prostaglandin-d2 and Inflammatory-Bowel-Diseases

This review summarizes recent developments in the role of soluble mediators of inflammation, particularly arachidonic acid metabolites, in inflammatory bowel disease (IBD).. The role of prostaglandin E2 in immune regulation has been better defined. Prostaglandin E2 promotes not only immune tolerance and epithelial homeostasis but also the proinflammatory Th17 pathway. Prostaglandin D2 has been established as promoting the resolution of inflammation in the gastrointestinal mucosa. The 12-lipoxygenase product hepoxilin A3 mediates the migration of neutrophils from the mucosa into the lumen.. Recent studies of soluble mediators, especially arachidonic acid metabolites, have defined their proinflammatory and anti-inflammatory roles in IBD.

Topics: 8,11,14-Eicosatrienoic Acid; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Cell Movement; Dinoprostone; Humans; Inflammation; Inflammatory Bowel Diseases; Intestinal Mucosa; Neutrophils; Prostaglandin D2; Signal Transduction; Th17 Cells

To review our current understanding of the relationship between absorption of nutrients and intestinal inflammatory response.. There is increasing evidence linking gut local inflammatory events with the intake of nutrients. Our recent studies, using the conscious lymph fistula rat model, demonstrate that fat absorption activates the intestinal mucosal mast cells. This is accompanied by a dramatic increase in the lymphatic release of mast cell mediators including histamine, rat mucosal mast cell protease II (RMCPII), as well as the lipid mediator prostaglandin D2 (PGD2). Clinical studies suggest that increased consumption of animal fat may play a role in the pathogenesis of inflammatory bowel disease. This impact of dietary fat may not be restricted to the gut but may extend to the whole body. There is evidence linking a high-fat diet-induced metabolic syndrome, with a low-grade chronic inflammatory state. In this review, we hope to convince the readers that fat absorption can have far reaching physiological and pathophysiological consequences.. Understanding the relationship between nutrient absorption and intestinal inflammation is important. We need a better understanding of the interaction between enterocytes and the intestinal immune cells in nutrient absorption and the gut inflammatory responses.

Topics: Amine Oxidase (Copper-Containing); Animals; Dietary Fats; Disease Models, Animal; Histamine; Inflammation; Inflammatory Bowel Diseases; Intestinal Absorption; Intestinal Mucosa; Mast Cells; Metabolic Syndrome; Prostaglandin D2; Rats; Serine Endopeptidases

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

Therapeutic interventions in the case of gastrointestinal disease are based on the understanding of the role of different inflammatory mediators. Reactive O2 and N2 metabolites are involved in IBD. Pro-inflammatory cytokines, apoptosis signalling and redox-response transcription factors are depended on free radicals. NO activates COX enzymes. PGE2 negatively modulates induction of NO synthase by interleukins and therefore regulation of gastric mucosal integrity by endogenous NO depends on arachidonic acid cascade. PG-s have pro-inflammatory and anti-inflammatory effects on the immune system. Dietary PUFA-s and eicosanoids have potential effects on the modulation of inflammatory processes and immune cells. The cholesterol level lowering activity of several cytokines and colony stimulating factor can be observed. Therapeutic efficacy of N-3 PUFA is described in cases of patients with chronic gastrointestinal disorders, but N-3 PUFA-s only delay early relapse of ulcerative colitis in remission. TNF is known as a pleiotropic cytokine. Strategies for TNF in IBD is very important part of therapeutical approaches. Therapy with infliximab and related ones are encouraging in critical cases. It is also believed recently, that NF-kappaB also may be a target of IBD treatment. It became known, that oxidized LDL can inhibit LPS-induced binding of the NF-kappaB to DNA and the subsequent expression of TNF-alpha and interleukin-1beta in macrophages as well as oxidized LDL modulates activation of NF-kappaB in mononuclear phagocytes by altering the degradation of I-kappaBs. 15-d-PGJ2 inhibits multiple steps in the NF-kappaB signaling pathway. 15-d-PGJ2 metabolite binds PPAR-gamma promotes adipocyte differentiation. PPAR-gamma ligand inhibits growth of cells through induction of apoptosis. Several nutritional polyphenols (the secondary metabolites of plants) are COX2 and/or LOX inhibitors and iNOS activators. The moderate nutritional customs with natural antioxidants can help restore to normal function of gastrointestinal tract, but the immoderate consumption of vitamins and polyphenol type antioxidant molecules is contraindicated.

Topics: Antibodies, Monoclonal; Antioxidants; Apoptosis; Cytokines; Enzyme Activation; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Flavonoids; Free Radicals; Humans; Hypolipidemic Agents; I-kappa B Proteins; Inflammatory Bowel Diseases; Infliximab; Interleukin-1; Interleukins; Lipoproteins, LDL; NF-kappa B; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nutritional Physiological Phenomena; Oxidation-Reduction; Phenols; Polyphenols; PPAR gamma; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Signal Transduction; Transcription Factors; Triglycerides; Tumor Necrosis Factor-alpha

Topics: Animals; Antineoplastic Agents; Colonic Neoplasms; Crohn Disease; Humans; Inflammatory Bowel Diseases; PPAR gamma; Prostaglandin D2; Thiazolidinediones

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

Endothelium-dependent dilation to acetylcholine (Ach) is reduced in mucosal arterioles from patients with inflammatory bowel disease (IBD). The contributions of both nitric oxide (NO) and endothelial-derived hyperpolarizing factor (EDHF) are decreased. We hypothesized that the remaining dilation results from products of cyclooxygenase.. High-performance liquid chromatography (HPLC) was used to isolate eicosanoid vasodilator products and videomicroscopy was used to examine vasomotor responses in human mucosal arterioles from subjects with or without IBD undergoing bowel resection surgeries. In subjects without IBD, Ach constricted (-52%+/-10%) arterioles devoid of endothelium. Indomethacin (INDO) (cyclooxygenase inhibitor) had no effect. In contrast, Ach dose-dependently dilated both intact and endothelial denuded arterioles from patients with IBD. The dilation was converted to constriction by INDO (-54%+/-9%; P<0.05 versus non-IBD) or by BWA868C (PGD2 receptor antagonist). Only in arterioles from subjects with IBD did Ach produce an arachidonic acid metabolite that comigrated on HPLC with PG D2 (PGD2). Exogenous PGD2 dilated (max=66%+/-4%) IBD arterioles.. In arterioles from IBD patients, Ach-mediated dilation shifts from endothelial production of NO and EDHF to nonendothelial generation of a PG, likely PGD2. This is a novel dilator mechanism arising from nonendothelial vascular tissue that compensates for loss of endothelium-dependent dilation. PGD2 appears to be important in regulating mucosal blood flow in patients with IBD, implicating potentially detrimental effects from nonsteroidal antiinflammatory drugs.

Topics: Acetylcholine; Adult; Aged; Arachidonic Acid; Arterioles; Biological Factors; Carbon Radioisotopes; Cyclooxygenase Inhibitors; Endothelium, Vascular; Female; Humans; In Vitro Techniques; Indomethacin; Inflammatory Bowel Diseases; Male; Microscopy, Video; Middle Aged; Nitric Oxide; Prostaglandin D2; Reactive Oxygen Species; Receptors, Immunologic; Receptors, Prostaglandin; Vasodilation; Vasodilator Agents

Peroxisome proliferator-activated receptor gamma (PPAR-gamma), a member of the nuclear hormone receptor superfamily originally shown to play a critical role in adipocyte differentiation and glucose homeostasis, has recently been implicated as a regulator of cellular proliferation and inflammatory responses. Colonic epithelial cells, which express high levels of PPAR-gamma protein, have the ability to produce inflammatory cytokines that may play a role in inflammatory bowel disease (IBD). We report here that PPAR-gamma ligands dramatically attenuate cytokine gene expression in colon cancer cell lines by inhibiting the activation of nuclear factor-kappaB via an IkappaB-alpha-dependent mechanism. Moreover, thiazolidinedione ligands for PPAR-gamma markedly reduce colonic inflammation in a mouse model of IBD. These results suggest that colonic PPAR-gamma may be a therapeutic target in humans suffering from IBD.

Topics: Animals; Caco-2 Cells; Colitis; Cytokines; DNA-Binding Proteins; Epithelium; Gene Expression; HT29 Cells; Humans; I-kappa B Proteins; Inflammation; Inflammatory Bowel Diseases; Interleukin-8; Ligands; Mice; Microbodies; NF-kappa B; NF-KappaB Inhibitor alpha; Prostaglandin D2; Receptors, Cytoplasmic and Nuclear; Rosiglitazone; Thiazoles; Thiazolidinediones; Transcription Factors

Intestinal mast cells are thought to contribute to the mucosal inflammation in ulcerative colitis and Crohn's disease through release of inflammatory mediators. Since sulfasalazine and its metabolite 5-aminosalicylic acid are effective therapeutic agents in inflammatory bowel disease and have been shown to inhibit generation of inflammatory products in other cells, we examined the effect of these agents in vitro on human intestinal mast cell mediator release. Sulfasalazine (5 x 10(-4)-10(-3) M) was found to significantly enhance goat anti-human IgE-induced histamine release from intestinal mast cells, which is the same response as seen in human blood basophils, whereas its metabolite 5-aminosalicylic acid was an effective inhibitor of stimulated histamine release in both mast cells and basophils. 5-Aminosalicylic acid also inhibited production of prostaglandin D2 by the stimulated intestinal mast cells. Sulfasalazine alone, without immunologic stimulation, did not induce histamine release from mast cells or basophils, but the enhancement of ongoing mast cell activation by sulfasalazine may explain some cases of adverse reactions to the drug. The inhibition of mast cell histamine release and prostaglandin generation by 5-aminosalicylic acid demonstrates a potential therapeutic modality of this agent.

Topics: Adult; Aged; Aminosalicylic Acids; Basophils; Cells, Cultured; Colon; Female; Histamine Release; Humans; Immunoglobulin E; In Vitro Techniques; Inflammatory Bowel Diseases; Male; Mast Cells; Mesalamine; Middle Aged; Prostaglandin D2; Sulfasalazine