Work

Up-Regulation of Heparan Sulfate 6-O-Sulfation in Idiopathic Pulmonary Fibrosis

Year: 2013

Type: article

Abstract: 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.

Source: American Journal of Respiratory Cell and Molecular Biology

DOI: 10.1165/rcmb.2013-0204oc

Authors: Jingning Lu, Linda Auduong, Eric S. White, Xinping Yue

Institutions: Louisiana State University Health Sciences Center New Orleans, University of Michigan, Michigan Medicine

Language: English

Topic: Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis

Subfield: Pulmonary and Respiratory Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Center for Research Resources