title: Targeting sphingosine kinase 1 attenuates bleomycin-induced pulmonary fibrosis.
abstract: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease, wherein transforming growth factor β (TGF-β) and sphingosine-1-phosphate (S1P) contribute to the pathogenesis of fibrosis. However, the in vivo contribution of sphingosine kinase (SphK) in fibrotic processes has not been documented. Microarray analysis of blood mononuclear cells from patients with IPF and SphK1- or SphK2-knockdown mice and SphK inhibitor were used to assess the role of SphKs in fibrogenesis. The expression of SphK1/2 negatively correlated with lung function and survival in patients with IPF. Also, the expression of SphK1 was increased in lung tissues from patients with IPF and bleomycin-challenged mice. Knockdown of SphK1, but not SphK2, increased survival and resistance to pulmonary fibrosis in bleomycin-challenged mice. Administration of SphK inhibitor reduced bleomycin-induced mortality and pulmonary fibrosis in mice. Knockdown of SphK1 or treatment with SphK inhibitor attenuated S1P generation and TGF-β secretion in a bleomycin-induced lung fibrosis mouse model that was accompanied by reduced phosphorylation of Smad2 and MAPKs in lung tissue. In vitro, bleomycin-induced expression of SphK1 in lung fibroblast was found to be TGF-β dependent. Taken together, these data indicate that SphK1 plays a critical role in the pathology of lung fibrosis and is a novel therapeutic target.
authors: Department of Pharmacology, University of Illinois, Chicago, Illinois 60612-7343, USA.
authors: Long Shuang
authors: LS
authors: Huang
authors: Evgeny
authors: E
authors: Berdyshev
authors: Biji
authors: B
authors: Mathew
authors: Panfeng
authors: P
authors: Fu
authors: Irina A
authors: IA
authors: Gorshkova
authors: Donghong
authors: D
authors: He
authors: Wenli
authors: W
authors: Ma
authors: Imre
authors: I
authors: Noth
authors: Shwu-Fan
authors: SF
authors: Ma
authors: Srikanth
authors: S
authors: Pendyala
authors: Sekhar P
authors: SP
authors: Reddy
authors: Tong
authors: T
authors: Zhou
authors: Wei
authors: W
authors: Zhang
authors: Steven A
authors: SA
authors: Garzon
authors: Joe G N
authors: JG
authors: Garcia
authors: Viswanathan
authors: V
authors: Natarajan
mesh_terms: D000368:Aged; D000818:Animals; D001761:Bleomycin / Q000009:adverse effects / Q000378:metabolism*; D005260:Female; D055785:Gene Knockdown Techniques / Q000379:methods; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008246:Lysophospholipids / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D000099157:Sphingosine Kinase
chemical_list: D001761:Bleomycin; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D016212:Transforming Growth Factor beta; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate