In vivo inefficiency of pentoxifylline and interferon-alpha on hepatic fibrosis in biliary-obstructed rats: assessment by tissue collagen content and prolidase activity.

BACKGROUND AND AIM: To evaluate the possible antifibrotic effects of two drugs, pentoxifylline (PTX) and interferon (IFN)-alpha as well as their combination, on a bile-duct-ligated rat hepatic fibrosis model. METHODS: Bile ducts of 34 female Wistar rats were ligated, and 24 bile ducts were sham operated. Bile-duct-ligated rats were divided into four groups, in which either sterile saline, IFN-alpha (100 000 IU/3 days a week), PTX (50 mg/kg/day) or IFN-alpha + PTX were administered. Sham-operated rats were treated at the same doses. On the 28th day, rats were decapitated to obtain blood for the measurements of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT) and bilirubins. Serum prolidase was assayed at the beginning and at the end of the study by the modified Chinard's colorimetric method. Liver prolidase was assayed after tissue homogenization. Liver collagen content was determined by the dye elution method described by Lopez de Leon. Morphometric-densitometric measurements of hepatic fibrosis were quantified by computerized image analysis. RESULTS: The AST, ALT, ALP, GGT and bilirubins, liver prolidase enzyme activity, collagen content and hepatic collagen surface density were found to be increased in bile-duct-ligated rats on day 28. There was no statistically significant recovery or even a change in collagen turnover rate in rats treated with alternate regimens applied in the study (P > 0.05). CONCLUSION: Pentoxifylline, IFN-alpha and their combination have no beneficial effect on experimental fibrosis induced by biliary obstruction.

Estradiol treatment ameliorates acetic acid-induced gastric and colonic injuries in rats.

To evaluate the role of estrogen treatment on the healing of acetic acid-induced gastric or colonic injury, rats were given 17beta estradiol benzoate (0.001, 0.1, and 10 mg/kg) or vehicle for 7 days (following the induction of ulcer) or 4 days (following the induction of colitis) until they were decapitated. Food intake and fecal output were decreased by estradiol treatment but gastric emptying rate was not changed. Estradiol (10 mg/kg) reduced gastric ulcer index and colonic damage score compared to vehicle-treated groups. SEM and light microscopy demonstrated a significant reduction in the severity of ulcers and colitis by estradiol treatment. Gastric microscopic score was not changed by estradiol treatment, whereas in the colonic tissue score was significantly reduced. Elevated gastric MPO levels were reduced in gastric but not in colonic tissues as compared with corresponding vehicle groups. In conclusion, exogenous estradiol treatment at pharmacological doses improves the healing of both gastric and colonic injury induced by acetic acid in rats.

Healing-promoting effect of bombesin treatment on chronic gastric ulcer in rats.

To evaluate whether bombesin treatment has a facilitatory effect on the healing of chronic gastric ulcer, following the induction of ulcer by serosal application of acetic acid, rats were given bombesin (30 microg/kg/day; subcutaneously) or vehicle three times a day for 7, 14 or 21 days until they were decapitated. Neither food intake nor gastric emptying rate in either vehicle-treated or bombesin-treated groups was not statistically different from control rats. Similarly, ulcer indices and gastric myeloperoxidase (MPO) activities at the first and second weeks of injury were not different among the groups. However, in the 3-week ulcer group, bombesin treatment reduced tissue MPO level significantly back to control levels. Moreover, the analysis of the surface epithelium by scanning electron and light microscopy demonstrated a significant reduction in the severity of ulcers by bombesin treatment. Pretreatment with CCK antagonists (L-364,718 or L365,260; 25 micromol/kg/day) before bombesin treatment showed that neither of the CCK antagonists had a significant effect on the bombesin-mediated healing process, suggesting that CCK receptors are not involved in the action of bombesin. In accordance with the previous studies that show its acute gastroprotective effects, bombesin is also effective in promoting the healing process of chronic gastric ulcer in rats.

Protective role of cyclooxygenase (COX) inhibitors in burn-induced intestinal and liver damage.

The aim of this study was to investigate the role of cyclooxygenase (COX) inhibition in intestinal motility and in the extent of tissue injury of the small intestine and liver with the use of various COX inhibitors. Wistar albino rats were exposed to 90 degrees C water bath for 10s. The intestinal transit index decreased compared to control group and treatment with nimesulide (NIM; 10mg/kg, subcutaneously) or piroxicam (Pir; 5mg/kg, orogastrically) reversed this effect significantly. The intestinal and liver glutathione levels showed a significant decrease in the burn group compared to sham (P<0.001 and P<0.05, respectively). Decrease in intestinal glutathione level was reversed by NIM or Pir treatment (P<0.01 and P<0.01, respectively), whereas all drugs tested were effective in reversing low liver glutathione level. The MPO activity in intestinal segments were significantly high in burned animals compared to sham. All test drugs reversed this effect but ketorolac (Ket; 3mg/kg, orogastrically) was the most effective one. The liver samples characterized by sinusoidal dilatation and pericentral atrophy in burn group were protected by treatment with Ket or Pir (P<0.05). Plasma ALT and AST activities were markedly high in this burn group compared to sham (P<0.0001 and P<0.001, respectively). None of the agents reversed these high enzyme activities. These data suggest that not only COX-2 but also COX-1 inhibition is required for protection against inflammatory changes in liver and small intestine following burn injury.

Endothelin receptor blockers reduce I/R-induced intestinal mucosal injury: role of blood flow.

The aim of the present study was to assess the role of endothelin (ET) in ischemia-reperfusion (I/R)-induced mucosal injury. Mucosal permeability ((51)Cr-EDTA clearance) and tissue myeloperoxidase (MPO) activity were significantly increased after 30 min of ischemia followed by 30 min of reperfusion. The I/R-induced increases in mucosal permeability and polymorphonuclear leukocyte (PMN) infiltration were significantly attenuated by pretreatments with ET(A) (BQ-485) and/or ET(B) (BQ-788) receptor antagonists. Monoclonal antibody (MAb) directed against intercellular adhesion molecule-1 (ICAM-1; MAb 1A29) and superoxide dismutase (SOD) pretreatments significantly attenuated the increased mucosal permeability and PMN infiltration in a similar manner as with ET receptor antagonists. Superior mesenteric artery blood flow was significantly reduced during the reperfusion period. Both ET receptor antagonists caused a significant rise in blood flow compared with an untreated I/R group. In conclusion, our data suggest that ET(A) and/or ET(B) receptors, ICAM-1, and superoxide play an important role in I/R-induced mucosal dysfunction and PMN infiltration. Furthermore, ET is involved in the pathogenesis of post-reperfusion-induced damage and beneficial effects of ET receptor antagonism are related to an improvement of disturbed blood flow during the reperfusion period.