Up-regulation of heparan sulfate 6-O-sulfation in idiopathic pulmonary fibrosis

TitleUp-regulation of heparan sulfate 6-O-sulfation in idiopathic pulmonary fibrosis
Publication TypeJournal Article
Year of Publication2014
AuthorsLu J, Auduong L, White ES, Yue X
JournalAm J Respir Cell Mol Biol
Date Published2014 Jan
KeywordsActins, Bronchi, Collagen Type I, Down-Regulation, Epithelial Cells, Female, Heparitin Sulfate, Humans, Idiopathic Pulmonary Fibrosis, Lung, Male, Middle Aged, Proteoglycans, Receptors, Transforming Growth Factor beta, RNA, Messenger, Smad2 Protein, Sulfotransferases, Up-Regulation

Heparan sulfate proteoglycans (HSPGs) are integral components of the lung. Changes in HSPGs have been documented in idiopathic pulmonary fibrosis (IPF). Many of the biological functions of HSPGs are mediated by heparan sulfate (HS) side chains, and little is understood about these side chains in the pathogenesis of IPF. The aims of this study were to compare HS structure between normal and IPF lungs and to examine how changes in HS regulate the fibrotic process. HS disaccharide analysis revealed that HS 6-O-sulfation was significantly increased in IPF lungs compared with normal lungs, concomitant with overexpression of HS 6-O-sulfotransferases 1 and 2 (HS6ST1/2) mRNA. Immunohistochemistry revealed that HS6ST2 was specifically expressed in bronchial epithelial cells, including those lining the honeycomb cysts in IPF lungs, whereas HS6ST1 had a broad expression pattern. Lung fibroblasts in the fibroblastic foci of IPF lungs expressed HS6ST1, and overexpression of HS6ST1 mRNA was observed in primary lung fibroblasts isolated from IPF lungs compared with those from normal lungs. In vitro, small interference RNA-mediated silencing of HS6ST1 in primary normal lung fibroblasts resulted in reduced Smad2 expression and activation and in reduced expression of collagen I and α-smooth muscle actin after TGF-β1 stimulation. Similar results were obtained in primary IPF lung fibroblasts. Furthermore, silencing of HS6ST1 in normal and IPF lung fibroblasts resulted in significant down-regulation of TβRIII (betaglycan). In summary, HS 6-O-sulfation is up-regulated in IPF with overexpression of HS6ST1 and HS6ST2, and overexpression of HS6ST1 in lung fibroblasts may regulate their fibrotic responses to TGF-β1.

Alternate JournalAm. J. Respir. Cell Mol. Biol.
PubMed ID23962103
PubMed Central IDPMC3930936
Grant ListHL095865 / HL / NHLBI NIH HHS / United States
P20 GM103514 / GM / NIGMS NIH HHS / United States
P20 RR018766 / RR / NCRR NIH HHS / United States
P41 GM103390 / GM / NIGMS NIH HHS / United States
P41GM103390 / GM / NIGMS NIH HHS / United States
R03 HL096949 / HL / NHLBI NIH HHS / United States
U01 HL111016 / HL / NHLBI NIH HHS / United States
U01 HL111016 / HL / NHLBI NIH HHS / United States