FOXM1 is a critical driver of lung fibroblast activation and fibrogenesis
Loka R. Penke, Jennifer M. Speth, Vijaya L. Dommeti, Eric S. White, Ingrid L. Bergin, Marc Peters-Golden
Loka R. Penke, Jennifer M. Speth, Vijaya L. Dommeti, Eric S. White, Ingrid L. Bergin, Marc Peters-Golden
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Research Article Pulmonology

FOXM1 is a critical driver of lung fibroblast activation and fibrogenesis

Abstract

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-β. The lipid mediator PGE2, 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.

Authors

Loka R. Penke, Jennifer M. Speth, Vijaya L. Dommeti, Eric S. White, Ingrid L. Bergin, Marc Peters-Golden

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Figure 9

Sio A treatment in a therapeutic protocol ameliorates bleomycin-induced fibrosis in mice.

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Sio A treatment in a therapeutic protocol ameliorates bleomycin-induced ...
(A) Schematic illustrating the timelines for in vivo administration of bleomycin and Sio A, for determination of experimental end points, and for the pertinent phases of the pulmonary response in the bleomycin model of pulmonary fibrosis. (B) Digital images of Masson’s trichrome staining for collagen deposition (blue) at days 14 (upper panels) and 21 (lower panels) in mice treated with and without bleomycin and Sio A. Original magnification, ×200. Scale bars: 500 μm. (C–F) Effect of Sio A treatment in mice treated with and without bleomycin, as reflected by values determined at days 14 and 21 for the Ashcroft histology score (C), lung hydroxyproline content (D), mRNA expression of the myofibroblast marker Acta2 (E), and levels of active TGF-β (F). (G) 20S proteasome activity in lung homogenates harvested at day 14 from mice treated with and without bleomycin and with and without Sio A. In C–G, each symbol represents an individual mouse. Values in each group represent results from 2 pooled independent experiments with a total of 5 to 8 mice per group. *P < 0.05; **P < 0.01, 2-way ANOVA with Tukey’s multiple comparisons test.