Fibulin-1 regulates the pathogenesis of tissue remodeling in respiratory diseases
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
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
View: Text | PDF
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

×

Figure 4

Fbln1c siRNA protects against airway and lung remodeling, emphysema-like alveolar enlargement, and impaired lung function in experimental COPD.

Options: View larger image (or click on image) Download as PowerPoint
Fbln1c siRNA protects against airway and lung remodeling, emphysema-lik...
WT mice were exposed to CS for 8 weeks to induce experimental COPD and were treated with Fbln1c or scrambled siRNA. (A) Total (left) and soluble collagen (right) in whole lungs. n = 4–6. (B) Col1a1 protein in whole lungs (left), and fold change of densitometry normalized to β-actin (right). n = 4–6. (C) Collagen stained with VVG (left; scale bar: 50 μm) and normalized to Pbm (right). n = 4–6. (D) Emphysema-like alveolar enlargement. n = 4–6. Lung function in terms of (E) pressure-volume loops and peak volumes and (F) static lung compliance. n = 4–6. Results are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 compared with normal air–exposed WT; $P < 0.05, $$P < 0.01 compared with CS-exposed controls treated with scrambled siRNA. Statistical differences were determined with 1-way ANOVA followed by Bonferroni post-test.