcer