Targeting sphingosine kinase 1 attenuates bleomycin-induced pulmonary fibrosis.

TitleTargeting sphingosine kinase 1 attenuates bleomycin-induced pulmonary fibrosis.
Publication TypeJournal Article
Year of Publication2013
AuthorsHuang LShuang, Berdyshev E, Mathew B, Fu P, Gorshkova IA, He D, Ma W, Noth I, Ma S-F, Pendyala S, Reddy SP, Zhou T, Zhang W, Garzon SA, Garcia JGN, Natarajan V
JournalFASEB J
Volume27
Issue4
Pagination1749-60
Date Published2013 Apr
ISSN Number1530-6860
KeywordsAged, Animals, Bleomycin, Female, Gene Knockdown Techniques, Humans, Idiopathic Pulmonary Fibrosis, Lung, Lysophospholipids, Male, Mice, Mice, Knockout, Middle Aged, Phosphotransferases (Alcohol Group Acceptor), Signal Transduction, Sphingosine, Transforming Growth Factor beta
Abstract

<p>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.</p>

DOI10.1096/fj.12-219634
Alternate JournalFASEB J.
PubMed ID23315259
PubMed Central IDPMC3606540
Grant ListHL P01 98050 / HL / NHLBI NIH HHS / United States
ES11863 / ES / NIEHS NIH HHS / United States
P01 58064 / / PHS HHS / United States
R01 ES011863 / ES / NIEHS NIH HHS / United States
HL66109 / HL / NHLBI NIH HHS / United States
R01 HL066109 / HL / NHLBI NIH HHS / United States
P01 HL098050 / HL / NHLBI NIH HHS / United States