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 2

Generation of Fbln1c–/– mice.

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Generation of Fbln1c–/– mice. (A) Mouse Fbln1 gene diagram with alternat...
(A) Mouse Fbln1 gene diagram with alternatively spliced exons that encode the C-terminal variable domains of the Fbln1c and -d variants. (B) Expanded region of Fbln1 gene showing exons 15–18. (C) Targeted Fbln1 allele following recombination including the Neo cassette. Gray triangles indicate loxP sites used to remove the Neo cassette. Southern blots of genomic DNA from an ES cell clone transfected with exon 15 targeting vector. (D) Probe1 was hybridized to EcoRV digested genomic DNA. The 9.8-kb fragment is from the WT allele, and the 6.8-kb fragment is from the targeted allele. (E) Probe2 was hybridized to ApaI digested DNA. The 10-kb fragment is derived from the WT allele and the 8.2 kb from the targeted allele. (F) PCR of genomic DNA from mice +/+, +/–, and –/– for the deletion of exon 15 and lacking the Neo cassette. (G) Reverse-transcriptase PCR of RNA from hearts of E13.5 WT embryos and embryos heterozygous and homozygous for the targeted deletion.