Abstract
Syndecan-4 is a transmembrane heparan sulfate proteoglycan expressed in a variety of cells, and its heparan sulfate glycosaminoglycan side chains bind to several proteins exhibiting various biological roles. The authors have previously demonstrated syndecan-4′s critical roles in pulmonary inflammation. In the current study, however, its role in pulmonary fibrosis was evaluated. Wild-type and syndecan-4-deficient mice were injected with bleomycin, and several parameters of inflammation and fibrosis were analyzed. The mRNA expression of collagen and α-smooth muscle action (α-SMA) in lung tissues, as well as the histopathological lung fibrosis score and collagen content in lung tissues, were significantly higher in the syndecan-4-deficient mice. However, the total cell count and cell differentiation in bronchoalveolar lavage fluid were equivalent between the wild-type and syndecan-4-deficient mice. Although there was no difference in the TGF-β expression in lung tissues between the wild-type and syndecan-4-deficient mice, significantly more activation of Smad3 in lung tissues was observed in the syndecan-4-deficient mice compared to the wild-type mice. Furthermore, in the in vitro experiments using lung fibroblasts, the co-incubation of syndecan-4 significantly inhibited TGF-β-induced Smad3 activation, collagen and α-SMA upregulation. Moreover, syndecan-4 knock-down by siRNA increased TGF-β-induced Smad3 activation and upregulated collagen and α-SMA expression. These findings showed that syndecan-4 inhibits the development of pulmonary fibrosis, at least in part, through attenuating TGF-β signaling.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive intractable fibrosing lung disease with a mean survival time of only 3–5 years from diagnosis
The treatment of mice with intratracheal BLM instillation resulted in an increase in syndecan-4 in the lungs, and the results from the in vivo experiments using Sdc4KO mice showed that the lack of this HSPG resulted in a significant increase in pulmonary fibrosis with more Smad3 activation following treatment with BLM
The in vitro experiments showed that TGF-β-induced collagen and α-smooth muscle action (α-SMA) upregulation as well as Smad3 activation was attenuated with recombinant syndecan-4 co-incubation and enhanced by syndecan-4 knockdown in lung fibroblasts
Summary
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive intractable fibrosing lung disease with a mean survival time of only 3–5 years from diagnosis. The annual incidence rate and prevalence of IPF in Japan are 2.5 and 11.0 per 100,000 population, respectively, and it is estimated that more than 13,000 patients are affected [1]. The mechanism of pulmonary fibrosis is complex, and various types of cells are involved. Pulmonary fibroblasts play an important role in pulmonary fibrosis by producing excessive extracellular matrix (ECM) and differentiating into myofibroblasts [2]. 2o01l8e,c1u9,lxar pathophysiology of pulmonary fibrosis remains unclear Mf tohl. eScmi. 2o01l8e,c1u9,lxar pathophysiology of pulmonary fibrosis remains unclear
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