Targeting sphingosine kinase 1 attenuates bleomycininduced pulmonary fibrosis

Long Shuang Huang, Evgeny Berdyshev, Biji Mathew, Panfeng Fu, Irina A. Gorshkova, Donghong He, Wenli Ma, Imre Noth, Shwu Fan Ma, Srikanth Pendyala, Sekhar P. Reddy, Tong Zhou, Wei Zhang, Steven A. Garzon, Joe GN Garcia, Viswanathan Natarajan

Research output: Contribution to journalArticle

50 Citations (Scopus)

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 bleomycinchallenged 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.

Original languageEnglish (US)
Pages (from-to)1749-1760
Number of pages12
JournalFASEB Journal
Volume27
Issue number4
DOIs
StatePublished - Apr 2013
Externally publishedYes

Fingerprint

Pulmonary Fibrosis
Bleomycin
Idiopathic Pulmonary Fibrosis
Transforming Growth Factors
Lung
Fibrosis
Tissue
Pulmonary diseases
Phosphorylation
Pathology
Fibroblasts
Microarrays
Blood
Survival
Interstitial Lung Diseases
Microarray Analysis
sphingosine kinase
Blood Cells
Mortality
Therapeutics

Keywords

  • S1P
  • S1P lyase
  • TGF-β

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Cite this

Huang, L. S., Berdyshev, E., Mathew, B., Fu, P., Gorshkova, I. A., He, D., ... Natarajan, V. (2013). Targeting sphingosine kinase 1 attenuates bleomycininduced pulmonary fibrosis. FASEB Journal, 27(4), 1749-1760. https://doi.org/10.1096/fj.12-219634

Targeting sphingosine kinase 1 attenuates bleomycininduced pulmonary fibrosis. / Huang, Long Shuang; Berdyshev, Evgeny; Mathew, Biji; Fu, Panfeng; Gorshkova, Irina A.; He, Donghong; Ma, Wenli; Noth, Imre; Ma, Shwu Fan; Pendyala, Srikanth; Reddy, Sekhar P.; Zhou, Tong; Zhang, Wei; Garzon, Steven A.; Garcia, Joe GN; Natarajan, Viswanathan.

In: FASEB Journal, Vol. 27, No. 4, 04.2013, p. 1749-1760.

Research output: Contribution to journalArticle

Huang, LS, Berdyshev, E, Mathew, B, Fu, P, Gorshkova, IA, He, D, Ma, W, Noth, I, Ma, SF, Pendyala, S, Reddy, SP, Zhou, T, Zhang, W, Garzon, SA, Garcia, JGN & Natarajan, V 2013, 'Targeting sphingosine kinase 1 attenuates bleomycininduced pulmonary fibrosis', FASEB Journal, vol. 27, no. 4, pp. 1749-1760. https://doi.org/10.1096/fj.12-219634
Huang LS, Berdyshev E, Mathew B, Fu P, Gorshkova IA, He D et al. Targeting sphingosine kinase 1 attenuates bleomycininduced pulmonary fibrosis. FASEB Journal. 2013 Apr;27(4):1749-1760. https://doi.org/10.1096/fj.12-219634
Huang, Long Shuang ; Berdyshev, Evgeny ; Mathew, Biji ; Fu, Panfeng ; Gorshkova, Irina A. ; He, Donghong ; Ma, Wenli ; Noth, Imre ; Ma, Shwu Fan ; Pendyala, Srikanth ; Reddy, Sekhar P. ; Zhou, Tong ; Zhang, Wei ; Garzon, Steven A. ; Garcia, Joe GN ; Natarajan, Viswanathan. / Targeting sphingosine kinase 1 attenuates bleomycininduced pulmonary fibrosis. In: FASEB Journal. 2013 ; Vol. 27, No. 4. pp. 1749-1760.
@article{24e51ed980784c35b2c633f56503c40f,
title = "Targeting sphingosine kinase 1 attenuates bleomycininduced 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 bleomycinchallenged 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.",
keywords = "S1P, S1P lyase, TGF-β",
author = "Huang, {Long Shuang} and Evgeny Berdyshev and Biji Mathew and Panfeng Fu and Gorshkova, {Irina A.} and Donghong He and Wenli Ma and Imre Noth and Ma, {Shwu Fan} and Srikanth Pendyala and Reddy, {Sekhar P.} and Tong Zhou and Wei Zhang and Garzon, {Steven A.} and Garcia, {Joe GN} and Viswanathan Natarajan",
year = "2013",
month = "4",
doi = "10.1096/fj.12-219634",
language = "English (US)",
volume = "27",
pages = "1749--1760",
journal = "FASEB Journal",
issn = "0892-6638",
publisher = "FASEB",
number = "4",

}

TY - JOUR

T1 - Targeting sphingosine kinase 1 attenuates bleomycininduced pulmonary fibrosis

AU - Huang, Long Shuang

AU - Berdyshev, Evgeny

AU - Mathew, Biji

AU - Fu, Panfeng

AU - Gorshkova, Irina A.

AU - He, Donghong

AU - Ma, Wenli

AU - Noth, Imre

AU - Ma, Shwu Fan

AU - Pendyala, Srikanth

AU - Reddy, Sekhar P.

AU - Zhou, Tong

AU - Zhang, Wei

AU - Garzon, Steven A.

AU - Garcia, Joe GN

AU - Natarajan, Viswanathan

PY - 2013/4

Y1 - 2013/4

N2 - 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 bleomycinchallenged 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.

AB - 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 bleomycinchallenged 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.

KW - S1P

KW - S1P lyase

KW - TGF-β

UR - http://www.scopus.com/inward/record.url?scp=84875702933&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84875702933&partnerID=8YFLogxK

U2 - 10.1096/fj.12-219634

DO - 10.1096/fj.12-219634

M3 - Article

C2 - 23315259

AN - SCOPUS:84875702933

VL - 27

SP - 1749

EP - 1760

JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

IS - 4

ER -