FOXM1 is a critical driver of lung fibroblast activation and fibrogenesis

被引：91

作者：

Penke, Loka R. ^{[1
]}

Speth, Jennifer M. ^{[1
]}

Dommeti, Vijaya L. ^{[2
]}

White, Eric S. ^{[1
]}

Bergin, Ingrid L. ^{[3
]}

Peters-Golden, Marc ^{[1
]}

机构：

[1] Univ Michigan, Dept Internal Med, Div Pulm & Crit Care Med, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Dept Pathol, Michigan Ctr Translat Pathol, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Unit Lab Anim Med, Ann Arbor, MI 48109 USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2018年 / 128卷 / 06期

关键词：

IDIOPATHIC PULMONARY-FIBROSIS; PROSTAGLANDIN-E-2 INHIBITS FIBROBLAST; SERUM RESPONSE FACTOR; TRANSCRIPTION FACTOR; MYOFIBROBLAST DIFFERENTIATION; PROTEASOME INHIBITOR; EPITHELIAL-CELLS; SUPPRESSION; GROWTH; INJURY;

D O I：

10.1172/JCI87631

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

While the transcription factor forkhead box M1 (FOXM1) is well known as a proto-oncogene, its potential role in lung fibroblast activation has never been explored. Here, we show that FOXM1 is more highly expressed in fibrotic than in normal lung fibroblasts in humans and mice. FOXM1 was required not only for cell proliferation in response to mitogens, but also for myofibroblast differentiation and apoptosis resistance elicited by TGF-beta. The lipid mediator PGE 2, acting via cAMP signaling, was identified as an endogenous negative regulator of FOXM1. Finally, genetic deletion of FOXM1 in fibroblasts or administration of the FOXM1 inhibitor Siomycin A in a therapeutic protocol attenuated bleomycin-induced pulmonary fibrosis. Our results identify FOXM1 as a driver of lung fibroblast activation and underscore the therapeutic potential of targeting FOXM1 for pulmonary fibrosis.

引用

页码：2389 / 2405

页数：17

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