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
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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 3

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

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Absence of Fbln1c protects against airway and lung remodeling, emphysema...
WT and Fbln1c–/– mice were exposed to cigarette smoke (CS) for 8 weeks to induce experimental COPD; controls were exposed to normal air. (A) Total (left) and soluble collagen (right) in whole lungs. n = 5–6. (B) Type I collagen (Col1a1) protein in whole lung tissues assessed by immunoblot (left), and fold change of densitometry normalized to β-actin (right). n = 5–6. (C) Collagen deposition around small airways in mouse lung sections stained with Verhoeff’s-Van Gieson (VVG, left; scale bar: 50 μm; inserts show expanded image of indicated regions; scale bar: 15 μm), and quantification is normalized to the perimeter of basement membrane (Pbm, right). n = 24–40 airways from n = 4–6 mice per group. (D) Col1a1 area around mouse small airways normalized to the Pbm. n = 24–40 airways from n = 4–6 mice per group. (E) α-Smooth muscle actin–positive (SMA-positive) cell (red) and nuclear staining (hoechst, blue) around small airways by immuofluorescence (top; SA, small airway; BV, blood vessel; scale bar: 50 μm), and quantification is normalized to the Pbm (bottom). n = 24–40 airways from n = 4–6 mice per group. (F) Emphysema-like alveolar enlargement was measured by assessment of alveolar diameter. n = 5–6. Lung function was measured in terms of (G) pressure-volume loops and peak volumes and (H) static lung compliance. n = 5–6. Results are mean ± SEM. *P < 0.05, **P < 0.01, ****P < 0.0001 compared with normal air–exposed WT or Fbln1c–/– controls. #P < 0.05, ##P < 0.01, ###P < 0.001 compared with CS-exposed WT controls. Statistical differences were determined with 1-way ANOVA followed by Bonferroni post-test.