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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.

SUBMITTER: Hernandez DM

PROVIDER: S-EPMC7136152 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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IPF pathogenesis is dependent upon TGFβ induction of IGF-1.

Hernandez Danielle M DM Kang Jeong-Han JH Choudhury Malay M Andrianifahanana Mahefatiana M Yin Xueqian X Limper Andrew H AH Leof Edward B EB

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20200217 4

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 progress ...[more]

PMID: 32067272

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IPF pathogenesis is dependent upon TGFβ induction of IGF-1.

Publications

IPF pathogenesis is dependent upon TGFβ induction of IGF-1.

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