Platelet-derived serotonin links vascular disease and tissue fibrosis

被引：203

作者：

Dees, Clara ^{[1
]}

Akhmetshina, Alfiya ^{[1
]}

Zerr, Pawel ^{[1
]}

Reich, Nicole ^{[1
]}

Palumbo, Katrin ^{[1
]}

Horn, Angelika ^{[1
]}

Juengel, Astrid ^{[2
]}

Beyer, Christian ^{[1
]}

Kroenke, Gerhard ^{[1
]}

Zwerina, Jochen ^{[1
]}

Reiter, Rudolf ^{[3
]}

Alenina, Natalia ^{[4
]}

Maroteaux, Luc ^{[5
]}

Gay, Steffen ^{[2
]}

Schett, Georg ^{[1
]}

Distler, Oliver ^{[2
]}

Distler, Joerg H. W. ^{[1
]}

机构：

[1] Univ Erlangen Nurnberg, Inst Clin Immunol, Dept Internal Med 3, D-91054 Erlangen, Germany

[2] Univ Zurich Hosp, Zurich Ctr Integrat Human Physiol, Ctr Expt Rheumatol, CH-8091 Zurich, Switzerland

[3] ErgoNex Pharma GmbH, CH-9050 Appenzell, Switzerland

[4] Max Delbruck Ctr Mol Med Berlin Buch, D-13092 Berlin, Germany

[5] INSERM, U839, Inst Fer Moulin, F-75005 Paris, France

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2011年 / 208卷 / 05期

关键词：

ENDOTHELIAL GROWTH-FACTOR; SYSTEMIC-SCLEROSIS; CARCINOID-SYNDROME; 5-HT2B RECEPTORS; DERMAL FIBROSIS; PLASMA THROMBOMODULIN; EXTRACELLULAR-MATRIX; POSSIBLE INVOLVEMENT; PULMONARY-FIBROSIS; INTERSTITIAL-CELLS;

D O I：

10.1084/jem.20101629

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Vascular damage and platelet activation are associated with tissue remodeling in diseases such as systemic sclerosis, but the molecular mechanisms underlying this association have not been identified. In this study, we show that serotonin (5-hydroxytryptamine [5-HT]) stored in platelets strongly induces extracellular matrix synthesis in interstitial fibroblasts via activation of 5-HT(2B) receptors (5-HT(2B)) in a transforming growth factor beta (TGF-beta)-dependent manner. Dermal fibrosis was reduced in 5-HT(2B)(-/-) mice using both inducible and genetic models of fibrosis. Pharmacologic inactivation of 5-HT(2B) also effectively prevented the onset of experimental fibrosis and ameliorated established fibrosis. Moreover, inhibition of platelet activation prevented fibrosis in different models of skin fibrosis. Consistently, mice deficient for TPH1, the rate-limiting enzyme for 5-HT production outside the central nervous system, showed reduced experimental skin fibrosis. These findings suggest that 5-HT/5-HT(2B) signaling links vascular damage and platelet activation to tissue remodeling and identify 5-HT(2B) as a novel therapeutic target to treat fibrotic diseases.

引用

页码：961 / 972

页数：12

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