Oral administration of curcumin ameliorates pulmonary fibrosis in mice through 15d-PGJ2-mediated induction of hepatocyte growth factor in the colon  

作　　者：Yu-meng Miao Ya-jing Zhang Si-miao Qiao Yu-feng Xia Zhi-feng Wei Yue Dai 

机构地区：[1]Department of Pharmacology of Chinese Materia Medica,School of Traditional Chinese Pharmacy,China Pharmaceutical University,Nanjing 210009,China

出　　处：《Acta Pharmacologica Sinica》2021年第3期422-435,共14页中国药理学报（英文版）

基　　金：supported by the"Double First-Class"University Project(CPU2018GY10);the University Innovation Research and Training Program of China Pharmaceutical University(201610316123).

摘　　要：Oral administration of curcumin has been shown to inhibit pulmonary fibrosis(PF)despite its extremely low bioavailability.In this study,we investigated the mechanisms underlying the anti-PF effect of curcumin in focus on intestinal endocrine.In bleomycin-and SiO2-treated mice,curcumin(75,150 mg·kg^(−1)per day)exerted dose-dependent anti-PF effect when administered orally or rectally but not intravenously,implying an intestinal route was involved in the action of curcumin.We speculated that curcumin might promote the generation of gut-derived factors and the latter acted as a mediator subsequently entering the lungs to ameliorate fibrosis.We showed that oral administration of curcumin indeed significantly increased the expression of gut-derived hepatocyte growth factor(HGF)in colon tissues.Furthermore,in bleomycin-treated mice,the upregulated protein level of HGF in lungs by oral curcumin was highly correlated with its anti-PF effect,which was further confirmed by coadministration of c-Met inhibitor SU11274.Curcumin(5−40μM)dose-dependently increased HGF expression in primary mouse fibroblasts,macrophages,CCD-18Co cells(fibroblast cell line),and RAW264.7 cells(monocyte-macrophage cell line),but not in primary colonic epithelial cells.In CCD-18Co cells and RAW264.7 cells,curcumin dose-dependently activated PPARγand CREB,whereas PPARγantagonist GW9662(1μM)or cAMP response element(CREB)inhibitor KG-501(10μM)significantly decreased the boosting effect of curcumin on HGF expression.Finally,we revealed that curcumin dose-dependently increased the production of 15-deoxy-Δ^(12,14)-prostaglandin J2(15d-PGJ2)in CCD-18Co cells and RAW264.7 cells,which was a common upstream of the two transcription factors.Moreover,both the in vitro and in vivo effects of curcumin were diminished by coadministration of HPGDS-inhibitor-1,an inhibitor of 15d-PGJ2 generation.Together,curcumin promotes the expression of HGF in colonic fibroblasts and macrophages by activating PPARγand CREB via an induction of 15d-PGJ2,and the HGF enter

关 键 词：CURCUMIN pulmonary fibrosis COLON intestinal endocrine hepatocyte growth factor 15D-PGJ2 

分 类 号：R285[医药卫生—中药学]