leukotriene-b4 and Body-Weight

Administration of eicosapentaenoic acid and docosahexanoic acid, omega-3 fatty acids in fish oil, has been associated with improved patient outcomes in acute lung injury when studied in a commercial enteral formula. However, fish oil has not been tested independently in acute lung injury. We therefore sought to determine whether enteral fish oil alone would reduce pulmonary and systemic inflammation in patients with acute lung injury.. Phase II randomized controlled trial.. Five North American medical centers.. Mechanically ventilated patients with acute lung injury ≥18 yrs of age.. Subjects were randomized to receive enteral fish oil (9.75 g eicosapentaenoic acid and 6.75 g docosahexanoic acid daily) or saline placebo for up to 14 days.. Bronchoalveolar lavage fluid and blood were collected at baseline (day 0), day 4 ± 1, and day 8 ± 1. The primary end point was bronchoalveolar lavage fluid interleukin-8 levels. Forty-one participants received fish oil and 49 received placebo. Enteral fish oil administration was associated with increased serum eicosapentaenoic acid concentration (p < .0001). However, there was no significant difference in the change in bronchoalveolar lavage fluid interleukin-8 from baseline to day 4 (p = .37) or day 8 (p = .55) between treatment arms. There were no appreciable improvements in other bronchoalveolar lavage fluid or plasma biomarkers in the fish oil group compared with the control group. Similarly, organ failure score, ventilator-free days, intensive care unit-free days, and 60-day mortality did not differ between the groups.. Fish oil did not reduce biomarkers of pulmonary or systemic inflammation in patients with acute lung injury, and the results do not support the conduct of a larger clinical trial in this population with this agent. This experimental approach is feasible for proof-of-concept studies evaluating new treatments for acute lung injury.

Topics: Acute Lung Injury; Adult; Aged; Biomarkers; Body Weight; Bronchoalveolar Lavage Fluid; Cell Count; Chemokine CCL2; Docosahexaenoic Acids; Drug Therapy, Combination; Eicosapentaenoic Acid; Enteral Nutrition; Female; Hospital Mortality; Humans; Interleukin-6; Interleukin-8; Leukotriene B4; Male; Middle Aged; Neutrophils; Pneumonia; Positive-Pressure Respiration, Intrinsic; Pulmonary Surfactant-Associated Protein D; Tidal Volume; von Willebrand Factor

The pharmacokinetics and pharmacodynamics of AA-2414 [(+-)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptano+ ++ ic acid] were evaluated in 39 healthy male subjects after four different oral multiple-dosing regimens. Population pharmacokinetic analysis with NONMEM showed plasma concentration-time profiles of AA-2414 to be best characterized by a two-compartment open model with zero-order input and first-order elimination. The final estimates for oral clearance, volume of distribution, and steady-state volume of distribution were 10.7 ml/hr/kg, 92.8 ml/kg, and 280 ml/kg, respectively; the corresponding coefficients of variation for interindividual variability were 21%, 10%, and 9%. The pharmacokinetic parameters were associated only with body weight. The residual variability was 25%. The ex vivo platelet aggregation response to U-46619, a thromboxane A2 mimetic, was significantly inhibited by AA-2414. The effect was found to be linearly related to plasma concentration with population estimates of 2.3 mumol/L and 2.38 for the baseline effect and slope, respectively; the corresponding coefficients of variation for interindividual variability were 22% and 38%. The residual variability was 39%. The leukotriene B4, thromboxane B2, and anti-platelet aggregation factor activity measurements were not significantly affected by administration of AA-2414.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Administration, Oral; Adolescent; Adult; Benzoquinones; Body Weight; Double-Blind Method; Heptanoic Acids; Humans; Leukotriene B4; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Prostaglandin Endoperoxides, Synthetic; Quinones; Receptors, Thromboxane; Thromboxane A2; Thromboxane B2

The goal of this work is to explore if the changes induced by d-fagomine in the gut microbiota are compatible with its effect on body weight and inflammation markers in rats. Methods: Sprague Dawley rats were fed a standard diet supplemented with d-fagomine (or not, for comparison) for 6 months. The variables measured were body weight, plasma mediators of inflammation (hydroxyeicosatetraenoic acids, leukotriene B4, and IL-6), and the concentration of acetic acid in feces and plasma. The composition and diversities of microbiota in cecal content and feces were estimated using 16S rRNA metabarcoding and high-throughput sequencing. We found that after just 6 weeks of intake d-fagomine significantly reduced body weight gain, increased the plasma acetate concentration, and reduced the plasma concentration of the pro-inflammatory biomarkers' leukotriene B4, interleukin 6 and 12 hydroxyeicosatetraenoic acids. These changes were associated with a significantly increased prevalence of

Topics: Animals; Body Weight; Dietary Fiber; Feces; Gastrointestinal Microbiome; Hydroxyeicosatetraenoic Acids; Inflammation; Leukotriene B4; Rats; Rats, Sprague-Dawley; RNA, Ribosomal, 16S

The anti-inflammatory profile of DPA was investigated via a dextran sulphate sodium (DSS)-induced colitis model, and was also compared with those of EPA and DHA. The results showed that DPA could significantly reduce (stronger than EPA and DHA) the disease activity index score, macroscopic appearance score, colon shortening, histological assessment, and myeloperoxidase accumulation in the colon. In addition, DPA also inhibited the abnormal production and mRNA expression of pro-inflammatory cytokines, namely tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 and improved the production and expression of an anti-inflammatory cytokine, IL-10. Furthermore, the molecular mechanisms underlying these effects were also explored through the synthesis pathway of eicosanoids. DPA could inhibit the synthesis of leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) more greatly while differences of cyclooxygenase (COX) and 5-lipoxidase (LOX) contents in these three groups were not significant. We ascribed these effects to the easier incorporation of DPA into inflammatory cells leading to the decrease in the substrate for the synthesis of pro-inflammatory eicosanoids (PGE2 and LTB4). Besides, DPA-derived mediators might also be involved.

Topics: Animals; Anti-Inflammatory Agents; Body Weight; Colitis, Ulcerative; Colon; Cytokines; Dextran Sulfate; Dinoprostone; Disease Models, Animal; Fatty Acids, Unsaturated; Inflammation; Interleukin-1beta; Leukotriene B4; Lipoxygenase; Male; Mice; Plant Extracts; Prostaglandin-Endoperoxide Synthases; RNA, Messenger; Tumor Necrosis Factor-alpha

Cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) play an important role in inflammatory bowel diseases (IBDs). We investigated the effects of flavocoxid, a dual COX/LOX inhibitor, in experimental colitis induced with either dinitrobenzenesulfonic acid (DNBS) or dextrane sulphate sodium (DSS) In the first model, colitis was induced in rats by a single intra-colonic instillation (25mg in 0.8ml 50% ethanol) of DNBS; after 24h animals were randomized to receive orally twice a day, flavocoxid (10mg/kg), zileuton (50mg/kg), or celecoxib (5mg/kg). Sham animals received 0.8ml of saline by a single intra-colonic instillation. Rats were killed 4 days after induction and samples were collected for analysis. In the second model, colitis was induced in rats by the administration of 8% DSS dissolved in drinking water; after 24h animals were randomized to the same above reported treatments. Sham animals received standard drinking water. Rats were killed 5 days after induction and samples were collected for analysis. Flavocoxid, zileuton and celecoxib improved weight loss, reduced colonic myeloperoxydase activity, macroscopic and microscopic damage, and TNF-α serum levels. Flavocoxid and celecoxib also reduced malondialdheyde, 6-keto PGF1α and PGE-2 levels while flavocoxid and zileuton decreased LTB-4 levels. In addition, flavocoxid treatment improved histological features and apoptosis as compared to zileuton and celecoxib; moreover only flavocoxid reduced TXB2, thus avoiding an imbalance in eicosanoids production. Our results show that flavocoxid has protective effect in IBDs and may represents a future safe treatment for inflammatory bowel diseases.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Apoptosis; Arachidonate 5-Lipoxygenase; Body Weight; Catechin; CD3 Complex; Celecoxib; Colitis; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprostone; Drug Combinations; Eating; Gene Expression Regulation; Hydroxyurea; Leukotriene B4; Lipid Peroxidation; Lipoxygenase Inhibitors; Male; Neutrophil Infiltration; Rats; Rats, Sprague-Dawley; Thromboxane B2; Tumor Necrosis Factor-alpha

Evidence suggests an important role of intestinal barrier dysfunction in the etiology of inflammatory bowel disease (IBD). Therefore stabilizing mucosal barrier function constitutes a new therapeutic approach in its management. Ectoine is a compatible solute produced by aerobic chemoheterotrophic and halophilic/halotolerant bacteria, where it acts as osmoprotectant and effective biomembrane stabilizer, protecting the producing cells from extreme environmental stress. Since this natural compound was also shown to prevent inflammatory responses associated with IBD, its potential usefulness was studied in a model of colitis. Groups of rats were treated orally with different doses of ectoine (30-300 mg/kg) or sulfasalazine (reference drug) daily for 11 days. On day 8 colitis was induced by intracolonic instillation of 2,4,6-trinitrobenzenesulfonic acid, when overt signs of lesions develop within the next 3 days. On day 12, blood was withdrawn from the retro-orbital plexus of the rats and the animals were sacrificed. The colon was excised and examined macroscopically and microscopically. Relevant parameters of oxidative stress and inflammation were measured in serum and colon homogenates. Induction of colitis led to marked weight loss, significant histopathological changes of the colon, and variable changes in levels of myeloperoxidase, reduced glutathione, malondialdehyde, and all inflammatory markers tested. Treatment with ectoine ameliorated the inflammatory changes in TNBS-induced colitis. This effect was associated with reduction in the levels of TNF-α, IL-1β, ICAM-1, PGE2 and LTB4. The findings suggest that intestinal barrier stabilizers from natural sources could offer new therapeutic measures for the management of IBD.

Topics: Amino Acids, Diamino; Animals; Body Weight; Colitis; Colon; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Glutathione; Intercellular Adhesion Molecule-1; Interleukin-1beta; Leukotriene B4; Male; Malondialdehyde; Rats; Rats, Wistar; Sulfasalazine; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

peroxisome proliferator-activated receptor α (PPARα) is a crucial regulator of liver lipid metabolism. As maternal diabetes impairs foetal lipid metabolism and growth, we aimed to determine whether PPARα activation regulates lipid metabolism in the foetal liver from diabetic rats as well as foetal weight and foetal liver weight.. diabetes was induced by neonatal streptozotocin administration (90 mg/kg). For ex vivo studies, livers from 21-day-old foetuses from control and diabetic rats were explanted and incubated in the presence of PPARα agonists (clofibrate and leukotriene B(4) ) for further evaluation of lipid levels (by thin layer chromatography and densitometry), de novo lipid synthesis (by (14) C-acetate incorporation) and lipid peroxidation (by thiobarbituric reactive substances evaluation). For in vivo studies, foetuses were injected through the uterine wall with leukotriene B(4) on days 19, 20 and 21 of gestation. On day 21 of gestation, foetal liver concentrations of lipids and lipoperoxides were evaluated.. foetuses from diabetic rats showed increased body weight and liver weight, as well as accumulation of triglycerides and cholesteryl esters, increased de novo lipid synthesis and lipid peroxidation in the liver when compared to controls. Ex vivo studies showed that PPARα ligands reduced both the concentrations and synthesis of the lipid species studied and lipid peroxidation in the foetal liver from diabetic rats. In vivo experiments showed that leukotriene B(4) reduced the concentrations of triglycerides, cholesteryl esters and phospholipids, as well as lipid peroxidation, foetal weight and foetal liver weight in diabetic rats.. PPARα activation regulates the impaired foetal liver lipid metabolism, prevents hepatomegaly and reduces foetal overgrowth induced by maternal diabetes.

Topics: Animals; Body Weight; Cell Nucleus; Diabetes Mellitus, Experimental; Female; Fetus; Leukotriene B4; Lipid Metabolism; Lipid Peroxidation; Liver; PPAR alpha; Pregnancy; Rats; Rats, Wistar; Triglycerides

Glomerular infiltration of macrophages is a characteristic alteration of renal pathology in hyperlipidaemic renal injury. Leukotriene B4 (LTB4) is a bioactive eicosanoid and macrophage and has two key enzymes for LTB4 synthesis, 5-lipoxygenase and leukotriene A4 (LTA4) hydrolase. The purpose of this study was to evaluate the role of LTB4 in accelerated hyperlipidaemic renal injury.. To induce accelerated hyperlipidaemic renal injury, 8 week old male spontaneously hypercholesterolaemic (SHC) rats were fed with a high cholesterol diet for 6 weeks. LTA4 hydrolase activities in the kidney and urine LTB4 levels were examined. The effects of LTB4 antagonist (ONO-4057) were also evaluated.. Urinary protein and LTB4 excretion was increased by a high cholesterol diet for 6 weeks. The scores of glomerular foam cell accumulation and sclerosis, numbers of infiltrated macrophages in glomeruli and interstitial area, LTA4 hydrolase activity in renal cortex were higher in the high cholesterol diet group than the normal diet group. LTB4 antagonist treatment reduced urinary protein and LTA4 activity and attenuated renal pathological changes.. These results suggest that LTB4 directly contributes to accelerated hyperlipidaemic renal injury and the therapeutic potential of LTB4 antagonist for renal damage induced by hyperlipidaemia.

Topics: Animals; Blood Pressure; Body Weight; Disease Models, Animal; Epoxide Hydrolases; Foam Cells; Hypercholesterolemia; Kidney Diseases; Kidney Glomerulus; Leukotriene Antagonists; Leukotriene B4; Male; Phenylpropionates; Proteinuria; Rats; Time Factors

COPD primarily affects the lungs but also produces systemic consequences that are not reflected by the recent staging according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. Body mass index (BMI) and fat-free mass index (FFMI) represent different aspects of nutrition abnormalities in COPD. We investigated whether BMI and FFMI could be related to parameters expressing airflow obstruction and limitation, exercise capacity, airway inflammation, and quality of life, and whether they would reflect the GOLD staging of the disease.. One hundred patients with clinically stable COPD equally classified into the five stages of the disease were evaluated for BMI, FFMI (measured by bioelectrical impedance analysis), airway obstruction and hyperinflation (FEV(1), FEV(1)/FVC, inspiratory capacity), exercise capacity (6-min walk distance [6MWD], Borg scale before and after 6MWD]), chronic dyspnea using the Medical Research Council (MRC) scale, airway inflammation (sputum differential cell counts, leukotriene B(4) in supernatant), and quality of life (emotional part of the chronic respiratory disease questionnaire).. 6MWD was significantly associated with both BMI and FFMI values, while FFMI additionally presented significant correlations with MRC scale, percentage of predicted FEV(1), and FEV(1)/FVC ratio. No association was observed between the two nutritional indexes. BMI was not statistically different among patients in the five stages of COPD, while FFMI reflected the staging of the disease, presenting the highest values in stage 0.. Nutritional status is mainly related to exercise capacity. FFMI seems to be more accurate in expressing variables of disease severity, as well as the current staging compared to BMI.

Topics: Adiposity; Aged; Body Mass Index; Body Weight; Exercise Tolerance; Forced Expiratory Volume; Health Surveys; Humans; Leukotriene B4; Middle Aged; Nutritional Status; Pulmonary Disease, Chronic Obstructive; Quality of Life; Severity of Illness Index; Sputum; Vital Capacity

Cysteinyl leukotrienes play a part in inflammatory processes such as inflammatory bowel diseases. The present study aimed to evaluate the effects of the cys-LT-1 receptor antagonist montelukast on a mild colitis model in rats. Colitis was induced by administrating 4% dextran sulphate sodium (DSS, MW 45,000) in drinking water for 9 days. Montelukast (10 mg/kg/day) or vehicle was given by gastric gavage once daily simultaneously with DSS administration. A healthy control group receiving water as drinking fluid and vehicle by gastric gavage was included. Body weight loss, consistency of faeces (loose/diarrhoea) and occult blood in the faeces/ gross bleeding were assessed on days 6 - 9. After sacrifice, the following were assessed: colonic histology, the expression of inducible nitric oxide synthase, macrophage/monocyte marker ED1, cyclooxygenase-1 and cyclooxygenase-2, as well as the production of leukotriene B(4) and E(4), prostaglandin E(2), its metabolite bicyclic-prostaglandin E(2) and thromboxane B(2) in the colonic tissue incubation in vitro. Rats receiving DSS exhibited bloody diarrhoea from day 6 onwards. Montelukast significantly reduced the occult blood in the faeces/ gross bleeding, maintained normal body weight gain and tended to decrease the ratio of leukotriene B(4)/ prostaglandin E(2) production in the colon in vitro. The results indicate that montelukast has some potential to ameliorate mild experimental colitis induced by DSS.

Topics: Acetates; Administration, Oral; Animals; Blotting, Western; Body Weight; Bridged Bicyclo Compounds; Colitis; Colon; Cyclooxygenase 1; Cyclooxygenase 2; Cyclopropanes; Dextran Sulfate; Dinoprostone; Immunochemistry; Immunoglobulin G; Leukotriene Antagonists; Leukotriene B4; Male; Nitric Oxide Synthase Type II; Occult Blood; Quinolines; Rats; Rats, Wistar; Severity of Illness Index; Sulfides; Thromboxane B2

The effect of smoke-dried bonito undigested fraction remaining after microbial protease treatment (SDBR) on a spontaneously occurring mouse model of atopic dermatitis was studied in male 5-wk-old, NC/Nga mice. Smoke-dried bonito, Katsuobushi, is a traditional Japanese food. SDBR contains 2 major components: bonito oil and protease-undigested proteins. Mice were fed a casein diet containing corn oil (C diet) or a diet containing SDBR (SDBR diet) for 18 wk. In comparison with the C diet, the SDBR diet alleviated the increase in skin severity score and plasma IgE concentration in a time-dependent manner, and lowered leucotriene B(4) (LTB(4))-releasing ability upon calcium ionophore A23187 stimulation. The SDBR diet did not affect scratching time. These results demonstrate that SDBR diet alleviates atopic dermatitis-like skin lesions in NC/Nga mice.

Topics: Animals; Behavior, Animal; Body Weight; Caseins; Corn Oil; Dehydration; Dermatitis, Atopic; Disease Models, Animal; Fish Oils; Fishes; Food Preservation; Immunoglobulin E; Leukotriene B4; Male; Mice; Mice, Inbred Strains; Peptide Hydrolases; Severity of Illness Index; Time Factors

Leptin is an adipocyte-derived hormone that declines dramatically during fasting and plays a pivotal role in the neuroendocrine response to starvation. Previously, we employed leptin-deficient (ob/ob) mice to identify an important role for leptin in the host defense against Klebsiella pneumonia.. To assess the effects of fasting on the innate immune response against pneumococcal pneumonia and to determine the effects of maintaining circulating leptin levels on host defense in fasted mice.. C57BL/6 mice were either fed ad libitum or fasted for 48 h and given an intraperitoneal injection of saline or recombinant leptin (1 microg/g of body weight) twice daily for 48 h before bacterial challenge. Mice were challenged with 10(5) cfu of Streptococcus pneumoniae via the intranasal route.. Lung homogenate S. pneumoniae burden was nearly 20-fold greater in the fasted as compared with fed mice. The impairment in bacterial clearance observed in fasted animals was associated with reduced bronchoalveolar lavage neutrophil counts and interleukin-6 and macrophage inflammatory protein-2 levels. Alveolar macrophages from fasted animals also exhibited defective phagocytosis and killing of S. pneumoniae and reduced calcium-ionophore-stimulated leukotriene B(4) synthesis in vitro. In contrast, the provision of exogenous leptin to fasted animals restored bacterial clearance, bronchoalveolar lavage levels of neutrophils and cytokines, alveolar macrophage bacterial killing, and leukotriene B(4) synthesis.. These results suggest that reduced leptin levels substantially contribute to the suppression of pulmonary antibacterial host defense during starvation and that administration of this adipokine may be of therapeutic benefit clinically.

Topics: Acute Disease; Animals; Blood Glucose; Body Weight; Bronchoalveolar Lavage; Corticosterone; Disease Models, Animal; Fasting; Interleukin-6; Leptin; Leukocytes; Leukotriene B4; Lung; Mice; Mice, Inbred C57BL; Neutrophils; Phagocytosis; Pneumonia, Pneumococcal; Sodium Chloride; Starvation; Streptococcus pneumoniae

Primary nonfunction (PNF) adversely impacts islet transplantation. In addition to determining whether sodium 4-phenylbutyrate (4-SPB), an anti-inflammatory agent, reduces PNF, this study investigates how 4-SPB affects PNF. Streptozotocin-induced diabetic C57BL/6 mice, that received 75 syngeneic islets underneath left subrenal space, were fed twice daily of either 4-SPB at 500 mg/kg body weight or isotonic saline (NaCl) from 2 days before through 7 days after transplantation. The graft was removed at days 3, 10 and 84 following transplantation. At 68 h following transplantation, serum levels of interleukin-1beta (IL-1beta) were 2.2+/-0.4 and 0.4+/-0.2 pmol/L (n=6, p<0.005) for NaCl and 4-SPB groups, respectively. Graft genetic expression of IL-1beta was significantly suppressed in 4-SPB group (p<0.01). At day 10, the blood glucose levels were 22.7+/-1.0 and 17.1+/-1.7 mmol/L (n=12, p<0.05) and graft insulin contents (IC) were 35.0+/-8.3 and 107.6+/-29.7 pmol (n=12, p<0.05) for NaCl and 4-SPB groups, respectively. Moreover, the 4-SPB group had a shorter temporary hyperglycemia (15+/-2, n=21 vs. 25+/-2 days, n=19, p=0.001) and a higher cumulative cure rate of diabetes (p<0.001) than the NaCl group. In-vitro studies indicated that 4-SPB did not impact the islets function. These experimental results demonstrated that perioperative administration of 4-SPB decreased serum level and graft genetic expression of IL-1beta and attenuated PNF, which enhanced islet engraftment in a syngeneic transplantation mouse model.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Gene Expression; Graft Survival; Insulin; Interleukin-1beta; Islets of Langerhans; Islets of Langerhans Transplantation; Leukotriene B4; Male; Mice; Mice, Inbred C57BL; Nitrates; Nitrites; Pancreas; Phenylbutyrates; Prostaglandins

Inhaled endotoxin is known to induce airway inflammation, causing bronchial hyperreactivity.. We characterized the response to lipopolysaccharide-inhalation by measuring exhaled nitric oxide (eNO) and inflammatory mediators.. A total of 43 adult volunteers (13 asthmatics, 30 healthy controls) inhaled stepwise LPS every 30 min up to a cumulative dose of 100 microg (2.5, 10.5, 42, 45 microg). After each provocation and up to 24 h later, FEV(1) was determined; the procedure was stopped when FEV(1) declined more than 12.5%. We measured eNO, leucocytes, eosinophils, polymorphonuclear neutrophils (PMNs), C-reactive protein (CrP), lipopolysaccharide binding protein (LBP), eosinophilic cationic protein (ECP), leucotriene B4 (LTB4), thromboxane B2 (TXB2), and body temperature.. Initial eNO values were higher in asthmatics (P < 0.01), but only increased in an asthmatic subgroup. Marked differences were observed in the systemic response to LPS inhalation. Significant increases were found for CrP, LBP, and PMNs. There was no correlation between FEV(1) decrease and basal eNO levels.. Inhalation of endotoxin was followed by clinical and laboratory signs of systemic inflammation, with asthmatics responding to the challenge similar as healthy subjects. Bronchial eNO increased only temporarily in asthmatics.

Topics: Administration, Inhalation; Adult; Animals; Asthma; Biomarkers; Body Size; Body Weight; C-Reactive Protein; Eosinophils; Female; Humans; Inflammation; Leukocytes; Leukotriene B4; Leukotrienes; Lipopolysaccharides; Male; Mites; Neutrophils; Nitric Oxide Synthase Type III; Reference Values

We examined the impact of dietary fatty acid intake on lipopolysaccharide (LPS)-induced endotoxic shock. C57Bl/6J mice were fed for 6 weeks with a commercial laboratory chow (CC) or with test chows containing 7% (w/w) canola oil (CO), sesame oil (SeO), soybean oil (SO), or virgin olive oil (OO). The increase in body weight and energy consumption were similar for all diets tested. In the sixth week, mice were injected intraperitoneally with 400 microg of bacterial LPS to induce endotoxic shock. LPS induced a massive neutrophil infiltration into the peritoneal cavity and an increase in lipid body (LB) formation in leukocytes recovered from the peritoneal fluid of mice fed with CC, CO, SeO, or SO. In addition, there were increases in prostaglandin E(2) (PGE(2)), leukotriene B4 (LTB(4)), and cytokines IL-6, IL-10, and MCP-1 in peritoneal lavage, as well as in plasma TNF-alpha. In contrast, mice fed with OO exhibited reduced neutrophil accumulation and LB formation, and also had lower levels of PGE(2), LTB(4), MCP-1, and TNF-alpha. All mice fed with CC, CO, SeO, or SO died within 48 to 72 h after LPS injection. Interestingly, mice fed with the OO diet were resistant to endotoxic shock, with 60% survival at 168 h. These data indicate that intake of OO may have a beneficial role, reducing the magnitude of the inflammatory process triggered by endotoxic shock through modulation of LB formation and of the production of inflammatory mediators.

Topics: Animal Feed; Animals; Body Weight; Cell Movement; Cell Survival; Chemokine CCL2; Cytokines; Diet; Dinoprostone; Endotoxins; Escherichia coli; Fatty Acids; Fatty Acids, Monounsaturated; Female; Inflammation; Interleukin-10; Interleukin-6; Leukotriene B4; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Neutrophils; Olive Oil; Plant Oils; Rapeseed Oil; Sesame Oil; Shock, Septic; Soybean Oil; Time Factors; Tumor Necrosis Factor-alpha

The direct examination of the effects that fish oil diets (composed of long-chain n-3 polyunsaturated fatty acids) exert on immune system function indicates a reduction of host natural resistance to infectious diseases mainly because of a suppression of immune function generated by the fatty acids contained in this diet. Here, we evaluated the concentration of IL-12, IL-4, prostaglandin E2 and leukotriene B4 in the serum from BALB/c mice receiving four different diets. Each group was fed a diet that differed only in the source of fat: a low-fat diet (2.5% by weight), an olive oil diet (20% by weight), a fish oil diet (20% by weight) or a hydrogenated coconut oil diet (20% by weight). Mice were fed for 4 weeks and then infected with the intracellular pathogen Listeria monocytogenes. An initial reduction in the Th1-type response as a result of a decrease in IL-12p70 secretion, an inefficient action of IL-4 (Th2-type response) and no modification of pro-inflammatory lipid-mediator production could be, at least in part, the key events responsible for the inadequate elimination of L. monocytogenes from the spleens of mice fed a fish oil diet. Furthermore, our results suggest that the type of dietary lipids may affect the circulating concentration of IL-12p70 and IL-4, leading to a modulation in the protective cellular immune response to L. monocytogenes infection.

Topics: Animals; Body Weight; Coconut Oil; Dietary Fats; Dinoprostone; Fatty Acids, Omega-3; Fish Oils; Interleukin-12; Interleukin-4; Leukotriene B4; Listeriosis; Mice; Olive Oil; Organ Size; Plant Oils; Protein Subunits; Spleen

Aberrant arachidonic acid (AA) metabolism, especially through the cyclooxygenase (Cox) and 5-lipoxygenase (5-Lox) pathways, has been suggested to play an important role in the development of esophageal adenocarcinoma (EAC). The purpose of this study was to investigate the expression of 5-Lox in EAC of a rat model and in human samples as well as the chemopreventive effects of zileuton (a specific 5-Lox inhibitor) and celecoxib (a specific Cox2 inhibitor) in the rat EAC model.. 5-Lox expression in EAC of a rat esophagogastroduodenal anastomosis model and of humans was examined with immunohistochemistry. A chemoprevention study was designed to test whether zileuton and celecoxib could suppress aberrant AA metabolism and esophageal adenocarcinogenesis.. With immunohistochemistry, we found that 5-Lox was overexpressed during esophageal adenocarcinogenesis in our rat model and in humans. In the chemoprevention study, EAC incidence was reduced in a dose-dependent manner from 68.8% (11 of 16) to 44.4% (8 of 18; P > 0.05) and 31.3% (5 of 16; P < 0.05) by 500 and 1,000 ppm zileuton, respectively, and to 33.3% (7 of 21; P < 0.05) and 20% (3 of 15; P < 0.05) by 500 and 1,000 ppm celecoxib, respectively. With isobolographic analysis, zileuton and celecoxib, both at a dose of 500 ppm, had an additive effect by reducing the tumor incidence to 16.7% (3 of 18, P < 0.01). Leukotriene B4 and prostaglandin E2 levels in the esophageal tissues were also significantly reduced by zileuton and celecoxib.. This study clearly demonstrated that 5-Lox and Cox2 play important roles in the development of EAC. Both zileuton and celecoxib had inhibitory effects on esophageal adenocarcinogenesis through inhibition on their respective enzymes of AA metabolism.

Topics: Adenocarcinoma; Anastomosis, Surgical; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonate 5-Lipoxygenase; Body Weight; Celecoxib; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Esophageal Neoplasms; Humans; Hydroxyurea; Immunohistochemistry; Leukotriene B4; Lipoxygenase Inhibitors; Male; Pyrazoles; Rats; Rats, Sprague-Dawley; Sulfonamides; Time Factors

Excessive fat consumption is a risk factor for colon carcinogenesis, and green tea consumption may reduce the risk of colon and other cancers. The current study was designed to investigate the effects of green tea and a high-fat diet on arachidonic acid metabolism and aberrant crypt foci formation in an azoxymethane (AOM)-induced colon carcinogenesis mouse model. We also determined whether green tea consumption altered the size of regional fat pads. CF-1 female mice were maintained on either a high-fat (20% corn oil) or a low-fat (5% corn oil) diet. AOM was given subcutaneous at a dose of 7.5 mg/kg body weight at 6 wk and then a dose of 10 mg/kg at 7 wk of age. Two weeks after the second AOM injection, 0.6% green tea (6 mg tea solids/ml) was given as the drinking fluid and continued for 10 wk until the experiment was terminated. In the AOM-treated mice not receiving green tea, the high-fat diet significantly enhanced colonic levels of 5-lipoxygenase, leukotriene A4 hydrolase, and leukotriene B4, but it did not significantly alter prostaglandin E2 levels and aberrant crypt foci formation. In AOM-treated mice on the high-fat diet, green tea significantly decreased colonic levels of cytosolic phospholipase A2, 5-lipoxygenase, and leukotriene B4; green tea treatment also decreased the number of aberrant crypt foci (P < 0.05). The weights of parametrial and retroperitoneal fat pads were increased by the high-fat diet and decreased by green tea treatment. The current results indicate that green tea consumption and dietary fat modulate 5-lipoxygenase-dependent pathway of arachidonic acid metabolism during AOM-induced colon carcinogenesis. Green tea inhibits ACF formation in mice on a high corn oil diet, suggesting its possible inhibitory effect on colon carcinogenesis in populations such as those in Western countries that consume high amounts of fat.

Topics: Adipose Tissue; Animals; Arachidonate 5-Lipoxygenase; Arachidonic Acid; Azoxymethane; Body Weight; Colon; Colonic Neoplasms; Cytosol; Dietary Fats; Dinoprostone; Drinking; Eating; Epoxide Hydrolases; Female; Leukotriene B4; Mice; Organ Size; Phospholipases A; Phospholipases A2; Tea

Human esophageal adenocarcinoma (EAC) develops in a sequence from gastroesophageal reflux disease (GERD), columnar-lined esophagus (CLE), dysplasia, and eventually to EAC. We established a rat surgical EAC model with esophagogastroduodenal anastomosis (EGDA) to mimic the staged process of esophageal adenocarcinogenesis. Profiling of the AA metabolites with mass spectrometry showed that prostaglandin E2 (PGE2), leukotriene B4 (LTB4), 15-hydroeicosatetraenoic acid (HETE), 12-HETE, 8-HETE and 5-HETE all increased at the esophagoduodenal junction after EGDA as compared with the proximal esophagus, with PGE2 as the major metabolite. Consistent with this profile, cyclooxygenase 2 (Cox2) was overexpressed in the basal cell layer of esophageal squamous epithelium, CLE cells and EAC tumor cells of the EGDA rats, as compared with the normal esophageal epithelium. Sulindac (a Cox inhibitor), nordihydroguaiaretic acid (NDGA, a lipoxygenase inhibitor) and alpha-difluoromethylornithine (DFMO, an ornithine decarboxylase inhibitor) were tested for their possible inhibitory actions against the formation of EAC in the rat EGDA model. In a short-term study (for 4 weeks after surgery), dietary administration of both sulindac (300 and 600 p.p.m.) and NDGA (100 p.p.m.) effectively reduced the EGDA-induced inflammation. In a long-term chemoprevention study (for 40 weeks after surgery), 300 p.p.m. sulindac, alone or in combination with 100 p.p.m. NDGA or 0.5% DFMO, decreased the tumor incidence from 57.7 to 26.9%, or 16.7 or 20%, respectively (P < 0.05). NDGA alone (100 and 200 p.p.m.) slightly decreased the tumor incidence to 52.4 and 37%, respectively, although the difference was not statistically significant. DFMO alone did not show significant effects on tumor incidence. Inhibition of tumor formation by sulindac was correlated with lowered levels of PGE2. In conclusion, sulindac exerted its chemopreventive effect against the formation of EAC in the rat EGDA model possibly through its inhibition of Cox.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Animals; Arachidonic Acid; Body Weight; Cyclooxygenase 2; Dinoprostone; Eflornithine; Esophageal Neoplasms; Esophagus; Gas Chromatography-Mass Spectrometry; Hydroxyeicosatetraenoic Acids; Immunoenzyme Techniques; In Situ Hybridization; Inflammation; Isoenzymes; Leukotriene B4; Male; Masoprocol; Mass Spectrometry; Neoplasms; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Sulindac; Time Factors

To study the effectiveness of a lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA), in the reduction of primary nonfunction, an insufficient number of syngeneic islets were transplanted underneath the renal capsule with NDGA administered daily for 4 weeks. After transplantation of the 150 islets, the decrement of blood glucose levels was significantly faster in the mice that had received NDGA than in the mice that had received no drug at all or dimethyl sulfoxide (DMSO) (p < 0.005, p < 0.05). The mean duration of temporary posttransplant hyperglycemia was 22.3 +/- 3.2 (n = 10), 35.9 +/- 2.3 (n = 14), and 33.7 +/- 4.1 (n = 6) days for the respective groups. The diabetic mice that received 300 islets had their blood glucose levels decrease faster than those that received 150 islets (19.7 +/- 1.6 vs. 35.9 +/- 2.3 days, n = 14. p < 0.0001). There was no significant difference in the blood glucose reducing effect between the mice that received 150 islets with NDGA and the mice that received 300 islets [22.3 +/- 3.2 (n = 10) vs. 19.7 +/- 1.6 (n = 14) days, p > 0.05]. The insulin content of the graft from the mice treated with 150 islets and NDGA (3.02 +/- 0.24 microg, n = 4) was higher than that from the mice that received 150 islets but no treatment (1.10 +/- 0.26 microg, n = 15, p < 0.005) or that had been treated with DMSO (1.21 +/- 0.30 microg, n = 4, p <0.05). The insulin content of the pancreas remnant had no significant differences among the three groups. The net glucose-stimulated insulin secretion was 0.82 +/- 0.14 vs. 0.20 +/- 0.10 microIU/islet x 60 min (n = 8, p < 0.005) and 0.59 +/- 0.08 vs. 0.04 +/- 0.02 microIU/islet x 60 min (n = 8, p < 0.0001) for islets cultured without NDGA vs. with NDGA at 1 and 2 weeks, respectively. However, the insulin content of the cultured islets was similar between the two groups for up to 2 weeks of incubation (at 1 week: 0.71 +/- 0.01 vs. 0.67 +/- 0.04 ng/islet, n = 8, p > 0.05; at 2 weeks: 0.71 +/- 0.02 vs. 0.80 +/- 0.07 ng/islet, n = 8, p > 0.05). Serum leukotriene B4 (LTB4) concentrations before and between the fifth and seventh days after transplantation were determined. For diabetic mice that received 150 islets, serum LTB4 levels were 25,835 +/- 3,335 and 27,631 +/- 3,136 pg/ml (n = 4, p > 0.05). For diabetic mice that received 150 islets and NDGA, the corresponding figures were 22,401 +/- 2,706 pg/ml and 27,530 +/- 2,190 pg/ml (n = 8, p > 0.05). The graft histology revealed viable islet cells and networ

Topics: Animals; Blood Glucose; Body Weight; Cyclooxygenase Inhibitors; Diabetes Mellitus, Experimental; Insulin; Insulin Secretion; Islets of Langerhans Transplantation; Leukotriene B4; Lipoxygenase Inhibitors; Male; Masoprocol; Mice; Mice, Inbred C57BL

We investigated the role of leukotriene B4 (LTB4) in murine arthritis models using a leukotriene A4 (LTA4) hydrolase inhibitor, SA6541. SA6541 inhibited the severity of collagen-induced arthritis and muramyl dipeptide (MDP)-induced hyperproliferation of synovial cells in vivo. SA6541 also inhibited LTA4-induced hyperproliferation of synovial stromal cells in vitro. These results suggest that LTB4 may play an important role in arthritis models.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Aniline Compounds; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis; Body Weight; Bone and Bones; Cell Division; Cell Survival; Collagen; Cysteine; Disease Models, Animal; Epoxide Hydrolases; Female; Leukotriene B4; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Prednisolone; Stromal Cells; Synovial Fluid; Tarsus, Animal

Omega-3 (omega-3) fatty acid rich-fish oil (FO) and vitamin E (vit-E) may delay the progress of certain autoimmune diseases. The present study examined the mechanism of action of omega-3 and omega-6 lipids and vit-E on the serum cytokines and lipid mediators in autoimmune-prone MRL/lpr mice (a model for rheumatoid arthritis, RA). The lpr (lymphoproliferative) gene is overexpressed in these mice causing extensive lymphoproliferation, lupus-like symptoms and accelerated aging.. Weanling female MRL/lpr and congenic control MRL/++ mice were fed 10% corn oil (CO, omega6) or FO-based semipurified diets containing two levels of vitamin E (vit-E-75, I.U. and vit-E-500 I.U./Kg diet) for four months. At the end of the experiment, serum anti-DNA antibodies, cytokines and lipid mediators levels were determined.. The appearance of enlarged lymph nodes was delayed in the mice fed FO, and the FO-500 IU vit-E diet offered further protection against enlargement of lymph nodes. The MRL/lpr mice exhibited significantly higher levels of serum anti-dsDNA antibodies. The FO-fed mice had significantly lower serum IL-6, IL-10, IL-12, TNF-alpha, PGE2, TXB2 and LTB4 levels compared with CO-fed mice. In mice fed 500 IU vit-E diets, the serum IL-6, IL-10, IL-12 and TNF-alpha levels were significantly lower and serum IL-1beta was significantly higher compared to 75 IU-vit-E-fed mice in CO/FO or both. The levels of anti-DNA antibodies, IL-4, IL-6, TNF-alpha, IL-10 and IL-12 were higher in the sera of MRL/lpr mice. The FO diet lowered the levels of these cytokines (except IL-4) and lipid mediators. Adding 500 IU of vit-E to the FO diet further lowered the levels of IL-6, IL-10, IL-12, and TNF-alpha.. It is clear from our observations that the beneficial effects of FO can be enhanced by the addition of 500 IU of vit-E in the diet. The FO diet containing 500 IU of vit-E may specifically modulate the levels of IL-6, IL-10, IL-12 and TNF-alpha and thereby may delay the onset of autoimmunity in the MRL/lpr mouse model. The observations from this study may form a basis for selective nutrition intervention based on specific fatty acids and antioxidants in delaying the progress of RA.

Topics: Animals; Antibodies, Antinuclear; Arthritis, Rheumatoid; Body Weight; Cytokines; Dietary Fats, Unsaturated; Dinoprostone; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; Female; Interleukins; Kidney; Leukotriene B4; Mice; Thromboxane B2; Tumor Necrosis Factor-alpha; Vitamin E; Weaning

This study was conducted to compare the effects of 60-day dietary exposure (2%) to low melt point paraffin wax (LMPW) on both general liver morphology and Kupffer cell (KC) function and morphology in female F-344 and Sprague-Dawley (SD) rats. Livers from only F-344 rats fed LMPW had granuloma formation/lymphoid cell aggregates with small areas of necrosis. Significant increases in serum alanine and aspartate aminotransferase as well as gamma-glutamyltransferase activities were detected only in treated F-344 rats. Additionally, detectable amounts of LMPW were present only in livers of treated F-344 rats. Because KC can be involved in granuloma formation, their morphology and function were examined. Electron microscopy revealed the presence of large, irregularly shaped, membrane-associated vacuoles in cells isolated from F-344 rats exposed to LMPW. These vacuoles were not seen in KC from control rats and rarely detected in KC isolated from LMPW-exposed SD rats. Moreover, indices of KC function including phagocytic activity and nitric oxide and superoxide anion production were significantly increased by KC isolated from F-344 rats exposed to LMPW (1.6-, 36-, and 2.2-fold increases, respectively) over untreated controls. In contrast, LPS-stimulated production of TNF and LTB4 was significantly decreased only in KC of LMPW-fed F-344 rats. No significant changes in these functions were observed in KC isolated from SD rats exposed to LMPW or from KC isolated from control F-344 or SD rats. These data provide evidence that dietary LMPW alters the morphology and functional capacity of KC of F-344 but not SD rats and these changes may ultimately lead to granuloma formation.

Topics: Animals; Body Weight; Enzymes; Female; Kupffer Cells; Leukocyte Count; Leukotriene B4; Liver; Nitrites; Paraffin; Phagocytosis; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Species Specificity; Superoxides; Tumor Necrosis Factor-alpha

Two groups of rats, ethanol-treated and sucrose-administered control rats, were fed diets with different AA content (0, 2 and 3% weight) for 14 days. Ethanol was administered by gavage at a single daily dose of 3 g/kg body weight. The ethanol-treated rats showed significantly higher levels (p < 0.01) of serum ALT activity. The dietary AA supplement lowered the serum ALT activity and liver triglyceride both in control and ethanol-treated rats. Significantly lower levels of 20:4n - 6 and 20:4n - 6/18:2n - 6 ratio and higher levels of 18:1n - 9 in both the serum and liver triglyceride were observed in the ethanol-treated rats. The AA-supplemented diet induced a marked increase of 20:4n - 6 and subsequent significant decrease of 18:2n - 6 both in the liver and serum phospholipid in control and ethanol-treated rats. 18:1n - 9 in the serum and liver triglyceride in both groups was also markedly decreased by AA supplement. No significant difference was observed in the liver 6-keto-PGF(1 alpha) level between the ethanol-treated and control rats. In the ethanol-treated rats, the level of 6-keto-PGF(1 alpha) was elevated in the rats fed the 3% AA-supplemented diet. Though the liver leukotriene B4 levels were increased by ethanol administration in all rats, these levels were not increased by dietary AA.

Topics: 6-Ketoprostaglandin F1 alpha; Alanine Transaminase; Animals; Arachidonic Acid; Body Weight; Dietary Fats; Ethanol; Fatty Acids; Feeding Behavior; Leukotriene B4; Lipid Metabolism; Lipids; Liver; Male; Organ Size; Rats; Rats, Sprague-Dawley

Broiler chicks were fed a diet containing 4% of either corn oil or fish oil from 3 to 14 d of age. From Days 15 to 23, half of the chicks in each dietary treatment were fed Lofrin (an experimental 5-lipoxygenase inhibitor) at 33 micrograms/kg feed. The remaining chicks within each dietary treatment were the untreated controls. At 24 d of age, half of the chicks within each diet-Lofrin treatment group were each infected with 4.6 x 10(4) sporulated Eimeria tenella oocysts, resulting in a 2 x 2 x 2 factorial arrangement of treatments. Body weight gain, feed consumption, and feed conversion efficiency were determined throughout the study. At 27 d of age, blood, liver, and ceca were sampled. Plasma tumor necrosis factor and hemopexin, hepatic fatty acid composition, and cecal inflammatory cell infiltration were determined. Liver fatty acid composition tended to reflect that of the diet. Chicks fed fish oil had livers that were enriched in (n-3) polyunsaturated fatty acids (PUFA) at the expense of (n-6) PUFA. Chicks fed fish oil gained body weight more rapidly than those fed corn oil. Infection of chicks with Eimeria decreased body weight gain of chicks fed corn oil, but not of chicks fed fish oil. The addition of Lofrin to the corn oil diets abrogated the growth-suppressing effects of infection, although there was no Lofrin effect among chicks fed fish oil. There was a diet by Lofrin interaction in which Lofrin treatment of birds fed corn oil decreased feed consumption and increased feed conversion efficiency, but had no effect on chicks fed diets containing fish oil. Plasma hemopexin was greater, but tumor necrosis factor was lower, in chicks fed fish oil than in chicks fed corn oil. Eimeria infection significantly increased cecal inflammatory cell infiltration across all dietary treatments. There were no clear relationships between growth rate or efficiency and the severity of the inflammatory response to Eimeria infection, as indicated by hemopexin levels and cecal inflammatory scores. These results indicate that Lofrin or fish oil, both of which modify eicosanoid metabolism, attenuate the growth-depressing effects of an Eimeria tenella infection.

Topics: Aging; Analysis of Variance; Animals; Body Weight; Cecum; Chickens; Coccidiosis; Corn Oil; Dietary Fats, Unsaturated; Eating; Eimeria tenella; Fatty Acids; Fish Oils; Hemopexin; Hydroxyurea; Leukotriene B4; Lipoxygenase Inhibitors; Liver; Poultry Diseases; Tumor Necrosis Factor-alpha

Glomerular infiltration of macrophages is a characteristic alteration of renal histopathology in hyperlipidemic renal injury. Each macrophage has two key enzymes to synthesize LTB4:5-lipoxygenase and LTA4 hydrolase. In this study we examined the long-term effects of LTB4 antagonist on real function and histopathology of spontaneously hypercholesterolemic (SHC) rat, which is model of hyperlipidemic renal injury, to see if the LTB4 antagonist could reduce the progression of renal damage. Spontaneously hypercholesterolemic rats fed a normal diet (C) developed end-stage renal failure in 26 weeks, while those fed a diet supplemented with LTB4 antagonist (E) showed normal renal function, and mild histopathological alterations (SCr: C, 1.4 +/- 0.3; E, 0.6 +/- 0.1 mg/dl, P < 0.03) without statistical differences in serum total cholesterol, body weight and blood pressure between two groups. These results suggest that LTB4 plays an important role in progression of hyperlipidemic renal injury.

Topics: Animals; Blood Pressure; Body Weight; Cholesterol; Creatinine; Hyperlipidemias; Immunosuppressive Agents; Kidney; Kidney Diseases; Leukotriene B4; Male; Phenylpropionates; Proteinuria; Rats; Rats, Inbred Strains

1. A controlled-release preparation of mesalazine microgranules (PentasaR; Ferring AS, Vanlose, Denmark) releases the active ingredient over a wide area from the small intestine to the rectum and is consequently expected to bring about therapeutic benefits to patients with ulcerative colitis and Crohn's disease. 2. Mesalazine microgranules (50 or 150 mg/kg per day) were administered orally to each rabbit with carrageenan-induced colitis for six weeks. Its inhibitory effect on colonic mucosal damage was assessed in terms of the microscopic damage scores, leukotriene B4 concentrations and concentrations of mesalazine derivatives. 3. At the end of the experiment, the mesalazine 150 mg group had gained a significantly greater bodyweight than the control group. Microscopic damage was significantly lower in the 150 mg group than in the untreated control group. Tissue concentrations of 5-aminosalicylic acid and acetyl-5-amino-salicylic acid in the small and large intestine were higher in the 150 mg group than in the 50 mg group. Mucosal leukotriene B4 levels tended to be lower in rabbits receiving the larger dose of mesalazine. 4. The present study indicates that slow release 5-amino-salicylic acid at the larger dose reaches the large bowel in sufficiently high concentrations following oral administration and significantly reduces carrageenan-induced colitis in the rabbit.

Topics: Aminosalicylic Acids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Carrageenan; Colitis; Delayed-Action Preparations; Intestinal Mucosa; Leukotriene B4; Male; Mesalamine; Rabbits; Tissue Distribution

The mechanism of anorexia in inflammatory bowel disease is poorly understood. To gain insight into possible pathophysiologic mechanisms, the feeding indices and food intake were studied in an animal model of Crohn's disease. The anorexia of indomethacin-induced ulcerative ileitis was compared with that of the well-known anorexia of total parenteral nutrition (TPN). Forty-five female Lewis rats were randomized to four groups: Control, Indomethacin, Indomethacin + TPN, and TPN. Feeding indices and food intake were continuously measured using the Automated Computerized Rat Eater Meter. Interleukin-1 alpha (IL-1 alpha), tumor necrosis factor-alpha (TNF-alpha), prostaglandin E2 (PGE2), and leukotriene B4 (LTB4) were assayed in plasma, mononuclear cell culture, or ileum to determine their role in mediating anorexia. In the TPN group, spontaneous food intake (SFI) decreased (52%; p < 0.05), primarily via reduction in meal number (MN, 54%; p < 0.05) and, to a lesser extent, meal size (MZ, 35%; p < 0.05). In comparison, in the Indomethacin group SFI decreased (74%; p < 0.05) primarily via reduction in MZ (67%, p < 0.05); MN also decreased but to a lesser extent (27%; p < 0.05). In the Indomethacin + TPN group, SFI decreased (55%; p > 0.05) primarily via reduction in MN (79%; p < 0.05), whereas MZ decreased slightly (19%; p < 0.05). Only in the Indomethacin group were IL-1 alpha and TNF-alpha detected in the mononuclear cell culture and plasma, respectively. In the Indomethacin group, an inverse correlation existed between MZ and TNF-alpha (p < 0.05). In the Indomethacin group, IL-1 alpha, PGE2, and LTB4 concentrations did not correlate with feeding indices. SFI reduction in this model was mediated primarily via a decrease in MZ. TNF-alpha is proposed to mediate this effect and TPN was shown to overcome the effect on MZ.

Topics: Animals; Anorexia; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Cells, Cultured; Dinoprostone; Disease Models, Animal; Eating; Female; Ileitis; Ileum; Indomethacin; Interleukin-1; Leukotriene B4; Monocytes; Parenteral Nutrition, Total; Rats; Rats, Inbred Lew; Tumor Necrosis Factor-alpha

The purpose of this study was to investigate the efficacy of alpha-linolenic acid-rich perilla oil emulsion (POE) in a rat model with trinitrobenzenesulfonic acid (TNB)-induced inflammatory bowel disease. Three different isocaloric solutions, which are glucose solution (FF), soybean oil emulsion (SOE) and POE, were infused for 14 days after instillation of TNB. After infusion, total cholesterol and phospholipid concentration in the plasma in the POE group were significantly decreased compared with the FF and SOE groups. Arachidonic acid level in the colonic phospholipids was significantly decreased and eicosapentaenoic acid level was significantly increased in the POE group compared with the FF and SOE groups. Thickness, damage score and leukotriene B4 content in the colon in the POE group were the lowest among the infusion groups. These results suggest that alpha-linolenic acid suppresses the synthesis of leukotriene B4 in the colon by changing the fatty acid composition in the colonic phospholipids and that POE may be effective in the improvement of inflammation in the colon.

Topics: alpha-Linolenic Acid; Animals; Body Weight; Cholesterol; Colon; Disease Models, Animal; Fatty Acids; Glucose; Inflammatory Bowel Diseases; Leukotriene B4; Male; Phospholipids; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Soybean Proteins; Trinitrobenzenesulfonic Acid

The binding of fluorescein-labelled recombinant human platelet factor 4 (rhPF4) to the vasculature of the hamster cheek pouch in vivo was compared with that to cultured endothelial cells (EC) from human umbilical veins (HUVEC) and arteries (HUAEC) and from human aorta (HAEC). In vivo data: systemically injected rhPF4 rapidly disappeared from plasma in a biphasic pattern (t1/2 = 2 and 41 min). High intensity non-uniform binding of rhPF4 occurred at short specific sites along both arterioles and venules. The length of the intense sites was 76 +/- 46 microns and their frequency was 10 +/- 4 per cm2 cheek pouch. Heparin was injected at 4 and 9 min, but not 30 min, post-rhPF4 displaced most of the high intensity labelling indicating internalization with time. Neither pretreatment with more than 50-fold excess of unlabelled rhPF4 nor histamine- or LTB4-induced vascular macromolecular leakage changed the frequency of short intense sites. In vitro data: uniform time-dependent intense binding of rhPF4 occurred in a similar fashion in subconfluent HUVEC, HUAEC and HAEC. All cell types showed nuclear staining, demonstrating internalization. When heparin was given to EC prior to rhPF4, binding was delayed in time but not blocked. In conclusion, rhPF4 does not bind uniformly with high intensity along pre- and post-capillary vessels of the hamster cheek pouch in vivo as predicted by the rhPF4-labelling of subconfluent (migrating/proliferating) human EC in vitro. The short infrequent sites of intense rhPF4-labeling in vivo may represent regions of endothelial cell migration/proliferation similar to subconfluent EC in culture.

Topics: Animals; Anticoagulants; Aorta; Body Weight; Cells, Cultured; Cricetinae; Endothelium, Vascular; Fluorescein-5-isothiocyanate; Heparin; Histamine; Humans; Leukotriene B4; Male; Mesocricetus; Microscopy, Video; Platelet Factor 4; Protein Binding; Umbilical Arteries; Umbilical Veins

To evaluate anti-colitic efficacy, eight cotton-top tamarins (CTTs) with histologically confirmed persistent active colitis were given the anti-inflammatory agent SC-41930 (10 mg/kg BW by gavage BID) for eight weeks. Colonic endoscopy and biopsy observations, CBCs and clinical chemistries, and stool consistency were evaluated pre-, mid-, and posttreatment. Colitic activity was graded histologically from A1 (mild) to A5 (severe); results varied among the seven animals that completed the study: five improved, one worsened, and one was unchanged. Serum enzyme levels were significantly reduced with treatment. Stool condition remained puddly throughout treatment and body weights did not vary from pretreatment levels. However, SC-41930 produced histological evidence (reduced numbers of polymorphonuclear cells) of anti-colitic efficacy over an eight-week treatment period in CTTs with persistent active colitis. These results support the use of the CTT colitis model to evaluate efficacy of therapeutic agents and provide useful predictive information to aid in the medical management of human IBD.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzopyrans; Body Weight; Colitis; Colon; Disease Models, Animal; Leukotriene B4; Saguinus

The effect of highly purified eicosapentaenoic acid ethyl ester (EPA-E) on colitis was investigated using a guinea pig model. The technique for preparing a degraded carrageenan with a molecular weight of about 30,000 from commercial iota-carrageenan was first refined. When this degraded carrageenan was fed to guinea pigs, localized ulcerations occurred in the cecum with infiltration of numerous mononuclear phagocytes. Oral administration of 300 mg.kg-1.day-1 of EPA-E for 3 weeks significantly prevented the development of colitis. The amounts of prostaglandin E2, thromboxane B2, and leukotriene B4 released from the cecal mucosa were also measured. The release of prostaglandin E2 and thromboxane B2 was significantly decreased in the animals fed EPA-E compared with those given olive oil or a vehicle alone. In addition, there was a positive correlation between the amounts of these eicosanoids and the degree of ulcer formation. However, there was no difference in the amount of leukotriene B4 among various experimental groups of animals. Furthermore, EPA-E feeding induced a significant decrease in the level of arachidonic acid and a significant increase in that of EPA in peritoneal macrophages. These results suggest that EPA has a prophylactic effect on the development of carrageenan-induced colitis, which may be ascribed in part to reduced eicosanoid production.

Topics: Animals; Body Weight; Carrageenan; Cecal Diseases; Colitis; Dinoprostone; Dose-Response Relationship, Drug; Eicosapentaenoic Acid; Fatty Acids; Guinea Pigs; Leukotriene B4; Macrophages; Male; Occult Blood; Thromboxane B2; Ulcer

Products of arachidonic acid metabolism are elevated in patients with inflammatory bowel disease and this elevation is correlated with disease activity. Eicosapentaenoic acid competes with arachidonic acid and alters eicosanoid biosynthesis. In this experiment, the possibility that eicosapentaenoic acid could be used in the treatment of inflammatory bowel disease was investigated by determining the effect of 6 weeks of a fish oil-supplemented diet, enriched in eicosapentaenoic acid, on colonic and ileal morphology, histology, and in vivo fluid absorption in rats with 4% acetic acid-induced colitis. The results of an eicosapentaenoic acid-enriched diet were compared with results of saturated and polyunsaturated fatty acid-enriched diets. In rats with misoprostol pretreated acetic acid-induced colitis, an eicosapentaenoic acid-enriched diet reversed net colonic fluid secretion to absorption and prevented macroscopic and histologic injury, compared with saturated and poly-unsaturated fatty acid-enriched diets, which did not. The fish oil mucosal protective effect occurred in the presence of a 30-fold enhancement of PGE2 synthesis. In rats with non-misoprostol pretreated acetic acid-induced colitis, an eicosapentaenoic acid-enriched diet returned ileal fluid absorption to control levels, as compared with saturated and polyunsaturated fatty acid-enriched diets, which did not. In conclusion, a fish oil (eicosapentaenoic acid)-enriched diet, but not a saturated- or a polyunsaturated-enriched diet, protected colonic and ileal net fluid absorption in an experimental model of inflammatory bowel disease.

Topics: Acetates; Acetic Acid; Animals; Body Fluids; Body Weight; Colon; Colonic Diseases, Functional; Dietary Fats; Dinoprostone; Eating; Fish Oils; Ileum; Intestinal Absorption; Intestinal Mucosa; Leukotriene B4; Male; Rats; Rats, Inbred Strains

This study characterized the induction of the rat hepatic cytochrome P-450-dependent mixed function oxidase system by SK&F 86002 [6-(4'-fluorophenyl)-5-(4'-pyridyl)-2,3-dihydroimidazo-(2,1-b)thia zole], an inhibitor of both the cyclooxygenase and 5-lipoxygenase pathways of arachidonic acid metabolism. The induction characteristics of SK&F 86002 were compared to those of the classical inducer, phenobarbital, and morphological features of both SK&F 86002 and phenobarbital induced hepatocellular hypertrophy were quantitated. Rats were administered either SK&F 86002 (6, 18, or 60 mg/kg/day, po) or phenobarbital (8, 24, 80 mg/kg/day, ip) for 3 or 14 consecutive days. Liver to body weight ratio, total hepatic microsomal protein and cytochrome P-450 content, ethoxycoumarin-O-deethylase (ECOD) and leukotriene B4(LTB4) omega- and omega-1 hydroxylase were measured. Ultrastructural morphometry of the liver from control, and high dose SK&F 86002 (60 mg/kg/day) and phenobarbital (80 mg/kg/day) treated rats was completed. On day 3, phenobarbital increased liver to body weight ratio but only at the 80 mg/kg/day dosage; microsomal protein content was unchanged. ECOD activity increased in a dose-dependent fashion. LTB4 omega- and omega-1 hydroxylase activities were unaffected. Administration of SK&F 86002 for 3 days increased the liver to body weight ratio at both the 18 and 60 mg/kg/day dosage; microsomal protein content was unchanged. ECOD activity was significantly increased by the 60 mg/kg/day dosages of SK&F 86002. On day 14, phenobarbital increased the liver to body weight ratio and microsomal protein content but again only at the 80 mg/kg/day dosage. Cytochrome P-450 content was increased by all dosages.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 7-Alkoxycoumarin O-Dealkylase; Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Cytochrome P-450 CYP4A; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Enzyme Induction; Hypertrophy; Imidazoles; Leukotriene B4; Liver; Male; Microscopy, Electron; Mixed Function Oxygenases; Organ Size; Organelles; Phenobarbital; Rats; Rats, Inbred Strains; Thiazoles

Chronic pulmonary infection in cystic fibrosis (CF) results in an inflammatory response with persistent neutrophil influx, which contributes to lung damage. Attenuating the response with antiinflammatory agents might delay progression of lung disease. We investigated the effects of the nonsteroidal antiinflammatory agent, ibuprofen, in a rat model of chronic Pseudomonas endobronchial infection and inflammation. The areal percentage of lung inflammation 14 days after animal inoculation with Pseudomonas-containing agarose beads was significantly less in animals treated with ibuprofen (35 mg/kg orally twice daily) (39 +/- 26% SD) compared to animals given placebo (55 +/- 25% SD) (p less than 0.05). Ibuprofen did not increase the pulmonary burden of Pseudomonas, and the ibuprofen-treated infected animals gained weight better than placebo-treated controls. The administered dose of ibuprofen provides plasma concentrations sufficient to inhibit the release of leukotriene B4 (LTB4) from rat neutrophils in vitro. Since LTB4 is a potent pro-inflammatory product that promotes neutrophil adherence, aggregation, migration, degranulation, and superoxide release, inhibition of its production by ibuprofen could inhibit inflammatory damage to the lung in this model. These data in an animal model, taken together with the success of a preliminary trial of alternate-day steroid therapy in mildly affected patients with CF, suggest that antiinflammatory therapy with ibuprofen should be considered for a new therapeutic strategy in CF.

Topics: Animals; Body Weight; Chronic Disease; Cystic Fibrosis; Dinoprostone; Humans; Ibuprofen; Leukotriene B4; Lung; Lung Diseases; Neutrophils; Pseudomonas Infections; Rats

Eicosanoids are modulators of defensive and inflammatory processes in the gut mucosa, and may be involved in the pathogenesis of chronic inflammatory lesions of the bowel. As omega-3 fatty acids compete with the omega-6 as precursors of eicosanoid synthesis, we compared the effects of dietary supplementation with either sunflower (source of omega-6) or cod liver (source of omega-3) oil on the development of chronic granulomatous lesions in the rat colon. After four weeks on the supplemented diets, plasma omega-6 fatty acid content was significantly higher in the sunflower group, while omega-3 fatty acids predominated in the cod liver group. Inflammatory colitis was then induced by intracolonic administration of trinitrobenzene sulphonic acid. Luminal eicosanoid release, as measured by radioimmunoassay of intracolonic dialysis fluid, increased significantly after the challenge in both groups. Generation of prostaglandin E2 (PGE2) and leucotriene B4 (LTB4) peaked by day 3 and thereafter declined; thromboxane B2 (TXB2), instead, continued to increase from day 3 to 20 in sunflower fed rats, whereas this change was blunted in cod liver animals. The rats were killed 20, 30, or 50 days after the induction of colitis, and the colonic lesions were scored macroscopically (adhesions to surrounding tissues, strictures, ulcerations, and wall thickness) and histologically (ulceration, inflammation, depth of the lesions, and fibrosis). In cod liver animals, the damage score was markedly reduced by day 30, and inflammation and ulceration were almost absent by day 50. In conclusion, a fish oil diet prevents the increase in thromboxane in the chronic state of inflammation and shortens the course of the colonic disease by diminishing both the severity of the lesions and their progression to chronicity.

Topics: Animals; Body Weight; Cod Liver Oil; Crohn Disease; Dietary Fats; Dinoprostone; Fatty Acids; Fatty Acids, Omega-3; Fish Oils; Helianthus; Leukotriene B4; Male; Plant Oils; Rats; Rats, Inbred Strains; Thromboxane B2; Trinitrobenzenesulfonic Acid

Male weanling F-344 rats were maintained on selenium-supplemented or -deficient diets and were exposed to fresh cigarette smoke daily for 28 weeks. The deficient status of animals was demonstrated by a significant reduction in the pulmonary and hepatic glutathione peroxidase (GSH-Px) activity of rats on selenium-deficient diet. Sham and smoke treatment did not influence the GSH-Px activity in either diet group. Elevated levels of blood carboxyhemoglobin and pulmonary aryl hydrocarbon hydroxylase activity in the smoke-exposed rats of both diet groups indicated effective inhalation of cigarette smoke by animals. Studies of the extracellular release of arachidonate metabolites by pulmonary alveolar macrophages (PAMs) indicated that resting cells released small amounts of prostaglandin E2 (PGE2), thromboxane B2 (TXB2) and leukotriene B4 (LTB4). Upon phagocytic challenge by opsonized zymosan particles, the release of the three metabolites was substantially increased in all diet and treatment groups. While the release of cyclooxygenase products, PGE2 and TXB2, remained unaffected by cigarette smoke, an inhibition of approximately 50% in the release of lipoxygenase product, LTB4, was observed in cells from selenium-fed animals. In selenium-deficient animals, cigarette smoke almost completely inhibited (greater than 80%) the zymosan-stimulated release of LTB4 by PAMs and additionally caused about 50% reduction in TXB2 release. These results suggest a specific inhibition of lipoxygenase pathway by cigarette smoke in PAMs of selenium-fed rats and suggest that cigarette smoke may additionally impair enzymes of the cyclooxygenase pathway in PAMs of selenium-deficient animals.

Topics: Administration, Oral; Animals; Arachidonic Acid; Arachidonic Acids; Body Weight; Cyclooxygenase Inhibitors; Dinoprostone; Glutathione Peroxidase; Leukotriene B4; Lipoxygenase; Lipoxygenase Inhibitors; Liver; Lung; Macrophages; Male; Nicotiana; Phagocytosis; Plants, Toxic; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; Pulmonary Alveoli; Rats; Rats, Inbred F344; Selenium; Smoke; Thromboxane B2