Heparan sulfate 6‐O‐sulfation is dynamically regulated in idiopathic pulmonary fibrosis

A glyco‐gene array approach was used to identify glyco‐genes involved in the development of idiopathic pulmonary fibrosis (IPF) with an emphasis on heparan sulfate (HS) biosynthesis and modification. Glyco‐gene expression profile (GlycoV4 oligonucleotide array) of normal and IPF human lungs identified 162 differentially expressed transcripts. Genes involved in HS biosynthesis and modification that were altered in IPF include HS N‐deacetylase/N‐sulfotransferase 1, HS 2‐O‐sulfotransferase, HS 6‐O‐sulfotransferases (HS6ST‐1 and ‐2), and HS 6‐O‐endosulfatases Sulf1 and Sulf2. The upregulation of both HS6STs and the Sulfs is intriguing as HS6STs add sulfates to the 6‐O‐position during HS biosynthesis, whereas the Sulfs remove them outside the cells. Quantitative RT‐PCR confirmed the upregulation of Sulf1, Sulf2 and HS6ST‐2. The overexpressed HS6ST‐2 was further identified as the HS6ST‐2S splice variant. Immunohistochemistry revealed that Sulf1 and Sulf2 were expressed in the fibrotic region and the hyperplastic type II alveolar epithelial cells, respectively, whereas HS6ST‐2S was localized in both epithelial and mesenchymal cells. Finally, HPLC analysis revealed that HS from IPF lungs were more 6‐O‐sulfated than that from normal lungs. In conclusion, HS 6‐O‐sulfation is dynamically regulated in IPF, and may play important roles in the development of IPF. This work was supported by NIH R03HL096949.