cyclic-gmp and Colitis--Ulcerative

Ulcerative colitis (UC) belongs to inflammatory bowel disorders, a group of gastrointestinal disorders that can produce serious recurring diarrhea in affected patients. The mechanism for UC- and inflammatory bowel disorder-associated diarrhea is not well understood. The cystic fibrosis transmembrane-conductance regulator (CFTR) chloride channel plays an important role in fluid and water transport across the intestinal mucosa. CFTR channel function is regulated in a compartmentalized manner through the formation of CFTR-containing macromolecular complexes at the plasma membrane. In this study, we demonstrate the involvement of a novel macromolecular signaling pathway that causes diarrhea in UC. We found that a nitric oxide-producing enzyme, inducible nitric oxide synthase (iNOS), is overexpressed under the plasma membrane and generates compartmentalized cGMP in gut epithelia in UC. The scaffolding protein Na(+)/H(+) exchanger regulatory factor 2 (NHERF2) bridges iNOS with CFTR, forming CFTR-NHERF2-iNOS macromolecular complexes that potentiate CFTR channel function via the nitric oxide-cGMP pathway under inflammatory conditions both in vitro and in vivo. Potential disruption of these complexes in Nherf2(-/-) mice may render them more resistant to CFTR-mediated secretory diarrhea than Nherf2(+/+) mice in murine colitis models. Our study provides insight into the mechanism of pathophysiologic occurrence of diarrhea in UC and suggests that targeting CFTR and CFTR-containing macromolecular complexes will ameliorate diarrheal symptoms and improve conditions associated with inflammatory bowel disorders.

Topics: Animals; Cell Membrane; Cells, Cultured; Colitis, Ulcerative; Cyclic GMP; Cystic Fibrosis Transmembrane Conductance Regulator; Diarrhea; Disease Models, Animal; Humans; Male; Mice, Inbred C57BL; Mice, Knockout; Phosphoproteins; Signal Transduction; Sodium-Hydrogen Exchangers

The concentrations of cyclic nucleotides (CN) were examined in rectal mucosal biopsy specimens from 52 patients with active ulcerative colitis (UC) and 10 healthy controls. The three degrees of inflammation, evaluated macroscopically by endoscopy and by morphometry in the specimens by estimating the cellular infiltration of the lamina propria, corresponded nicely with each other. The proliferative-regenerative morphologic changes in the rectal mucosa were graded qualitatively and quantitatively in three groups in accordance with defined criteria. A significant difference in cAMP concentration was only found between the most severe degree of inflammation (infiltration, 44.6%) in UC and healthy controls. cAMP concentration in rectal mucosal specimens was lower at the highest degree of regeneration than in specimens with lower degrees. Thus cAMP may play a role in the epithelial regeneration of rectal mucosa. The values of CN concentration did not correlate with the degree of inflammation in rectal mucosa from patients with UC.

Topics: Adult; Colitis, Ulcerative; Cyclic AMP; Cyclic GMP; Female; Humans; Intestinal Mucosa; Male; Middle Aged; Rectum

Topics: Adult; Biopsy; Colitis, Ulcerative; Cyclic AMP; Cyclic GMP; Female; Humans; Inflammation; Male; Middle Aged; Nucleotides, Cyclic; Rectum; Wound Healing

The blood levels of cyclic nucleotides and serotonin were measured in 143 patients with functional and inflammatory diseases of the large intestine. The patients were divided into 3 groups administered various treatment: drug (basic) therapy in Group 1, basic therapy + alternating magnetic field in Group 2, and basic therapy + sinusoidal modulated currents in Group 3. Follow-up of the examined parameters over the course of treatment has shown that by day 16 of inpatient treatment they normalize, this demonstrating the treatment efficacy.

Topics: Colitis; Colitis, Ulcerative; Colonic Diseases, Functional; Cyclic AMP; Cyclic GMP; Fluorometry; Humans; Radioimmunoassay; Serotonin

Topics: Adenylyl Cyclases; Adult; Aged; Colitis, Ulcerative; Cyclic AMP; Cyclic GMP; Diarrhea; Female; Humans; Intestinal Mucosa; Male; Middle Aged; Rectum

Topics: Adolescent; Adult; Cholera; Colitis, Ulcerative; Cyclic AMP; Cyclic GMP; Diarrhea; Female; Humans; Male; Middle Aged