prostaglandin-d2 and Colitis--Ulcerative

PPARgamma has been recently described as being a gene of susceptibility for Intestinal Bowel Diseases (IBD) as NOD2/CARD15 gene. IBD are pathologies due to an abnormal immune response, in genetically predisposed patients, to the bacteria of the intestinal flora. PPARgamma, known for its significant role in adipogenesis, is strongly expressed by the epithelial cells of the colon mucosa. PPARgamma is implicated in the regulation of inflammation. Indeed, agonists of this nuclear receptor decrease strongly the intensity of inflammation during experimental colitis induced by chemical agents. A deficit of PPARgamma in patients with ulcerative colitis has been highlighted, that could in part explain the acute inflammation. In addition, bacteria, including those of the commensal flora, are able to regulate PPARgamma. Toll Like Receptor-4 (TLR-4), responsible for the recognition of bacterial motif as lipopolysaccharide (LPS), is implicated in PPARgamma regulation and its anti-inflammatory properties. All these arguments make of PPARgamma a very interesting therapeutic target for the treatment of IBD.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Bacterial Physiological Phenomena; Colitis, Ulcerative; Crohn Disease; Eicosanoids; Fatty Acids, Omega-3; Homeostasis; Humans; Inflammation; Inflammatory Bowel Diseases; Insulin Resistance; Intestinal Mucosa; Ligands; Lipid Metabolism; Mice; PPAR gamma; Prostaglandin D2; Thiazolidinediones; Toll-Like Receptor 4

Proresolution functions were reported for PGD2 in colitis, but the role of its two receptors, D-type prostanoid (DP) and, in particular, chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2), is less well defined. We investigated DP and CRTH2 expression and function during human and murine ulcerative colitis (UC). Expression of receptors was measured by flow cytometry on peripheral blood leukocytes and by immunohistochemistry and immunoblotting in colon biopsies of patients with active UC and healthy individuals. Receptor involvement in UC was evaluated in a mouse model of dextran sulfate sodium colitis. DP and CRTH2 expression changed in leukocytes of patients with active UC in a differential manner. In UC patients, DP showed higher expression in neutrophils but lower in monocytes as compared with control subjects. In contrast, CRTH2 was decreased in eosinophils, NK, and CD3(+) T cells but not in monocytes and CD3(+)/CD4(+) T cells. The decrease of CRTH2 on blood eosinophils clearly correlated with disease activity. DP correlated positively with disease activity in eosinophils but inversely in neutrophils. CRTH2 internalized upon treatment with PGD2 and 11-dehydro TXB2 in eosinophils of controls. Biopsies of UC patients revealed an increase of CRTH2-positive cells in the colonic mucosa and high CRTH2 protein content. The CRTH2 antagonist CAY10595 improved, whereas the DP antagonist MK0524 worsened inflammation in murine colitis. DP and CRTH2 play differential roles in UC. Although expression of CRTH2 on blood leukocytes is downregulated in UC, CRTH2 is present in colon tissue, where it may contribute to inflammation, whereas DP most likely promotes anti-inflammatory actions.

Topics: Adolescent; Adult; Animals; Blotting, Western; CD3 Complex; Colitis; Colitis, Ulcerative; Colon; Dextran Sulfate; Female; Flow Cytometry; Humans; Immunohistochemistry; Indoles; Killer Cells, Natural; Male; Mice; Mice, Inbred C57BL; Middle Aged; Neutrophils; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; T-Lymphocytes; Th2 Cells; Young Adult

Patients with ulcerative colitis (UC) experience unpredictable bouts of active inflammation and ulceration. Relatively little attention has been paid to the role of antiinflammatory mediators in the pathogenesis of UC, although rodent studies suggest an important role of prostaglandin (PG) D(2) in the resolution of tissue injury and inflammation. The present study was performed to determine if colonic PGD(2) synthesis was altered in patients in remission from UC and if expression of the key enzymes and receptors related to PGD(2) was altered. During routine colon-cancer screening, colonic biopsies were obtained from healthy individuals, some of whom had been in remission from UC, without treatment, for >4 y. UC patients with active disease or in medically induced remission were also biopsied. Only patients with active UC exhibited elevated expression of several proinflammatory cytokines (TNFalpha and IFNgamma) and colonic PGE(2) synthesis. In contrast, colonic PGD(2) synthesis was only elevated ( approximately 3-fold) in the healthy individuals with a prior history of UC. This group also exhibited significantly elevated expression of DP1, the key receptor mediating the antiinflammatory actions of PGD(2). Expression of the synthetic enzymes cyclooxygenase-1, cyclooxygenase-2, and hematopoietic PGD synthase was not altered in the healthy individuals with a prior history of UC. These results show a marked up-regulation of synthesis of an antiinflammatory prostanoid and expression of its receptor, specifically in individuals in long-term remission from UC. This is consistent with animal studies showing the importance of PGD(2) in the induction and maintenance of remission from colitis.

Topics: Adult; Case-Control Studies; Colitis, Ulcerative; Colon; Cyclooxygenase 1; Cyclooxygenase 2; Female; Humans; Immunohistochemistry; Inflammation Mediators; Interferon-gamma; Intramolecular Oxidoreductases; Lipocalins; Male; Middle Aged; Prostaglandin D2; Receptors, Prostaglandin; RNA, Messenger; Tumor Necrosis Factor-alpha; Up-Regulation

Clinical and animal studies indicate that stress can contribute to the onset and/or the worsening of the course of inflammatory bowel diseases (IBD). In a model (inmobilisation stress for 6 h.) in rats it has been demonstrated that stress increases colonic inflammatory damage, as well as antiinflammatory prostaglandins and of the nuclear receptor PPARgamma. This inflammation is followed by an increase in the permeability of the colonic mucosa barrier and a decrease in IgA levels. All these parameters contribute to the bacterial traslocation to other organs. PPARgamma agonists drugs prevent these inflammatory changes as well as the disfunction of the mucosal colonic barrier, which suggests its use in the worsening episodes of IBD produced by stress.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Bacterial Translocation; Colitis, Ulcerative; Disease Models, Animal; Humans; Immobilization; Immunoglobulin A; Inflammatory Bowel Diseases; PPAR gamma; Prostaglandin D2; Prostaglandins; Rats; Rosiglitazone; Stress, Psychological; Thiazolidinediones; Time Factors

In this study, we have evaluated the efficacy of dosmalfate, a new flavonoid derivative compound, for the prevention and treatment of experimental colitis. To induce colitis, BALB/c mice received 5% dextran sulphate sodium (DSS) in their drinking water continuously for 7 days. Colitis was quantified by a clinical damage score, colon length, weight loss, stool consistency and rectal bleeding. Inflammatory response was assessed by neutrophil infiltration, determined by histology and myeloperoxidase (MPO) activity. Interleukin (IL)-1 beta, prostaglandins (PG)E(2) and (PG)D(2) concentrations in colonic tissue, histological and histochemical analysis of the lesions were also measured. Dosmalfate (400-800 mg/kg body weight, p.o.) ameliorated severe colitis reduced the degree of inflammation through reduction of neutrophil infiltration and IL-1 beta levels. (PG)E(2) and (PG)D(2) synthesis were significantly reduced in colitis control group and treatment with dosmalfate abolished the decrease in PG synthesis in colon mucosa. We conclude that dosmalfate is protective in acute DSS-induced colitis. The beneficial effects seem to be related to a decrease of neutrophil infiltration, absence of up-regulation of IL-1 beta and increase of PG production in colon mucosa.

Topics: Administration, Oral; Animals; Colitis, Ulcerative; Colon, Descending; Colon, Transverse; Dextran Sulfate; Dinoprostone; Diosmin; Disease Models, Animal; Drinking; Flavonoids; Interleukin-1; Intestinal Mucosa; Male; Mice; Mice, Inbred BALB C; Neutrophil Infiltration; Peroxidase; Prostaglandin D2; Time Factors; Water

The synthesis of 14C labelled arachidonic acid metabolites was measured in colonic tissues obtained from mice, rats, guinea pigs, rabbits, piglets and in colonic biopsies from humans during colonoscopy. The main eicosanoids formed after stimulation with calcium ionophore A23187 were: in humans, 15-hydroxy-eicosatetraenoic acid (15-HETE); in mice, 12-HETE; in rats, 12-HETE, 12-hydroxy-5,8,10-heptadecatrienoic acid (HHT) and 6-keto-prostaglandin F1 alpha (6kPGF1 alpha); in guinea pigs, PGD2; in rabbits, 6kPGF1 alpha, PGE2 and 15-HETE; and in pigs PGE2 and 12-HETE. In inflamed 15-HETE production was increased in man, HHT and 12-HETE production in rats and overall eicosanoid production in mice.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; 6-Ketoprostaglandin F1 alpha; Animals; Calcimycin; Colitis, Ulcerative; Colon; Dinoprostone; Eicosanoids; Fatty Acids, Unsaturated; Guinea Pigs; Humans; Hydroxyeicosatetraenoic Acids; Intestinal Mucosa; Mice; Mice, Inbred BALB C; Prostaglandin D2; Rabbits; Rats; Rats, Wistar; Species Specificity

To further define the role of mast cells in the idiopathic inflammatory bowel diseases, mediator release from intestinal mast cells derived from actively inflamed and relatively quiescent areas of ulcerative colitis was studied. It was hypothesized that mast cells in the actively diseased segments would indicate involvement in the disease process by releasing a different profile of mediators than cells in uninflammed tissue. Mast cell-containing suspensions derived from matched segments of 12 ulcerative colitis specimens were compared for responsiveness to the mast cell stimulus goat anti-human immunoglobulin E. Supernatants from challenged cells were analyzed for levels of three mast cell mediators, histamine, prostaglandin D2, and the sulfidopeptide leukotriene C. Mast cells from the actively involved areas released significantly greater amounts of histamine, prostaglandin D2, and sulfidopeptide leukotriene. The difference in histamine release was not a result of greater stores of histamine in the active tissue cells, because the total histamine content of the mast cells from the active areas was not significantly greater. The enhanced release of both preformed and newly generated mediators indicates activation of those cells in the course of the disease and points to the mast cell contribution to the inflammatory process in these disorders.

Topics: Adult; Cells, Cultured; Colitis, Ulcerative; Female; Histamine Release; Humans; Intestinal Mucosa; Male; Mast Cells; Middle Aged; Prostaglandin D2; Radioimmunoassay; SRS-A