thiourea and Colitis

Nucleotides are danger signals that activate inflammatory responses via binding P2 receptors. The nucleoside triphosphate diphosphohydrolase-8 (NTPDase8) is an ectonucleotidase that hydrolyses P2 receptor ligands. We investigated the role of NTPDase8 in intestinal inflammation.. We generated NTPDase8-deficient (. NTPDase8 is the dominant enzyme responsible for the hydrolysis of nucleotides in the lumen of the colon. Compared with wild-type (WT) control mice, the colon of. NTPDase8 protects the intestine from inflammation most probably by limiting the activation of P2Y

Topics: Adenosine Triphosphatases; Animals; Apoptosis; Bone Marrow Transplantation; Colitis; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Epithelial Cells; Humans; Immunohistochemistry; Intestinal Mucosa; Isothiocyanates; Mice, Inbred C57BL; Mice, Knockout; Real-Time Polymerase Chain Reaction; Receptors, Purinergic P2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thiourea

Endoplasmic reticulum (ER) stress in the intestine is closely associated with the development of inflammatory bowel disease (IBD). However, the role of the protein kinase RNA-like ER kinase in this disease is not fully known. We studied whether an inhibitor of the dephosphorylation of eukaryotic initiation factor 2α, salubrinal, improves murine experimental colitis through the amelioration of ER stress.. Colitis was induced by the administration of 3% dextran sulfate sodium (DSS) for 5 days. Mice were injected salubrinal intraperitoneally from the commencement of DSS treatment and were sacrificed on day 10. The severity of colitis was evaluated histologically using a scoring system.Myeloperoxidase activity and the expression of proinflammatory cytokine genes in the colon were analyzed. The expression levels of ER stress-related proteins were evaluated by Western blotting.. The administration of salubrinal significantly attenuated body weight loss and improved colitis, as assessed histologically. The elevation of myeloperoxidase activity and the expression of proinflammatory cytokine genes were suppressed in salubrinal-treated mice. The expression of glucose-regulated protein 78, activating translation factor 4, and heat-shock protein 70 was elevated in mice treated with salubrinal.. The amelioration of ER stress may be a therapeutic target for the treatment of IBD.

Topics: Animals; Cinnamates; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; DNA-Binding Proteins; eIF-2 Kinase; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Eukaryotic Initiation Factor-2; Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Injections, Intraperitoneal; Interleukins; Male; Mice; Mice, Inbred C57BL; Peroxidase; Regulatory Factor X Transcription Factors; RNA, Messenger; Thiourea; Transcription Factors; Tumor Necrosis Factor-alpha; Weight Loss

The transient receptor potential vanilloid 1 receptor (TRPV1) is an important nociceptor involved in neurogenic inflammation. We aimed to examine the role of TRPV1 in experimental colitis and in the development of visceral hypersensitivity to mechanical and chemical stimulation. Male Sprague-Dawley rats received a single dose of trinitrobenzenesulfonic acid (TNBS) in the distal colon. In the preemptive group, rats received the TRPV1 receptor antagonist JYL1421 (10 mumol/kg, i.v.) or vehicle 15 min prior to TNBS followed by daily doses for 7 days. In the post-inflammation group, rats received JYL1421 daily for 7 days starting on day 7 following TNBS. The visceromotor response (VMR) to colorectal distension (CRD), intraluminal capsaicin, capsaicin vehicle (pH 6.7) or acidic saline (pH 5.0) was assessed in all groups and compared with controls and naïve rats. Colon inflammation was evaluated with H&E staining and myeloperoxidase (MPO) activity. TRPV1 immunoreactivity was assessed in the thoraco-lumbar (TL) and lumbo-sacral (LS) dorsal root ganglia (DRG) neurons. In the preemptive vehicle group, TNBS resulted in a significant increase in the VMR to CRD, intraluminal capsaicin and acidic saline compared the JYL1421-treated group (P<0.05). Absence of microscopic colitis and significantly reduced MPO activity was also evident compared with vehicle-treated rats (P<0.05). TRPV1 immunoreactivity in the TL (69.1+/-4.6%) and LS (66.4+/-4.2%) DRG in vehicle-treated rats was increased following TNBS but significantly lower in the preemptive JYL1421-treated group (28.6+/-3.9 and 32.3+/-2.3 respectively, P<0.05). JYL1421 in the post-inflammation group improved microscopic colitis and significantly decreased the VMR to CRD compared with vehicle (P<0.05, >/=30 mm Hg) but had no effect on the VMR to chemical stimulation. TRPV1 immunoreactivity in the TL and LS DRG was no different from vehicle or naïve controls. These results suggest an important role for TRPV1 channel in the development of inflammation and subsequent mechanical and chemical visceral hyperalgesia.

Topics: Animals; Capsaicin; Colitis; Disease Models, Animal; Drug Administration Schedule; Drug Interactions; Electromyography; Ganglia, Spinal; Gastrointestinal Motility; Hyperalgesia; Male; Neurons; Rats; Rats, Sprague-Dawley; Reflex, Abdominal; Sulfonamides; Thiourea; Time Factors; Trinitrobenzenesulfonic Acid; TRPV Cation Channels; Visceral Afferents