Madecassoside ameliorates bleomycin-induced pulmonary fibrosis in mice through promoting the generation of hepatocyte growth factor via PPAR-γ in colon.

Abstract

BACKGROUND AND PURPOSE:

Madecassoside has potent anti-pulmonary fibrosis (PF) effects when administered p.o., despite having extremely low oral bioavailability. Herein, we explored the mechanism of this anti-PF effect with regard to gut hormones.

EXPERIMENTAL APPROACH:

A PF model was established in mice by intratracheal instillation of bleomycin. Haematoxylin and eosin stain and Masson's trichrome stain were used to assess histological changes in the lung. Quantitative-PCR and Western blot detected mRNA and protein levels, respectively, and cytokines were measured by ELISA. Small interfering RNA was used for gene-silencing. EMSA was applied to detect DNA-binding activity.

KEY RESULTS:

Administration of madecassoside, p.o., but not its main metabolite madecassic acid, exhibited a direct anti-PF effect in mice. However, i.p. madecassoside had no anti-PF effect. Madecassoside increased the expression of hepatocyte growth factor (HGF) in colon tissues, and HGF receptor antagonists attenuated its anti-PF effect. Madecassoside facilitated the secretion of HGF from colonic epithelial cells by activating the PPAR-γ pathway, as shown by an up-regulation of PPAR-γ mRNA expression, nuclear translocation and DNA-binding activity both in vitro and in vivo. Also GW9662, a selective PPAR-γ antagonist, almost completely prevented the madecassoside-induced increased expression of HGF and amelioration of PF.

CONCLUSIONS AND IMPLICATIONS:

The potent anti-PF effects induced by p.o. madecassoside in mice are not mediated by its metabolites or itself after absorption into blood. Instead, madecassoside increases the activity of PPAR-γ, which subsequently increases HGF expression in colonic epithelial cells. HGF then enters into the circulation and lung tissue to exert an anti-PF effect.

• Authors: Ying Xia, Yu-Feng Xia, Qi Lv, Meng-Fan Yue, Si-Miao Qiao, Yan Yang, Zhi-Feng Wei, Yue Dai
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 173 Issue 7 Pg. 1219-35 (Apr 2016) ISSN: 1476-5381 [Electronic] England
• PMID: 26750154 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 The British Pharmacological Society.

Chemical References

• PPAR gamma
• Triterpenes
• Bleomycin
• Hepatocyte Growth Factor
• madecassoside
• madecassic acid

Topics

• Animals
• Bleomycin
• Cell Line, Tumor
• Cell Survival (drug effects)
• Colon (drug effects, metabolism)
• Female
• Gene Silencing
• Hepatocyte Growth Factor (antagonists & inhibitors, metabolism)
• Intestinal Mucosa (drug effects, metabolism)
• Lung (drug effects, pathology)
• Mice, Inbred ICR
• PPAR gamma (antagonists & inhibitors, genetics, metabolism)
• Pulmonary Fibrosis (chemically induced, drug therapy, metabolism)
• Triterpenes (pharmacology, therapeutic use)