transforming-growth-factor-beta and Intestinal-Obstruction

Intestinal fibrostenosis is a frequent and debilitating complication of Crohn's disease (CD), not only resulting in small bowel obstruction, but eventually in repeated bowel resection and short bowel syndrome. Over one third of patients with CD have a clear stenosing disease phenotype, often in the absence of luminal inflammatory symptoms. Intestinal fibrosis is a consequence of chronic transmural inflammation in CD. As in other organs and tissues, phenotypic transformation and activation of resident mesenchymal cells, such as fibroblasts and smooth muscle cells, underlie fibrogenesis in the gut. The molecular mechanisms and growth factors involved in this process have not been identified. However, it is clear that inflammatory mediators may have effects on mesenchymal cells in the submucosa and the muscle layers that are profoundly different from their action on leukocytes or epithelial cells. Transforming growth factor-beta (TGF-beta), for instance, has profound anti-inflammatory activity in the mucosa and probably serves to keep physiologic inflammation at bay, but at the same time it appears to be driving the process of fibrosis in the deeper layers of the gut. Tumor necrosis factor, on the other hand, has antifibrotic bioactivity and pharmacologic inhibition of this cytokine carries a theoretical risk of enhanced stricture formation. Endoscopic management of intestinal strictures with balloon dilation is an accepted strategy to prevent or postpone repeated surgery, but careful patient selection is of paramount importance to ensure favorable long-term outcomes. Specific medical therapy aimed at preventing or reversing intestinal fibrosis is not yet available, but candidate molecules are emerging from research in the liver and in other organs.

Topics: Catheterization; Colonoscopy; Crohn Disease; Humans; Intestinal Obstruction; Transforming Growth Factor beta

Bacteria and their products stimulate inflammatory responses. Certain mediators, such as transforming growth factor beta1 (TGF-beta1), induce collagen synthesis. Excess collagen deposition results in bowel strictures. The aim of this study was to investigate the role of bacteria and TGF-beta1 in the pathogenesis of intestinal fibrosis.. In rats with colitis, the effects of bowel decontamination with antibiotics on TGF-beta1, tumor necrosis factor alpha (TNF-alpha), and collagen content in colonic tissue were studied. In normal rats, bacteria of the predominant flora were inoculated into the colonic wall. The effect of neutralizing antibody to TGF-beta1 on tissue collagen deposition was studied.. Rats with chronic colitis showed increased levels of TGF-beta1, TNF-alpha, and collagen in the tissue and a high rate of bowel strictures. Antibiotic treatment significantly prevented the increase in TGF-beta1 and collagen and the formation of strictures. Inoculation of bacterial suspensions into the colonic wall increased tissue TGF-beta1 and collagen content. Neutralizing antibody to TGF-beta1 prevented collagen deposition. Colonic wall inoculations with single anaerobic strains (Clostridium ramosum, Bacteroides fragilis, and Bacteroides uniformis), but not with aerobes, induced collagen deposition.. Certain strains of the common flora stimulate TGF-beta1 and induce deposition of collagen in the colonic wall.

Topics: Animals; Anti-Bacterial Agents; Bacteria; Colitis; Collagen; Fibrosis; Intestinal Obstruction; Intestines; Male; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta

A strain difference in the development of radiation-induced fibrosis of the colorectum was recently observed. C57B1/6 mice developed colorectal obstruction with significantly higher incidence compared to C3Hf/Kam mice after partial volume irradiation with 30 Gy. Previous reports have demonstrated differences in cytokine mRNA levels in fibrosis-prone and -resistant mice after lung irradiation. The aims of this study are to determine if there are strain differences in: 1) the histology of the lesion, 2) mRNA levels for transforming growth factor beta (TGFbeta) isoforms and tumor necrosis factor alpha (TNFalpha), and 3) immunohistochemical staining patterns using antibodies against the TGFbeta isoforms and latency-associated peptide (LAP).. The colorectum of male C3Hf/Kam (C3H) and C57B1/6 (B6) mice were irradiated using a dose/length combination (30 Gy to 13.7 mm) that resulted in 10 or 100% incidence of obstruction by 6 months in each strain, respectively. Colorectal tissue was removed from 6 hours to 120 days after irradiation as well as from obstructed mice and prepared for histology, RNase protection assay, and immunofluorescence.. Distinct differences in the histological phenotype for the two strains were observed at times preceding obstruction. Samples from B6 mice showed increased hyperplastic crypts, colitis cystica profunda, and fibrosis within the lamina propria, compared to identically treated C3H mice. Fibrosis in the lamina propria of B6 mice appeared early, beginning at 75 days after irradiation, and was progressive, whereas fibrosis in C3H mice appeared simultaneous with obstruction and may have been a reaction to ulceration. No consistent strain difference in mRNA levels for TGFbeta1, 2, 3 or TNFalpha were observed, although mRNA levels of TGFbeta1 and TNFalpha were significantly elevated in both strains relative to nonirradiated controls. Immunofluorescent staining for TGFbeta1, 3 and LAP was observed in hyperplastic crypts and colitis cystica profunda adjacent to regions of fibrosis, histological changes that were present predominately in the B6 strain.. The response of the colorectum to irradiation involves changes in the expression of several different cytokines. However, the lack of a consistent strain difference in TGFbeta1, 2, 3 and TNFalpha mRNA levels, despite strain differences in both the incidence of colorectal obstruction and histological features preceding obstruction, suggests that mRNA changes in these fibrogenic cytokines are not the critical determinant of the strain difference and are not related to the process of radiation-induced colorectal fibrosis in these mouse strains. Strain-dependent differences were observed in the localization of active TGFbeta, but these differences were related to the histological changes specifically found in the irradiated colon of the B6 strain.

Topics: Animals; Colon; Intestinal Mucosa; Intestinal Obstruction; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Radiation Injuries, Experimental; Rectum; RNA, Messenger; Species Specificity; Transforming Growth Factor beta

Insulin-like growth factor-I (IGF-I) and/or transforming growth factor-beta (IGF-beta), may be involved in gut fibrous strictures.. Concentrations of these two peptides have been measured by enzyme-linked immunosorbent assays (ELISAs) in whole gut lavage fluid from 57 patients, of whom 14 had strictures of the small intestine or colon associated with Crohn's disease, irradiation injury, ischaemia or diverticulitis.. IGF-I was detected in fluid from 11 of 14 patients with strictures, and 5 of 43 others (P < 0.01). TGF-beta was detectable in all 57 samples and concentrations were unrelated to the presence or absence of strictures.. Clinical studies of growth factors in intestinal fluid should facilitate research on intestinal fibrogenesis, and the diagnosis of fibrous stricturing in Crohn's disease.

Topics: Crohn Disease; Enzyme-Linked Immunosorbent Assay; Fibrosis; Humans; Insulin-Like Growth Factor I; Intestinal Diseases; Intestinal Mucosa; Intestinal Obstruction; Intestines; Ischemia; Radiation Injuries; Sensitivity and Specificity; Solutions; Therapeutic Irrigation; Transforming Growth Factor beta

Polyunsaturated phosphatidylcholine stimulates collagen breakdown in experimental models of liver cirrhosis. Bowel strictures are characterized by excess deposition of collagen in the intestinal wall. The aim of this study was to investigate the effect of polyunsaturated phosphatidylcholine in the prevention of bowel strictures.. Colitis was induced by trinitrobenzenesulfonic acid. On day 21, the presence of strictures was assessed in control rats, rats with colitis, and phosphatidylcholine-fed (100 mg/day) rats with colitis. Furthermore, serum transforming growth factor beta1, collagen deposition, and collagenase activity in colonic tissue were measured in all groups.. None of the control rats but 12 of 16 rats with colitis developed colonic strictures. In contrast, only 2 of 15 phosphatidylcholine-fed rats with colitis showed strictures. Collagen content was much higher in rats with colitis than in phosphatidylcholine-fed rats with colitis and control rats. Phosphatidylcholine-fed rats showed significantly higher collagenase activity in colonic tissue than rats with colitis and control rats. In an ancillary study, free linoleic acid-fed rats showed no differences when compared with rats with colitis. Stimulation of transforming growth factor beta1 was similar in all rats with colitis.. Oral supplementation with polyunsaturated phosphatidylcholine prevents the accumulation of collagen in inflamed intestinal tissue and the formation of strictures. This effect is associated with an enhanced collagen catabolism.

Topics: Analysis of Variance; Animals; Chronic Disease; Colitis; Collagen; Collagenases; Colon; Colonic Diseases; Constriction, Pathologic; Dietary Fats, Unsaturated; Disease Models, Animal; Intestinal Obstruction; Male; Phosphatidylcholines; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta; Trinitrobenzenesulfonic Acid