Stimulating healthy tissue regeneration by targeting the 5-HT2B receptor in chronic liver disease

被引：182

作者：

Ebrahimkhani, Mohammad R. ^{[1
,2
]}

Oakley, Fiona ^{[1
]}

Murphy, Lindsay B. ^{[1
]}

Mann, Jelena ^{[1
]}

Moles, Anna ^{[1
]}

Perugorria, Maria J. ^{[1
]}

Ellis, Elizabeth ^{[1
]}

Lakey, Anne F. ^{[1
]}

Burt, Alastair D. ^{[1
]}

Douglass, Angela ^{[1
]}

Wright, Matthew C. ^{[1
]}

White, Steven A. ^{[1
]}

Jaffre, Fabrice ^{[3
,4
,5
]}

Maroteaux, Luc ^{[3
,4
,5
]}

Mann, Derek A. ^{[1
]}

机构：

[1] Newcastle Univ, Fibrosis Lab, Liver Grp, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[2] MIT, Ctr Environm Hlth Sci, Dept Biol Engn, Dept Biol, Cambridge, MA 02139 USA

[3] INSERM, Unite Mixte Rech S 839, Paris, France

[4] Univ Paris 06, Paris, France

[5] Inst Fer Moulin, Paris, France

来源：

NATURE MEDICINE | 2011年 / 17卷 / 12期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

HEPATIC STELLATE CELLS; BILE-DUCT LIGATION; FIBROSIS; RAT; GROWTH; INJURY; JUND; PROLIFERATION; TRANSCRIPTION; ANTAGONIST;

D O I：

10.1038/nm.2490

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Tissue homeostasis requires an effective, limited wound-healing response to injury. In chronic disease, failure to regenerate parenchymal tissue leads to the replacement of lost cellular mass with a fibrotic matrix. The mechanisms that dictate the balance of cell regeneration and fibrogenesis are not well understood(1). Here we report that fibrogenic hepatic stellate cells (HSCs) in the liver are negative regulators of hepatocyte regeneration. This negative regulatory function requires stimulation of the 5-hydroxytryptamine 2B receptor (5-HT2B) on HSCs by serotonin, which activates expression of transforming growth factor beta 1 (TGF-beta 1), a powerful suppressor of hepatocyte proliferation, through signaling by mitogen-activated protein kinase 1 (ERK) and the transcription factor JunD. Selective antagonism of 5-HT2B enhanced hepatocyte growth in models of acute and chronic liver injury. We also observed similar effects in mice lacking 5-HT2B or JunD or upon selective depletion of HSCs in wild-type mice. Antagonism of 5-HT2B attenuated fibrogenesis and improved liver function in disease models in which fibrosis was pre-established and progressive. Pharmacological targeting of 5-HT2B is clinically safe in humans and may be therapeutic in chronic liver disease.

引用

页码：1668 / U189

页数：7

共 31 条

[1]

LIPOCYTES FROM NORMAL RAT-LIVER RELEASE A NEUTRAL METALLOPROTEINASE THAT DEGRADES BASEMENT-MEMBRANE (TYPE-IV) COLLAGEN [J].