Rationale We have earlier reported that sphingosine kinase 1 (SphK1) is up-regulated in lung tissues from idiopathic pulmonary fibrosis (IPF) patients and SphK1/sphingosine-1-phosphate (S1P) signaling axis plays a key role in bleomycin- and radiation-induced pulmonary fibrosis in mice. Further, SphK1 mRNA levels in PBMCs from IPF patients directly and significantly correlated with pulmonary function outcomes and overall survival. In this study, we investigated the effect of administration of PF-543, a specific SphK1 inhibitor, 7 days post-bleomycin (BLM) challenge on the development of pulmonary fibrosis in mice.
Objectives To determine the efficacy of PF-543 in attenuating pulmonary fibrosis in mice post BLM challenge.
Methods SphK1 inhibitor PF-543 (5 mg/kg body weight, i.p.; twice a week) was administered to control and BLM (1.5 U/kg, intratracheal) challenged mice on day 7 post BLM challenge, and development of pulmonary fibrosis was determined on day 21 by Mason-Trichrome staining of lung tissues, total collagen, fibronectin and α-SMA protein levels in lung tissues. In vitro, the effect of PF-543 on TGF-β (5 ng/ml) induced Yap1 activation, and differentiation, contraction, and proliferation of human lung fibroblast were assessed.
Results Administration of PF-543 to BLM treated mice on day 7 post challenge, dramatically inhibited BLM-induced lung injury, and attenuated collagen deposition and expression of fibronectin, α-SMA and TGF-β in lung tissues on day 21 post-BLM challenge. In vitro, PF-543 inhibited TGF-β induced differentiation, contraction and proliferation of human lung fibroblasts, as well as blocked TGF-β induced expression and nuclear translocation of YAP, a transcriptional co-factor involved in pulmonary fibrosis. Additionally, siRNA knockdown of YAP1 inhibited TGF-β induced fibroblast differentiation.
Conclusion These studies demonstrate ability of SphK1 inhibitor, PF-543 to ameliorate BLM-induced pulmonary fibrosis in mice when administered on day 7 after BLM challenge. Also, PF-543 blocked YAP1 activation, a co-transcriptional factor involved in pulmonary fibrosis development. Thus, PF-543 may serve as a potential therapeutic drug in treating pulmonary fibrosis. This work was supported by P01 HL098050 (VN).
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