Fibulin-1 regulates the pathogenesis of tissue remodeling in respiratory diseases
Gang Liu, … , Janette K. Burgess, Philip M. Hansbro
Gang Liu, … , Janette K. Burgess, Philip M. Hansbro
Published June 16, 2016
Citation Information: JCI Insight. 2016;1(9):e86380. https://doi.org/10.1172/jci.insight.86380.
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Research Article Cell biology Immunology

Fibulin-1 regulates the pathogenesis of tissue remodeling in respiratory diseases

Abstract

Airway and/or lung remodeling, involving exaggerated extracellular matrix (ECM) protein deposition, is a critical feature common to pulmonary diseases including chronic obstructive pulmonary disease (COPD), asthma, and idiopathic pulmonary fibrosis (IPF). Fibulin-1 (Fbln1), an important ECM protein involved in matrix organization, may be involved in the pathogenesis of these diseases. We found that Fbln1 was increased in COPD patients and in cigarette smoke–induced (CS-induced) experimental COPD in mice. Genetic or therapeutic inhibition of Fbln1c protected against CS-induced airway fibrosis and emphysema-like alveolar enlargement. In experimental COPD, this occurred through disrupted collagen organization and interactions with fibronectin, periostin, and tenascin-c. Genetic inhibition of Fbln1c also reduced levels of pulmonary inflammatory cells and proinflammatory cytokines/chemokines (TNF-α, IL-33, and CXCL1) in experimental COPD. Fbln1c–/– mice also had reduced airway remodeling in experimental chronic asthma and pulmonary fibrosis. Our data show that Fbln1c may be a therapeutic target in chronic respiratory diseases.

Authors

Gang Liu, Marion A. Cooley, Andrew G. Jarnicki, Alan C-Y. Hsu, Prema M. Nair, Tatt Jhong Haw, Michael Fricker, Shaan L. Gellatly, Richard Y. Kim, Mark D. Inman, Gavin Tjin, Peter A.B. Wark, Marjorie M. Walker, Jay C. Horvat, Brian G. Oliver, W. Scott Argraves, Darryl A. Knight, Janette K. Burgess, Philip M. Hansbro

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Figure 1

Fbln1 is increased in human COPD patients and cigarette smoke–induced (CS-induced) experimental COPD in mice.

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Fbln1 is increased in human COPD patients and cigarette smoke–induced (C...
Primary bronchoepithelial cells (pBECs) and serum were collected from COPD patients, non-COPD smokers, and nonsmoking healthy controls. (A) Fbln1 protein in pBEC lysates assessed by immunoblot (left), and fold change of densitometry normalized to GAPDH (right). n = 5–9. (B) Fbln1 protein in serum by immunoblot (left), and fold change of densitometry normalized to total protein (right). n = 8–9. *P < 0.05 compared with human nonsmoking control, unpaired 2-tailed Student’s t test. WT mice were exposed to CS for 8 weeks to induce experimental COPD; controls were exposed to normal air. n = 5–6. (C) Time course of total (left) and soluble collagen (right) in whole lungs. (D) Time course of collagen deposition around airways in lung sections stained with Verhoeff’s-Van Gieson (VVG, left; scale bar: 50 μm) and quantified by normalization to perimeter of basement membrane (Pbm) (right). n = 24–40 airways from n = 4–6 mice per group. (E) Fbln1 protein in mouse lungs by immunoblot (top), and fold change of densitometry normalized to β-actin (bottom). n = 5–6. (F) Time course of Fbln1 protein around small airways by IHC (left; scale bar: 50 μm), and quantification normalized to Pbm (right). n = 24–32 airways from n = 4–6 mice per group. (G) Time course of Fbln1 protein in serum, and fold change of densitometry normalized to total protein. n = 5–6. Results are mean ± SEM. *P < 0.05 compared with human nonsmoking control or normal air–exposed WT mice controls. ##P < 0.01 compared with non-COPD smokers. Statistical differences were determined with 1-way ANOVA followed by Bonferroni post-test.