Inhibition of pulmonary fibrosis in mice by CXCL10 requires glycosaminoglycan binding and syndecan-4.

dc.contributor.author

Jiang, D

dc.contributor.author

Liang, J

dc.contributor.author

Campanella, GS

dc.contributor.author

Guo, R

dc.contributor.author

Yu, S

dc.contributor.author

Xie, T

dc.contributor.author

Liu, N

dc.contributor.author

Jung, Y

dc.contributor.author

Homer, R

dc.contributor.author

Meltzer, EB

dc.contributor.author

Li, Y

dc.contributor.author

Tager, AM

dc.contributor.author

Goetinck, PF

dc.contributor.author

Luster, AD

dc.contributor.author

Noble, PW

dc.coverage.spatial

United States

dc.date.accessioned

2011-06-21T17:27:54Z

dc.date.issued

2010-06

dc.description.abstract

Pulmonary fibrosis is a progressive, dysregulated response to injury culminating in compromised lung function due to excess extracellular matrix production. The heparan sulfate proteoglycan syndecan-4 is important in mediating fibroblast-matrix interactions, but its role in pulmonary fibrosis has not been explored. To investigate this issue, we used intratracheal instillation of bleomycin as a model of acute lung injury and fibrosis. We found that bleomycin treatment increased syndecan-4 expression. Moreover, we observed a marked decrease in neutrophil recruitment and an increase in both myofibroblast recruitment and interstitial fibrosis in bleomycin-treated syndecan-4-null (Sdc4-/-) mice. Subsequently, we identified a direct interaction between CXCL10, an antifibrotic chemokine, and syndecan-4 that inhibited primary lung fibroblast migration during fibrosis; mutation of the heparin-binding domain, but not the CXCR3 domain, of CXCL10 diminished this effect. Similarly, migration of fibroblasts from patients with pulmonary fibrosis was inhibited in the presence of CXCL10 protein defective in CXCR3 binding. Furthermore, administration of recombinant CXCL10 protein inhibited fibrosis in WT mice, but not in Sdc4-/- mice. Collectively, these data suggest that the direct interaction of syndecan-4 and CXCL10 in the lung interstitial compartment serves to inhibit fibroblast recruitment and subsequent fibrosis. Thus, administration of CXCL10 protein defective in CXCR3 binding may represent a novel therapy for pulmonary fibrosis.

dc.description.version

Version of Record

dc.identifier

http://www.ncbi.nlm.nih.gov/pubmed/20484822

dc.identifier

38644

dc.identifier.eissn

1558-8238

dc.identifier.uri

https://hdl.handle.net/10161/4322

dc.language

eng

dc.language.iso

en_US

dc.publisher

American Society for Clinical Investigation

dc.relation.ispartof

J Clin Invest

dc.relation.isversionof

10.1172/JCI38644

dc.relation.journal

Journal of Clinical Investigation

dc.subject

Animals

dc.subject

Bleomycin

dc.subject

Extracellular Matrix

dc.subject

Fibroblasts

dc.subject

Fibrosis

dc.subject

Glycosaminoglycans

dc.subject

Heparan Sulfate Proteoglycans

dc.subject

Lung

dc.subject

Lung Diseases, Interstitial

dc.subject

Mice

dc.subject

Mice, Inbred C57BL

dc.subject

Mice, Knockout

dc.subject

Pulmonary Fibrosis

dc.subject

Syndecan-4

dc.title

Inhibition of pulmonary fibrosis in mice by CXCL10 requires glycosaminoglycan binding and syndecan-4.

dc.title.alternative
dc.type

Journal article

duke.date.pubdate

2010-6-0

duke.description.issue

6

duke.description.volume

120

pubs.author-url

http://www.ncbi.nlm.nih.gov/pubmed/20484822

pubs.begin-page

2049

pubs.end-page

2057

pubs.issue

6

pubs.organisational-group

Clinical Science Departments

pubs.organisational-group

Duke

pubs.organisational-group

Faculty

pubs.organisational-group

Medicine

pubs.organisational-group

Medicine, Pulmonary, Allergy, and Critical Care Medicine

pubs.organisational-group

School of Medicine

pubs.publication-status

Published

pubs.volume

120

Files

Original bundle

Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
278324400028.pdf
Size:
2.59 MB
Format:
Adobe Portable Document Format