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Proc Natl Acad Sci U S A. 2017 May 2;114(18):4757-4762. doi: 10.1073/pnas.1621375114. Epub 2017 Apr 19.

Unifying mechanism for different fibrotic diseases.

Author information

1
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; gwernig@stanford.edu irv@stanford.edu.
2
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305.
3
Baxter Laboratories Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305.
4
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305.
5
Fred Hutchinson/University of Washington Cancer Consortium, Seattle, WA 98109.
6
Ludwig Center for Cancer Stem Cell Biology and Medicine, Stanford University School of Medicine, Stanford, CA 94305.

Abstract

Fibrotic diseases are not well-understood. They represent a number of different diseases that are characterized by the development of severe organ fibrosis without any obvious cause, such as the devastating diseases idiopathic pulmonary fibrosis (IPF) and scleroderma. These diseases have a poor prognosis comparable with endstage cancer and are uncurable. Given the phenotypic differences, it was assumed that the different fibrotic diseases also have different pathomechanisms. Here, we demonstrate that many endstage fibrotic diseases, including IPF; scleroderma; myelofibrosis; kidney-, pancreas-, and heart-fibrosis; and nonalcoholic steatohepatosis converge in the activation of the AP1 transcription factor c-JUN in the pathologic fibroblasts. Expression of the related AP1 transcription factor FRA2 was restricted to pulmonary artery hypertension. Induction of c-Jun in mice was sufficient to induce severe fibrosis in multiple organs and steatohepatosis, which was dependent on sustained c-Jun expression. Single cell mass cytometry revealed that c-Jun activates multiple signaling pathways in mice, including pAkt and CD47, which were also induced in human disease. αCD47 antibody treatment and VEGF or PI3K inhibition reversed various organ c-Jun-mediated fibroses in vivo. These data suggest that c-JUN is a central molecular mediator of most fibrotic conditions.

KEYWORDS:

anti-CD47 antibody therapy; c-JUN; fibrotic disease; scleroderma; signaling pathways

PMID:
28424250
PMCID:
PMC5422830
DOI:
10.1073/pnas.1621375114
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflict of interest statement: I.L.W. and G.W. have filed a patent, Docket No. S14-256: “(CD47) CD47 as potential single or combinatorial treatment in idiopathic lung fibrosis and systemic sclerosis.” I.L.W. cofounded 47Inc, a company developing anti-CD47 antibody treatment as anticancer therapy.

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