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 7

Absence of Fbln1c protects against airway remodeling in experimental chronic asthma and pulmonary fibrosis.

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Absence of Fbln1c protects against airway remodeling in experimental chr...
WT and Fbln1c–/– mice were administered house dust mite (HDM) extract for 5 days per week for 5 weeks; controls were administered sterile saline. (A) Collagen deposition around small airways in lung sections stained with Verhoeff’s-Van Gieson stain (VVG, left; scale bar: 500 μm). Inserts show expanded image of indicated regions (scale bar: 50 μm). Quantification of collagen deposition normalized to the perimeter of basement membrane (Pbm) (right). n = 24–40 airways from n = 6–8 mice per group. WT and Fbln1c–/– mice were administered bleomycin sulphate once, controls were administered sterile PBS, and tissues were collected 28 days later. (B) Collagen deposition around small airways and normalized to Pbm (scale bar: 500 μm). Inserts show expanded image of indicated regions (scale bar: 50 μm). n = 24–32 airways from n = 8 mice per group. Results are mean ± SEM. **P < 0.01 compared with WT or Fbln1c–/– controls; #P < 0.05, ##P < 0.01 compared with HDM or bleomycin-treated WT controls. Statistical differences were determined with 1-way ANOVA followed by Bonferroni post-test.