ABSTRACT
Crohn 's disease is characterized by a chronic relapsing inflammation of the bowel in which pro-inflammatory cytokines play an important role. Rebamipide is an anti-gastric ulcer drug with anti-inflammatory properties in vivo and in vitro. The effects of rebamipide on Crohn 's disease have not been carefully evaluated. This study investigated the potential of rebamipide to protect Crohn 's disease using a murine model of colitis induced by trinitrobenzene sulfonic acid (TNBS). Rebamipide dramatically improved histopathological symptom involving myeloperoxidase (MPO)activation and increase of microscopic damage score in TNBS induced colitis. Rebamipide suppressed IL-8 secretion, ICAM-1 induction and nuclear factor-kappaB (NF-kappaB) activation by TNF-alpha and induced heme oxygenase-1(HO-1)in HT-29 cells. HO-1 inducer cobalt protoporphyrin IX (CoPPIX)suppressed NF-kappaB activation by TNF-alpha in HT-29 cells like rebamipide, and mimicked the protective effects of rebamipide on TNBS induced colitis. This suggests that rebamipide exerts anti-inflammatory effects by down-regulating NF-kappaB activity via inducting HO-1 expression. In conclusion, this study suggests that rebamipide represents a potential therapeutic agent and HO-1 is an important therapeutic target for the treatment of Crohn's disease.
Subject(s)
Humans , Cobalt , Colitis , Colon , Crohn Disease , Cytokines , Down-Regulation , Heme Oxygenase (Decyclizing) , Heme , HT29 Cells , Inflammation , Intercellular Adhesion Molecule-1 , Interleukin-8 , NF-kappa B , Peroxidase , Tumor Necrosis Factor-alpha , UlcerABSTRACT
Heme oxygenase-1 (HO-1) is a stress-inducible enzyme with anti-inflammatory activity, but the mechanisms underlying this activity are incompletely understood. Nuclear transcription factor kappa B (NF-kappa B) activation is an important factor in the pathogenesis of inflammatory bowel disease (IBD). We investigated the suppressive effects of HO-1 on the activation of NF-kappa B by pro-inflammatory cytokines in cultured colonic epithelial cells and by trinitrobenzene sulfonic acid (TNBS) in the colon of mice. The expression level of HO-1 in the colonic epithelium of a patient with inflammatory bowel disease and pseudo-membranous colitis was lower than that in a healthy control subject. In cultured human colonic epithelial HT-29 cells, pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha ) and IL-1 beta down-regulate HO-1 expression. The HO-1 inducer, cobalt protoporphyrin IX (CoPPIX), dramatically down-regulated NF-kappa B activation in HT-29 cells by TNF-alpha. In addition, bilirubin-a product of heme catabolism by HO-1-and the carbon monoxide donor tricarbonyldichlororuthenium (II) dimer also suppressed NF-kappa B activation by TNF-alpha. However, iron, another heme metabolite, did not suppress NF-kappa B activation by TNF-alpha. Furthermore, CoPPIX diminished the macroscopic and histopathological symptoms of TNBS-induced colitis and down-regulated NF-kappa B activation in mice. In conclusion, this study suggests that HO-1 plays an important role in the down-regulation of NF-kappa B activation, which is a key factor in the pathogenesis of IBD and is thus an excellent therapeutic target for the treatment of IBD.
Subject(s)
Animals , Humans , Mice , Carbon Monoxide , Cobalt , Colitis , Colon , Cytokines , Down-Regulation , Epithelial Cells , Epithelium , Heme Oxygenase-1 , Heme , HT29 Cells , Inflammation , Inflammatory Bowel Diseases , Interleukin-1beta , Iron , Metabolism , NF-kappa B , Tissue Donors , Transcription Factors , Tumor Necrosis Factor-alphaABSTRACT
PURPOSE: To evaluate the prognosis of patients with paraquat poisoning by measuring the extent of lunginvolvement, as seen on HRCT. MATERIALS AND METHODS: Forty-one patients with paraquat poisoning were treatedaccording to our hospital's routine protocol and underwent HRCT scanning 1-21(mean 7-8) days later. In 31, theresults were abnormal, and these were retrospectively analysed. Differences in the extent of lung involvement,patient age, ingested amount of paraquat, and blood WBC count were compared between the group of survivors andthose who had died. RESULTS: Among the 31 patients with abnormal HRCT findings, 11 died and 20 patients survived.The extent of lung involvement among the group of survivors was 14.8+/-14.8%; among the deceased group, it was72.3+/-16.3%. The age of the survivors was 37.5+/-13.5(11-67) years, while that of the deceased was25+/-8.9(16-41)years. Those who died showed a significantly higher extent of lung involvement than the survivors,and were younger (p0.05). CONCLUSION: In paraquat poisoning, the extent of lung involvement onHRCT, is useful for prediction of the prognosis and severity of poisoning.