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Sphingosine-1-phosphate metabolism: can its enigmatic lyase promote the autophagy of fibrosis?
  1. Amanda L Tatler,
  2. Gisli Jenkins
  1. Centre for Respiratory Research, University of Nottingham, Nottingham City Hospital, Nottingham, UK
  1. Correspondence to Dr Gisli Jenkins, Centre for Respiratory Research, University of Nottingham, Nottingham City Hospital, Clinical Sciences Building Nottingham NG51PB, UK; gisli.jenkins{at}

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Idiopathic pulmonary fibrosis (IPF) is a devastating disease with a poorly understood pathogenesis and a rising incidence.1 Recently, an important role for bioactive lipids such as sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA), which have a diverse range of cellular functions including proliferation, cell death, adhesion and migration, has emerged. Both S1P and LPA are increased within the bronchoalveolar lavage fluid of patients with IPF2 ,3 and levels of sphingosine kinase1/2 (SPK1/2), which catalyses the synthesis of S1P from sphingosine, correlate negatively with survival in patients with IPF,4 highlighting an important role in disease.

Studies have shown that there is crosstalk between bioactive lipids such as S1P and LPA and the potently pro-fibrotic cytokine transforming growth factor β (TGF-β), which is known to be fundamental to IPF pathogenesis.5 Both S1P and LPA may promote lung fibrosis via activation of TGF-β in multiple cell types.6–8 Activation of TGF-β by S1P and LPA occurs via signalling through their respective G-protein coupled receptors. In vivo animal studies have shown that loss of such receptors, including LPAR1, LPAR2 or S1P3 receptors, can ameliorate bleomycin-induced lung fibrosis in rodents.3 ,9 ,10 …

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