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 6

Absence of Fbln1c protects against inflammation in experimental COPD.

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Absence of Fbln1c protects against inflammation in experimental COPD. WT...
WT and Fbln1c–/– mice were exposed to cigarette smoke (CS) for 8 weeks to induce experimental COPD; controls were exposed to normal air. (A) Differential inflammatory cell counts in bronchoalveolar lavage fluid (BALF). (B) TNF-α, (C) IL-33, (D) TGF-β, and (E) CXCL1 protein in whole lungs measured by ELISA. WT mice were treated with Fbln1c or scrambled siRNA from weeks 6–8 of 8 weeks of CS exposure. (F) Differential inflammatory cell counts in BALF. (G) TNF-α, (H) IL-33, (I) TGF-β, and (J) CXCL1 protein in whole lungs. Results are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 compared with normal air–exposed WT or Fbln1c–/– controls; #P < 0.05, ##P < 0.01, ####P < 0.0001 compared with CS-exposed WT controls; $P < 0.05 compared with CS-exposed controls treated with scrambled siRNA. Statistical differences were determined with 1-way ANOVA followed by Bonferroni post-test.