title: Sphingolipids in pulmonary fibrosis.
abstract: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by alveolar epithelial cell injury, accumulation of fibroblasts/myofibroblasts and deposition of extracellular matrix proteins. Levels of sphingosine-1-phosphate (S1P), a naturally occurring bioactive lipid, are elevated in bronchoalveolar fluids and lung tissues from IPF patients and animal models of pulmonary fibrosis. However, the in vivo contribution of S1P, regulated by its synthesis catalyzed by Sphingosine kinases (SphKs) 1 & 2 and catabolism by S1P phosphatases and S1P lyase (S1PL), in the pathogenesis of pulmonary fibrosis is not well defined. Microarray analysis of blood mononuclear cells from patients with IPF and SphK1-, SphK2- or S1PL-knockout mice and SphK inhibitor were used to assess the role of S1P in fibrogenesis. The expression of SphK1 negatively correlated with lung function and survival of patients with IPF. Further, the expressions of SphK1 and S1PL were increased in lung tissues from patients with IPF and bleomycin-challenged mice. Genetic knockdown of SphK1, but not SphK2, ameliorated bleomycin-induced pulmonary fibrosis in mice while deletion of S1PL (SGPL1(+/-)) in mice potentiated fibrosis post-bleomycin challenge. TGF-β increased the expression of SphK1 and S1PL in human lung fibroblasts and knockdown of SphK1 or treatment with SphK inhibitor attenuated S1P generation and TGF-β mediated signal transduction. Over-expression of S1PL attenuated bleomycin-induced TGF-β secretion and S1P mediated differentiation of human lung fibroblasts through regulation of autophagy. Administration of SphK1 inhibitor 8 days post-bleomycin challenge reduced bleomycin-induced mortality and pulmonary fibrosis. Our results suggest that SphK1 and S1PL play critical roles in the pathology of lung fibrosis and may be novel therapeutic targets.
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago, IL, USA.
authors.forename: Long Shuang
authors.initials: LS
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago, IL, USA; Department of Medicine, University of Illinois at Chicago, IL, USA. Electronic address: visnatar@uic.edu.
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Natarajan
mesh_terms: D000446:Aldehyde-Lyases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000494:pharmacology; D001761:Bleomycin / Q000009:adverse effects / Q000494:pharmacology; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism* / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D013107:Sphingolipids / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D000446:Aldehyde-Lyases; D000903:Antibiotics, Antineoplastic; D001761:Bleomycin; D017853:Phosphotransferases (Alcohol Group Acceptor); D013107:Sphingolipids; D016212:Transforming Growth Factor beta; D000099157:Sphingosine Kinase; C000594250:sphingosine kinase 2, human; C022649:sphingosine 1-phosphate lyase (aldolase)
keywords: Autophagy; Pulmonary fibrosis; S1P lyase; Sphingosine kinase 1; Sphingosine-1-phosphate; TGF-β