The PPARγ On Ulcerative Colitis And Therapeutic Effect Of Rosiglitazone

PART â…  : The Therapeutic Effect of Rosiglitazone for Ulcentive ColitisObjective Etiology and pathogenesis of ulcerative colitis (UC) are still unknown and there are no important breakthroughs of its treatment. Recently as being deeply understood of the pathogenesis, the treatment could be aimed with more targets and achieved more progresses. Nuclear factor kappa B (NF-kB), a multifunctional transcriptional factor, plays an important role in UC and controls various functions of immune cells. Peroxisome proliferators-activated receptor gamma (PPAR 7) can down-regulate the overactive immune reaction through inhibiting NF-kB and reducing transcription and expression of pro-inflammatory cytokines. Thiazolidinediones (TZDs) , a high affinity ligands to PPAR 7, such as rosiglitazone used for the 2 type diabetes treatment at first, can inhibit the pro-inflammatory gene's expression in macrophages. James D etc. reported that UC patients treated by 5-aminosalicylic acid (5-ASA) and rosiglitazone have achieved clinical and endoscopic remissions. However, the conclusion from this open trial with small sized samples needs to be testified by furtherstudying. Therefore in this therapeutic trial the clinical , endoscopic and histological changes as well as related cytokines' expressions are observed for the approach of PPAR7ligands in UC treatment.Methods From July to November 2004, 42 chronic mild or moderate active UC, were included and randomly divided into treatment group and control group . Rosiglitazone (4mg. po. qd) plus SASP (3 g /d) or 5-ASA (2g/d) and SASP or 5-ASA along were used I two groups for 4 weeks respectively, Infectious colitis, intestinal amoebiasis have been excluded and at same time these with heart ^ renal or hepatic failure were also excluded. Those patients who had been treated with corticosteroids or immunosuppressants in recent 1 month were excluded, too. All patients had been observed for 4 weeks and sigmoidoscoped in the end of observation.Results Clinical, endoscopic and histological remission rates (71.4 % vs. 57.1 %, 76.19% vs. 60.67%) and histological remission of treatment group are higher than control. Compared with control, the expression of PPAR7 are obviously higher in treatment group as well as their expression of NF-kB are markedly lower after treatment than before. No side-effect was found.Conclusion PPAR7 expression in active UC was low and ligands of PPARYcan promote its expression. Through inhibition of activation of NF-kB PPARYcan reduce colonic inflammation and further studies are required for its mechanism. Co-administration of rosiglitazone and 5-ASA can achieve better therapic effects than use 5-ASA only. It may represent a novel approach of UC treatment.PART IIThe PPARy on mice oxalzolone colitisObjective: Intestinal lesion of UC is realized not only the epithelial inflammation and necrosis but also to its excessive apoptosis. Recently many studies reported that PPAR7 involve in the inflammation and apoptosis of UC. In this study, pioglitazone was used in mice oxalzolone colitis and disease activity inflammatory factors and apoptosis-associated factors (Fas> FasI^ Caspase-3) of the colon were investigated.Methods At first mice oxalzolone colitis models were established then divided them into two groups , treatment group and control , the former treated with pioglitazone. The body weight, disease active index (DAI) were recorded and killed two groups mice atlCK IK ^ 13 day in two groups . Macrographic and histological changes were observed. The expression levels of PPARy^ NF-kB p65s Fas^ FasL ,caspas-3 were evaluated by immunohistochemical methods (IHC).Results The body weight recovery of treatment group was better and DAI lower than control. Compared with control, expressions of PPAR7were increased and NF-kB p65 > Fas > FasL. caspas-3 were decreased in pioglitazone group.Conclusion In oxalzolone colitis mice, expressions of PPARy were increased and NF-kB p65 > Fas -, FasL > caspas-3 were various decreased related following PPARy ligands treatment with decreased of colonic inflammation accordingly . This observation showed that PPARy have abilities to inhibit activation of NF-kB and apoptosis of colonic epithelial cells. The resultsupported that pioglitazone, PPARy ligands, can increase expression of PPAR7 and decreased colonic inflammation, also may inhibit excess apoptosis of intestinal epithelial cells .