@article{a5d1160330f94120b80305f19ba83e3a,
title = "IPF pathogenesis is dependent upon TGFβ induction of IGF-1",
abstract = "Pathogenic fibrotic diseases, including idiopathic pulmonary fibrosis (IPF), have some of the worst prognoses and affect millions of people worldwide. With unclear etiology and minimally effective therapies, two-thirds of IPF patients die within 2-5 years from this progressive interstitial lung disease. Transforming Growth Factor Beta (TGFβ) and insulin-like growth factor-1 (IGF-1) are known to promote fibrosis; however, myofibroblast specific upregulation of IGF-1 in the initiation and progression of TGFβ-induced fibrogenesis and IPF have remained unexplored. To address this, the current study (1) documents the upregulation of IGF-1 via TGFβ in myofibroblasts and fibrotic lung tissue, as well as its correlation with decreased pulmonary function in advanced IPF; (2) identifies IGF-1's C1 promoter as mediating the increase in IGF-1 transcription by TGFβ in pulmonary fibroblasts; (3) determines that SMAD2 and mTOR signaling are required for TGFβ-dependent Igf-1 expression in myofibroblasts; (4) demonstrates IGF-1R activation is essential to support TGFβ-driven profibrotic myofibroblast functions and excessive wound healing; and (5) establishes the effectiveness of slowing the progression of murine lung fibrosis with the IGF-1R inhibitor OSI-906. These findings expand our knowledge of IGF-1's role as a novel fibrotic-switch, bringing us one step closer to understanding the complex biological mechanisms responsible for fibrotic diseases and developing effective therapies.",
keywords = "fibroblast, promoter, signaling, transcription",
author = "Hernandez, {Danielle M.} and Kang, {Jeong Han} and Malay Choudhury and Mahefatiana Andrianifahanana and Xueqian Yin and Limper, {Andrew H.} and Leof, {Edward B.}",
note = "Funding Information: We would like to thank: Dr Carol Feghali-Bostwick (Medical University of South Carolina) and Dr Nathan Sandbo (University of Wisconsin-Madison Department of Medicine, UW-Madison Carbone Cancer Center Biobank, P30 CA014520) for graciously providing primary fibroblasts from healthy and IPF patients; Dr Robert Vassallo for kindly sharing the NGS profiling dataset; Dr Eunhee S. Yi and Dr Anja C. Roden for histological pathology review of patient samples; Kyle J. Schaefbauer for help with animal procedures; Dr Ruth Lupu for teaching immunohistochemical techniques; and Dr Douglas Yee, Dr Scott Kaufmann, and Dr Dan Billadeau for insightful discussions. This work was supported by grants from the US Department of Health and Human Services National Institute of General Medical Sciences (R01-GM054200, R37-GM055816), the Caerus Foundation (91736058), Hurvis Accelerate the Cure for IPF (91736063), and the Mayo Foundation (to EBL). Funding Information: We would like to thank: Dr Carol Feghali‐Bostwick (Medical University of South Carolina) and Dr Nathan Sandbo (University of Wisconsin‐Madison Department of Medicine, UW‐Madison Carbone Cancer Center Biobank, P30 CA014520) for graciously providing primary fibroblasts from healthy and IPF patients; Dr Robert Vassallo for kindly sharing the NGS profiling dataset; Dr Eunhee S. Yi and Dr Anja C. Roden for histological pathology review of patient samples; Kyle J. Schaefbauer for help with animal procedures; Dr Ruth Lupu for teaching immunohistochemical techniques; and Dr Douglas Yee, Dr Scott Kaufmann, and Dr Dan Billadeau for insightful discussions. This work was supported by grants from the US Department of Health and Human Services National Institute of General Medical Sciences (R01‐GM054200, R37‐GM055816), the Caerus Foundation (91736058), Hurvis Accelerate the Cure for IPF (91736063), and the Mayo Foundation (to EBL). Publisher Copyright: {\textcopyright} 2020 Federation of American Societies for Experimental Biology",
year = "2020",
month = apr,
day = "1",
doi = "10.1096/fj.201901719RR",
language = "English (US)",
volume = "34",
pages = "5363--5388",
journal = "FASEB Journal",
issn = "0892-6638",
publisher = "FASEB",
number = "4",
}