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Pancreas. 2009 May;38(4):427-35. doi: 10.1097/MPA.0b013e3181967670.

Inhibition of transforming growth factor beta signaling by halofuginone as a modality for pancreas fibrosis prevention.

Author information

1
Institute of Animal Sciences, The Volcani Center, Bet Dagan, Israel.

Abstract

OBJECTIVES:

Chronic pancreatitis is characterized by inflammation and fibrosis. We evaluated the efficacy of halofuginone, an inhibitor of collagen synthesis and myofibroblast activation, in preventing cerulein-induced pancreas fibrosis.

METHODS:

Collagen synthesis was evaluated by in situ hybridization and staining. Levels of prolyl 4-hydroxylase beta (P4Hbeta), cytoglobin/stellate cell activation-associated protein (Cygb/STAP), transgelin, tissue inhibitors of metalloproteinases, serum response factor, transforming growth factor beta (TGFbeta), Smad3, and pancreatitis-associated protein 1 (PAP-1) were determined by immunohistochemistry. Metalloproteinase activity was evaluated by zymography.

RESULTS:

Halofuginone prevented cerulein-dependent increase in collagen synthesis, collagen cross-linking enzyme P4Hbeta, Cygb/STAP, and tissue inhibitors of metalloproteinase 2. Halofuginone did not affect TGFbeta levels in cerulein-treated mice but inhibited serum response factor synthesis and Smad3 phosphorylation. In culture, halofuginone inhibited pancreatic stellate cell (PSC) proliferation and TGFbeta-dependent increase in Cygb/STAP and transgelin synthesis and metalloproteinase 2 activity. Halofuginone increased c-Jun N-terminal kinase phosphorylation in PSCs derived from cerulein-treated mice. Halofuginone prevented the increase in acinar cell proliferation and further increased the cerulein-dependent PAP-1 synthesis.

CONCLUSIONS:

Halofuginone inhibits Smad3 phosphorylation and increases c-Jun N-terminal kinase phosphorylation, leading to the inhibition of PSC activation and consequent prevention of fibrosis. Halofuginone increased the synthesis of PAP-1, which further reduces pancreas fibrosis. Thus, halofuginone might serve as a novel therapy for pancreas fibrosis.

PMID:
19188864
DOI:
10.1097/MPA.0b013e3181967670
[Indexed for MEDLINE]

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