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
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2021,（3）
• 所属期刊栏目: Pulmonary and Renal Pharmacology
• 页码范围: 422-435
• 页数: 14页
• 语种: 英文

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 Si02-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(5-40 μM)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 PPARy and CREB,whereas PPARy antagonist GW9662(1 μM)or cAMP response element(CREB)inhibitor KG-501(10 μM)significantly decreased the boosting effect of curcumin on HGF expression.Finally,we revealed that curcumin dose-dependently increased the production of 15-deoxy-△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 PPARy and CREB via an induction of 15d-PGJ2,and the HGF enters the lungs giving rise to an anti-PF effect.