Induction of colonic transmural inflammation by Bacteroides fragilis: implication of matrix metalloproteinases.

BACKGROUND: Commensal bacteria are implicated in the pathophysiology of intestinal inflammation, but the precise pathogenetic mechanisms are not known. We hypothesized that Bacteroides fragilis-produced metalloproteinases (MMPs) are responsible for bacterial migration through the intestinal wall and transmural inflammation. AIM: To investigate the role of bacterial-MMP activity in an experimental model of colitis induced by the intramural injection of bacteria. METHODS: Suspensions of viable B. fragilis or Escherichia coli were injected into the colonic wall, and the effect of the MMP inhibitor (phenantroline) on histologic lesion scores was tested. MMP activity in bacterial suspensions was measured by azocoll assay. RESULTS: The inoculation with B. fragilis induced chronic inflammatory lesions that were preferentially located in the subserosa, whereas inoculation with E. coli induced acute-type inflammatory reactions, evenly distributed in both the submucosa and subserosa. Treatment with phenantroline significantly decreased subserosal lesion scores in rats inoculated with B. fragilis, but not in rats inoculated with E. coli. Bacterial suspensions of B. fragilis showed MMP activity, but E. coli suspensions did not. Sonication of B. fragilis reduced MMP activity and virulence to induce serosal lesions. CONCLUSION: Our data suggest that bacterial MMPs may be implicated in the serosal migration of B. fragilis and in the induction of transmural inflammation.

Effect of short-term octreotide therapy and total parenteral nutrition on the development of biliary sludge and lithiasis.

BACKGROUND/AIMS: Both total parenteral nutrition and long-term octreotide treatment (> 2 months) may induce biliary sludge and lithiasis. However, the lithogenic capacity of the combination of the two treatments in the short-term is unknown. This study was undertaken to evaluate the lithogenic capacity of short-term octreotide treatment (< 1 month) in patients with acute pancreatitis who are also receiving total parenteral nutrition, and to determine the evolution of patients who develop biliary sludge and/or lithiasis. METHODOLOGY: Thirty patients with acute pancreatitis were studied (21 males, 9 females; average age: 38). All patients received total parenteral nutrition and analgesics. In a double-blind random manner, 15 patients were treated with a continuous subcutaneous administration of octreotide (200 micrograms/8 h) and a further 15 patients received placebo. Biliary sludge and/or lithiasis were examined by ultrasonography. An echographic examination of the gallbladder was performed every seven days while the patients were in hospital. They were followed up every month, when another ultrasound of the gallbladder was carried out. RESULTS: Sixteen patients (53%) developed sludge: ten (67%) from the octreotide group and six (33%) from the placebo group (P = 0.29). Two of the patients from the octreotide group had microlithiasis (P = 0.34) and a cholecystectomy was required. In the other 14 patients, sludge had disappeared by the time of the check-up performed one month after discharge. CONCLUSIONS: Short-term octreotide treatment does not increase the risk of developing biliary sludge and/or lithiasis in patients also receiving total parenteral nutrition. Biliary sludge formed during total parenteral nutrition and short-term octreotide therapy may disappear when patients begin oral intake. Therefore, preventive measures are not required.

Modulatory effect of nitric oxide on mast cells during induction of dextran sulfate sodium colitis.

Nitric oxide (NO) is implicated in the pathophysiology of intestinal inflammation. Intestinal mast cells may amplify inflammatory response and mucosal injury in inflammatory bowel disease. Our aim was to examine the role of NO and intestinal mast cells by investigating the effects of NO synthase (NOS) inhibitors and a mast cell stabilizer during induction of dextran sulfate sodium (DSS) colitis. Colitis was induced by 4% DSS in drinking water, in rats pretreated with L-NAME or aminoguanidine. In another set of experiments, we investigated the effect of ketotifen in this setting. Inhibition of NO by L-NAME worsened DSS-induced inflammation, however, aminoguanidine had no effect. On the other hand, ketotifen abolished the deleterious effects of L-NAME on colonic inflammation, suggesting that hyperactivation of mast cells by NOS inhibition amplifies mucosal injury induced by DSS. Our results suggest that constitutive isoforms of NOS prevent mast cell activation.

Long-term efficacy of octreotide in the prevention of recurrent bleeding from gastrointestinal angiodysplasia.

OBJECTIVES: Preliminary studies suggested that octreotide may be therapeutic in bleeding angiodysplasia. Our aim was to investigate the efficacy of long-term octreotide therapy in the prevention of rebleeding from gastrointestinal angiodysplasia. METHODS: A cohort of 32 patients diagnosed with bleeding from angiodysplasia was treated with octreotide 50 mu 12 h subcutaneously for a 1-2 yr period. This cohort was compared with an external control group (38 patients who had received placebo [1 tablet/day] in a concurrent randomized clinical trial for the same period. RESULTS: Two patients of the octreotide group were lost to follow-up. Treatment failure occurred in seven of 30 (23%) patients in the octreotide group and in 17 of 35 (48%) in the placebo group (three dropouts before first visit) (P= 0.043). The actuarial probability of remaining free of rebleeding at 1 and 2 yr of follow-up was 77% and 68%, respectively, for the octreotide group and 55% and 36%, respectively, for the placebo group (log rank P= 0.030). Multivariate proportional hazards-regression analysis showed that octreotide therapy and previous bleeding episodes were positive and negative predictors of efficacy, respectively. No significant differences between the groups were observed according to number of bleeding episodes (0.4 +/- 0.7 vs 0.9 +/- 1.5, P= 0.070) and transfusion requirements (1.1 +/- 2.6 vs 0.7 +/- 1.5 units); however, iron requirements were lower in the octreotide than in the placebo group (22 +/- 62 vs 166 +/- 267 units; P < 0.001). Likewise, major adverse events (1 vs 1) and mortality (0 vs 1) were similar between groups. CONCLUSIONS: This study suggests that octreotide treatment may be beneficial in preventing rebleeding from gastrointestinal angiodysplasia.

Polyethylene glycol enhances colonic barrier function and ameliorates experimental colitis in rats.

OBJECTIVE: Polyethylene glycol (PEG) has been suggested to protect against pathogen colonization by improving colonic barrier function. We aimed to establish whether PEG 4000 affects colonic barrier function and the development of colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) in rats. MATERIALS AND METHODS: PEG was included in the drinking water for a period of 48 h before intracolonic administration of TNBS. RESULTS AND DISCUSSION: PEG increased colonic surface hydrophobicity and diminished luminal bacterial load. Moreover, PEG markedly reduced mucosal damage and inflammation induced by TNBS. This protection effect appeared to be independent of its laxative properties since the laxatives mannitol or senna extracts had no effect on TNBS colitis. Using everted colonic sacs, pretreatment with PEG produced a lasting reduction in epithelial permeability to mannitol and dextran-70 K that correlated with decreased surface hydrophobicity. CONCLUSION: Our results suggest that the protective effect of PEG on TNBS colitis is associated with reinforcement of the epithelial barrier.

Anisakis simplex-induced small bowel obstruction after fish ingestion: preliminary evidence for response to parenteral corticosteroids.

BACKGROUND & AIMS: Gastrointestinal anisakiasis, a fish-borne zoonoses, may be acquired by humans after the ingestion of raw marine fish infested with larvae of the nematode Anisakis simplex. Because of the invasive nature of the parasite, inflammatory obstruction or perforation of the gut wall may result. Although rare, Anisakis-induced intestinal obstruction is becoming a growing public health problem in Mediterranean areas, such as Spain, with a high fish-intake-based diet. Unawareness of this entity and nonspecific clinical symptoms, along with the lack of alternative therapeutic options other than conservative measures, may explain why half of these patients require abdominal laparotomy for diagnostic and therapeutic purposes. METHODS: We describe a series of 8 patients with acute intestinal anisakiasis treated in our center from July 2001 to January 2004. RESULTS: The first 3 patients underwent segmental ileal resection for imminent peritonitis. The remaining 5 patients were treated with intravenous 6-methylprednisolone (1 mg/kg/24 h) for 5 days with fast clinical and radiologic resolution in all 5 patients with no adverse reactions. CONCLUSIONS: Although preliminary, our data may suggest that parenteral corticosteroids could be a reasonable, inexpensive, and safe alternative in these patients to prevent intestinal resection.

Outcome of patients with ischemic colitis: review of fifty-three cases.

PURPOSE: Ischemic colitis is a disease of elderly patients and includes a wide clinical spectrum ranging from mild to severe forms. Some patients may develop complications. Management of this disorder depends on disease severity. Our aim was to review the clinical characteristics of patients diagnosed of ischemic colitis and analyze predictive factors of poor prognosis. METHODS: This study is a retrospective analysis of 53 cases of ischemic colitis (33 men, 20 women), 35 with moderate and 18 with severe forms, respectively. Clinical characteristics, diagnostic procedures, segment of colon involved and long-term evolution after discharge were analyzed. RESULTS: Hypertension (51 percent) was the main risk factor associated with ischemic colitis. Clinical presentation did not differ between groups, except for peritonitis which was present only in the severe group. Colonoscopy and histologic studies were the most used diagnostic procedures (90 percent). Peripheral vasculopathy (P < 0.01) and right colonic involvement (P < 0.001) were risk factors for severe outcome. Five patients died during admission. Among these, the right colon was affected in four (80 percent). No patient in either group developed chronic ischemic colitis during follow-up. CONCLUSION: Ischemic colitis usually runs a benign course after acute colonic insult. Peripheral vasculopathy and right colonic involvement are associated with severe forms of ischemic colitis.

Increased activity and expression of matrix metalloproteinase-9 in a rat model of distal colitis.

Matrix metalloproteinases may play a role in tissue remodelling and destruction associated with inflammation. We investigated activity and expression of matrix metalloproteinases in a rat model of colitis and tested the therapeutic potential of a synthetic inhibitor (CGS-27023-A). Colitis was induced by dextran sulphate sodium (at 5% in drinking water for 5 days) in a group of eight rats, whereas a matched control group received plain water. Activity and expression of matrix metalloproteinases were measured in colonic tissue homogenates using zymography and Western blot on days 3 and 5 after induction of colitis. In another set of experiments, two groups of colitic rats (20 per group) were treated with CGS-27023-A (20 mg/kg) or vehicle, respectively. On days 5 and 14, colonic mucosal lesions were blindly scored by microscopic examination. Induction of colitis led to a significant upregulation of matrix metalloproteinase-9 protein and its activity, but no change in matrix metalloproteinase-2 activity was observed. Treatment with CGS-27023-A significantly decreased the extent and severity of epithelial injury but did not influence mucosal repair. We conclude that increased activity of matrix metalloproteinases may contribute to epithelial damage in this model of colitis.