Silencing of Carbohydrate Sulfotransferase 15 Hinders Murine Pulmonary Fibrosis Development.
Pulmonary fibrosis is a progressive lung disorder characterized by interstitial fibrosis, for which no effective treatments are available. Chondroitin sulfate proteoglycan (CSPG) has been shown to be a mediator, but the specific component of glycosaminoglycan chains of CSPG has not been explored. We show that chondroitin sulfate E-type (CS-E) is involved in fibrogenesis. Small interfering RNA (siRNA) targeting carbohydrate sulfotransferase 15 (CHST15) was designed to inhibit CHST15 mRNA and its product, CS-E. CS-E augments cell contraction and CHST15 siRNA inhibits collagen production. We found that bleomycin treatment increased CHST15 expression in interstitial fibroblasts at day 14. CHST15 siRNA was injected intranasally on days 1, 4, 8, and 11, and CHST15 mRNA was significantly suppressed by day 14. CHST15 siRNA reduced lung CSPG and the grade of fibrosis. CHST15 siRNA repressed the activation of fibroblasts, as evidenced by suppressed expression of α smooth muscle actin (αSMA), connective tissue growth factor (CTGF), lysyl oxidase like 2 (LOXL2), and CC-chemokine ligand 2 (CCL2)/monocyte chemoattractant protein-1 (MCP-1). Inflammatory infiltrates in the bronchoalveolar lavage fluid (BALF) and interstitium were diminished by CHST15 siRNA. These results indicate a pivotal role for CHST15 in fibroblast-mediated lung fibrosis and suggest a possible new therapeutic role for CHST15 siRNA in pulmonary fibrosis.
Second Department of Internal Medicine, Nara Medical University, Nara 634-8522, Japan. Electronic address: y-kai@eco.ocn.ne.jp.
Yoshiro
Y
Kai
Second Department of Internal Medicine, Nara Medical University, Nara 634-8522, Japan.
Koichi
K
Tomoda
Stelic Institute and Co. Inc., Tokyo 106-0044, Japan.
Hiroyuki
H
Yoneyama
Department of Immunology, Nara Medical University, Nara 634-8522, Japan.
Masahiro
M
Kitabatake
Second Department of Internal Medicine, Nara Medical University, Nara 634-8522, Japan.
Atsuhiro
A
Nakamura
Department of Immunology, Nara Medical University, Nara 634-8522, Japan.
Toshihiro
T
Ito
Second Department of Internal Medicine, Nara Medical University, Nara 634-8522, Japan.
Masanori
M
Yoshikawa
Second Department of Internal Medicine, Nara Medical University, Nara 634-8522, Japan.
Hiroshi
H
Kimura
bleomycin; chondroitin sulfate; chondroitin sulfate proteoglycans; fibroblasts; idiopathic pulmonary fibrosis; macrophages; pulmonary fibrosis