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NADPH oxidase-mediated induction of reactive oxygen species and extracellular matrix deposition by insulin-like growth factor binding protein-5
Journal article   Open access   Peer reviewed

NADPH oxidase-mediated induction of reactive oxygen species and extracellular matrix deposition by insulin-like growth factor binding protein-5

Hidekata Yasuoka, Sara M Garrett, Xinh-Xinh Nguyen, Carol M Artlett and Carol A Feghali-Bostwick
American journal of physiology. Lung cellular and molecular physiology, v 316(4), pp L644-L655
01 Apr 2019
DOI: https://doi.org/10.1152/ajplung.00106.2018
PMID: 30810066
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1152/ajplung.00106.2018View
Published, Version of Record (VoR)Maybe Open Access (Publisher Bronze),  Open

Abstract

Animals Cells, Cultured Extracellular Matrix - metabolism Fibroblasts - metabolism Humans Idiopathic Pulmonary Fibrosis - etiology Idiopathic Pulmonary Fibrosis - genetics Idiopathic Pulmonary Fibrosis - metabolism Insulin-Like Growth Factor Binding Protein 5 - antagonists & inhibitors Insulin-Like Growth Factor Binding Protein 5 - genetics Insulin-Like Growth Factor Binding Protein 5 - metabolism Lung - metabolism MAP Kinase Signaling System Mice Mice, Inbred C57BL Mice, Knockout NADPH Oxidases - metabolism Oxidative Stress Reactive Oxygen Species - metabolism Recombinant Proteins - genetics Recombinant Proteins - metabolism RNA, Small Interfering - genetics Scleroderma, Systemic - etiology Scleroderma, Systemic - genetics Scleroderma, Systemic - metabolism
Insulin-like growth factor binding protein-5 (IGFBP-5) induces production of the extracellular matrix (ECM) components collagen and fibronectin both in vitro and in vivo and is overexpressed in patients with fibrosing lung diseases, such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc). However, the mechanism by which IGFBP-5 exerts its fibrotic effect is incompletely understood. Recent reports have shown a substantial role of reactive oxygen species (ROS) in fibrosis; thus we hypothesized that IGFBP-5 induces production of ROS to mediate the profibrotic process. In vitro analyses revealed that ROS production was induced by recombinant and adenoviral vector-mediated IGFBP-5 (AdBP5) in a dose- and time-dependent manner, regulated through MEK/ERK and JNK signaling, and primarily mediated by NADPH oxidase (Nox). Silencing IGFBP-5 in SSc and IPF fibroblasts reduced ROS production. The antioxidants diphenyleneiodonium and N-acetylcysteine blocked IGFBP-5-stimulated ECM production in normal, SSc, and IPF human primary lung fibroblasts. In murine fibroblasts lacking critical components of the Nox machinery, AdBP5-stimulated ROS production and fibronectin expression were reduced compared with wild-type fibroblasts. IGFBP-5 stimulated transcriptional expression of Nox3 in human fibroblasts while selective knockdown of Nox3 reduced ROS production by IGFBP-5. Thus IGFBP-5 mediates fibrosis through production of ROS in a Nox-dependent manner.

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Collaboration types
Domestic collaboration
International collaboration
Web of Science research areas
Physiology
Respiratory System
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