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Madecassoside ameliorates bleomycin-induced pulmonary fibrosis in mice through
promoting the generation of hepatocyte growth factor via PPAR-? in colon
#MMPMID26750154
Xia Y
; Xia YF
; Lv Q
; Yue MF
; Qiao SM
; Yang Y
; Wei ZF
; Dai Y
Br J Pharmacol
2016[Apr]; 173
(7
): 1219-35
PMID26750154
show ga
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-? pathway, as shown by an up-regulation
of PPAR-? mRNA expression, nuclear translocation and DNA-binding activity both in
vitro and in vivo. Also GW9662, a selective PPAR-? 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-?,
which subsequently increases HGF expression in colonic epithelial cells. HGF then
enters into the circulation and lung tissue to exert an anti-PF effect.
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