Betulinic acid hydroxamate prevents colonic inflammation and fibrosis in murine models of inflammatory bowel disease  

作　　者：María EPrados Adela García-Martín Juan DUnciti-Broceta Belén Palomares Juan ACollado Alberto Minassi Marco ACalzado Giovanni Appendino Eduardo Muñoz 

机构地区：[1]Emerald Health Biotechnology,Cordoba,Spain [2]Maimonides Biomedical Research Institute of Cordoba,Cordoba,Spain [3]Department of Cellular Biology,Physiology and Immunology,University of Cordoba,Cordoba,Spain [4]University Hospital Reina Sofia,Cordoba,Spain [5]Department of Drug Science,University of Piemonte Oriental,Novara,Italy

出　　处：《Acta Pharmacologica Sinica》2021年第7期1124-1138,共15页中国药理学报（英文版）

基　　金：We thank Carmen-Cabrero for revising the manuscript.This work was supported by grants RTC-2017-6109-1(EM)from the Ministry of the Economy and Competition(MINECO)and was co-financed with European Union FEDER funds.This work was also partially supported by Emerald Health Biotechnology Espana(Cordoba,Spain).

摘　　要：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, α-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.

关 键 词：inflammatory bowel disease colon inflammation FIBROSIS betulinic acid hydroxamate hypoxia-inducible factor prolyl hydroxylases TNBS DSS 

分 类 号：R96[医药卫生—药理学]