Intestinal fibrosis is a common complication of inflammatory bowel disease(IBD)and is defined as an excessive accumulation of scar tissue in the intestinal wall.Intestinal fibrosis occurs in both forms of IBD:ulcerative colitis and Crohn's disease.Small-molecule inhibitors targeting hypoxia-inducing factor(HIF)prolyl-hydroxylases are promising for the development of novel antifibrotic therapies in IBD.Herein,we evaluated the therapeutic efficacy of hydroxamate of betulinic acid(BHA),a hypoxia mimetic derivative of betulinic acid,against IBD in vitro and in vivo.We showed that BAH(5-20 μM)dose-dependently enhanced collagen gel contraction and activated the HIF pathway in NIH-3T3 fibroblasts;BAH treatment also prevented the loss of trans-epithelial electrical resistance induced by proinflammatory cytokines in Caco-2 cells.In two different murine models(TNBS-and DSS-induced IBD)that cause colon fibrosis,oral administration of BAH(20,50 mg/kg·d,for 17 days)prevented colon inflammation and fibrosis,as detected using immunohistochemistry and qPCR assays.BAH-treated animals showed a significant reduction of fibrotic markers(Tnc,Col1a2,Col3a1,Timp-1,a-SMA)and inflammatory markers(F4/80+,CD3+,Il-1β,Ccl3)in colon tissue,as well as an improvement in epithelial barrier integrity and wound healing.BHA displayed promising oral bioavailability,no significant activity against a panel of 68 potential pharmacological targets and was devoid of genotoxicity and cardiotoxicity.Taken together,our results provide evidence that oral administration of BAH can alleviate colon inflammation and colitis-associated fibrosis,identifying the enhancement of colon barrier integrity as a possible mechanism of action,and providing a solid rationale for additional clinical studies.
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