dinoprost and Colitis

Early diagnosis of colorectal cancer is needed to reduce the mortal consequence by cancer. Lipid mediators play critical role in progression of colitis and colitis-associated colon cancer (CAC) and some of their metabolites are excreted in urine. Here, we attempted to find novel biomarkers in urinary lipid metabolite of a murine model of CAC. Mice were received single administration of azoxymethane (AOM) and repeated administration of dextran sulfate sodium (DSS). Lipid metabolites in their urine was measured by liquid chromatography mass spectrometry and their colon was collected to perform morphological study. AOM and DSS caused inflammation and tumor formation in mouse colon. Liquid chromatography mass spectrometry-based comprehensive analysis of lipid metabolites showed that cyclooxygenase-mediated arachidonic acid (AA) metabolites, prostaglandins, and reactive oxygen species (ROS)-mediated AA metabolites, isoprostanes, were predominantly increased in the urine of tumor-bearing mice. Among that, urinary prostaglandin (PG)E2 metabolite tetranor-PGEM and PGD2 metabolite tetranor-PGDM were significantly increased in both of urine collected at the acute phase of colitis and the carcinogenesis phase. On the other hand, two F2 isoprostanes (F2-IsoPs), 8-iso PGF2α and 2,3-dinor-8-iso PGF2α, were significantly increased only in the carcinogenesis phase. Morphological study showed that infiltrated monocytes into tumor mass strongly expressed ROS generator NADPH (p22phox). These observations suggest that urinary 8-iso PGF2α and 2,3-dinor-8-iso PGF2α can be indexes of CAC.

Topics: Animals; Biomarkers; Chromatography, High Pressure Liquid; Colitis; Colitis-Associated Neoplasms; Cyclooxygenase 2; Cytochrome b Group; Dextran Sulfate; Dinoprost; Disease Models, Animal; F2-Isoprostanes; Female; Lipid Metabolism; Mass Spectrometry; Mice; Mice, Inbred C57BL; Monocytes; NADPH Oxidases; Reactive Oxygen Species

Topics: Adiponectin; Animals; Colitis; Colon; Cytokines; Dextran Sulfate; Dinoprost; Dinoprostone; Growth Hormone-Releasing Hormone; Male; Mice, Inbred C57BL; Mice, Knockout; Neoplasms

Intestinal wound healing is a new therapeutic goal for inflammatory bowel disease (IBD) as complete healing of the mucosa is the key element of clinical remission in IBD. Previous studies showed that termination of inflammation can be achieved by adding pro-resolving lipids like DHA and EPA exogenously. However, the roles of these lipids in mucosal healing have not been investigated. To recapitulate intestinal healing process, mice were received dextran sodium sulfate (DSS) for 7 days in the drinking water followed by regular tap water for 5 additional days. DSS-induced intestinal inflammation featuring body weight loss, histological tissue damage, increased cytokine production and infiltration of inflammatory cells was gradually reduced upon switching to water. To investigate whether endogenous lipids play a role in mucosal healing, the lipidomics analysis of mouse serum was performed. Reduced levels of arachidonic acid, the biosynthetic precursor of prostaglandin F (PGF)2α, 19H-PGF1α, the metabolite of prostacyclin, and 20H-PGF2α, the metabolite of PGF2α, suggest subsiding inflammation. In contrast, increased levels of an active metabolite of resolvin D1 along with decreased levels of its precursor DHA as well as decreased levels of the precursor of resolvin E, 18-hydroxy-eicosapentaenoic acid, suggest inauguration of mucosal healing by endogenous lipids. Furthermore, exogenously supplied fish oil enhanced the process even further. These results suggest the presence of mucosal healing regulated by endogenous pro-healing lipids and also indicate that the remission state of IBD could be prolonged by enhancing the levels of these lipids.

Topics: Animals; Arachidonic Acid; Colitis; Colon; Dextran Sulfate; Dinoprost; Disease Models, Animal; Docosahexaenoic Acids; Eicosapentaenoic Acid; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Recovery of Function; Remission, Spontaneous; Weight Loss

Endocannabinoids are protective in animal colitis models. As endocannabinoids also form novel prostaglandin ethanolamides (prostamides) via COX-2, we investigated the effects of prostamides and other COX-2 mediators on tissue damage in an ex vivo human mucosal explant colitis model. Healthy human colonic mucosae were incubated with pro-inflammatory cytokines TNF-α and IL-1β to elicit colitis-like tissue damage. The PGF-ethanolamide analogue, bimatoprost decreased colitis scores which were reversed by a prostamide-specific antagonist AGN 211334, but not the FP receptor antagonist AL-8810. PGF-ethanolamide and PGE-ethanolamide also reduced cytokine-evoked epithelial damage. Anandamide was protective in the explant colitis model; however COX-2 inhibition did not alter its effects, associated with a lack of COX-2 induction in explant mucosal tissue. These findings support an anti-inflammatory role for prostamides and endocannabinoids in the human colon.

Topics: Adult; Amides; Arachidonic Acids; Bimatoprost; Cloprostenol; Colitis; Colon, Sigmoid; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dinoprost; Dinoprostone; Endocannabinoids; Female; Humans; Immunohistochemistry; Interleukin-1beta; Male; Middle Aged; Oxazoles; Polyunsaturated Alkamides; Receptors, Prostaglandin; Sulfonamides; Tissue Culture Techniques; Tumor Necrosis Factor-alpha; Young Adult

We have previously shown that α-linolenic acid (ALA), a (n-3) PUFA exerts in vitro antiinflammatory effects in the intestine. In this study, we aimed to evaluate its effect on inflammatory and oxidative stress in a colitis model. Colitis was induced in 2 groups at d 0 by intrarectal injection of 2-4-6-trinitrobenzen sulfonic acid (TNBS), whereas the control group received the vehicle. Rats we fed 450 mg . kg(-1) . d(-1) of ALA (TNBS+ALA) while the other colitic group (TNBS) and the control group were fed an isocaloric corn oil formula for 14 d (from d -7 to d 7). RBC fatty acid composition was assessed. Oxidative stress was studied by measuring urinary 8-isoprostanes (8-IP) and colon glutathione (GSH) concentration and inducible nitric oxide synthase (iNOS) expression. Colitis was assessed histologically, by production of proinflammatory mediators, including cytokines, leukotrienes B(4) (LTB(4)), and cyclooxygenase-2 (COX-2) and by nuclear factor-κB (NF-κB) activation. The ALA-rich diet significantly increased the RBC levels of ALA, eicosapentaenoic acid, and docosapentaenoic acid (n-3) compared with the TNBS group (P < 0.01 for all). The beneficial effect of ALA supplementation on oxidative stress was reflected by lower urinary 8-IP levels (P < 0.05), a normalized colon GSH concentration (P < 0.01), and reduced colon iNOS expression (P < 0.05) compared with the TNBS group. ALA also protected against colon inflammation as assessed by lower tumor necrosis factor-α secretion and mRNA level (P < 0.05), reduced NF-κB activation (P = 0.01), and lower colon lipid mediator concentrations such as LTB(4) and COX-2 (P < 0.05) compared with the TNBS group. These findings show that an ALA-rich formula is beneficial to TNBS-induced colitic rats via inhibition of oxidative and inflammatory stress.

Topics: alpha-Linolenic Acid; Animals; Chymotrypsin; Colitis; Colon; Cytokines; Diet; Dinoprost; Eicosanoids; Erythrocytes; Fatty Acids; Glutathione; Interferons; Male; NF-kappa B; Nitric Oxide Synthase Type II; Oxidative Stress; Rats; Rats, Sprague-Dawley; Trinitrobenzenesulfonic Acid

Although substance P (SP) has been implicated as a mediator of neurogenic inflammation in the small intestine, little information is available regarding the role of SP in the pathogenesis of chronic ulcerative colitis. In this study, our aim was to investigate whether the intraperitoneal administration of a nonpeptide neurokinin-1 (NK-1) antagonist, CP-96345, which antagonizes the binding of SP to its NK-1 receptor, results in the attenuation of colonic inflammation induced in rats by 5% dextran sodium sulfate (DSS) in drinking water for 10 days compared with an inactive enantiomer, CP-96344. Disease activity was assessed daily for 10 days, after which colonic tissue damage was scored and myeloperoxidase activity and colon and urinary 8-isoprostanes were measured. Animals receiving DSS exhibited marked physical signs of colitis by day 5 compared with controls. Chronic administration of the NK-1 antagonist significantly reduced the disease activity index, mucosal myeloperoxidase activity, colonic tissue damage score, and mucosal and urinary levels of 8-isoprostanes compared with inactive enantiomer- or vehicle-injected (saline) animals receiving DSS alone. These data indicate that the administration of an NK-1 antagonist can attenuate colonic inflammation and oxidative stress and suggest a novel therapeutic approach in the treatment of chronic ulcerative colitis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Colitis; Dextran Sulfate; Dinoprost; F2-Isoprostanes; Isomerism; Male; Neurokinin-1 Receptor Antagonists; Oxidative Stress; Rats; Rats, Sprague-Dawley; Substance P

Plasma prostaglandins have been studied in 306 patients with chronic nonspecific ulcerative colitis. These were found elevated and related to the disease gravity. Treatment succeeded in normalizing prostaglandin, concentrations only in mild ulcerative colitis. In catarrhal pancolitis PGE levels moderately increased before treatment returned to normal at the end of it. In spastic colon pretreatment lack of PGF2 alpha persisted. Evaluation of plasma prostaglandins can serve an additional diagnostic procedure to improve pathogenetic therapy of chronic colitis.

Topics: Adolescent; Adult; Chronic Disease; Colitis; Dinoprost; Humans; Middle Aged; Prednisolone; Prostaglandins E; Severity of Illness Index; Sulfasalazine

To compare the local release of arachidonic acid metabolites in inflammatory diarrheal disease, in vivo equilibrium dialysis of the rectum was done in consecutive untreated patients with ulcerative colitis (n = 20), Crohn's colitis (n = 10), and Clostridium difficile colitis (n = 7). All patients had endoscopically proven rectal inflammation. Eicosanoid profiles were determined in rectal dialysates by radioimmunoassay after preliminary purification. Concentrations of prostaglandin E2, prostaglandin F2 alpha, and thromboxane B2, but not 6-keto-prostaglandin F1 alpha, were raised in all groups and compared with healthy controls. The highest levels within each group were obtained in patients with widespread epithelial damage, as judged by endoscopy. In patients with ulcerative colitis, an extreme rise in prostaglandin E2 and thromboxane B2 were observed. Similarly, concentrations of leukotriene B4 were substantially increased in ulcerative colitis, but in Crohn's colitis and Clostridium difficile colitis only those patients with rectal ulcerations showed elevations. These findings probably reflect more severe tissue damages in ulcerative colitis, but differences between disease groups in cell-to-cell interaction may also contribute. The data suggest, therefore, that therapeutic inhibition of lipoxygenase pathways may prove more effective in ulcerative colitis than in Crohn's disease.

Topics: Adolescent; Adult; Aged; Arachidonic Acid; Arachidonic Acids; Colitis; Colitis, Ulcerative; Crohn Disease; Dialysis; Dinoprost; Dinoprostone; Eicosanoic Acids; Enterocolitis, Pseudomembranous; Female; Humans; Leukotriene B4; Male; Middle Aged; Prostaglandins E; Prostaglandins F; Rectum; Thromboxane B2

Topics: Adult; Colitis; Dinoprost; Female; Gastrointestinal Hemorrhage; Humans; Male; Mesenteric Arteries; Middle Aged; Prostaglandins F; Radiography; Vasoconstrictor Agents