Protection of LPS-induced murine acute lung injury by sphingosine-1- phosphate lyase suppression

Yutong Zhao, Irina A. Gorshkova, Evgeny Berdyshev, Donghong He, Panfeng Fu, Wenli Ma, Yanlin Su, Peter V. Usatyuk, Srikanth Pendyala, Babak Oskouian, Julie D. Saba, Joe GN Garcia, Viswanathan Natarajan

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

A defining feature of acute lung injury (ALI) is the increased lung vascular permeability and alveolar flooding, which leads to associated morbidity and mortality. Specific therapies to alleviate the unremitting vascular leak in ALI are not currently clinically available; however, our prior studies indicate a protective role for sphingosine-1-phosphate (S1P) in animal models of ALI with reductions in lung edema. As S1P levels are tightly regulated by synthesis and degradation, we tested the hypothesis that inhibition of S1P lyase (S1PL), the enzyme that irreversibly degrades S1P via cleavage, could ameliorate ALI. Intratracheal instillation of LPS to mice enhanced S1PL expression, decreased S1P levels in lung tissue, and induced lung inflammation and injury. LPS challenge of wild-type mice receiving 2-acetyl-4(5)-[1(R),2(S),3(R),4- tetrahydroxybutyl]-imidazole to inhibit S1PL or S1PL+/- mice resulted in increased S1P levels in lung tissue and bronchoalveolar lavage fluids and reduced lung injury and inflammation. Moreover, down-regulation of S1PL expression by short interfering RNA (siRNA) in primary human lung microvascular endothelial cells increased S1P levels, and attenuated LPS-mediated phosphorylation of p38 mitogen-activated protein kinase and I-κB, IL-6 secretion, and endothelial barrier disruption via Rac1 activation. These results identify a novel role for intracellularly generated S1P in protection against ALI and suggest S1PL as a potential therapeutic target.

Original languageEnglish (US)
Pages (from-to)426-435
Number of pages10
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume45
Issue number2
DOIs
StatePublished - Aug 1 2011
Externally publishedYes

Fingerprint

Acute Lung Injury
Lyases
Lung
Bronchoalveolar Lavage Fluid
Lung Injury
Pneumonia
Tissue
Proto-Oncogene Proteins c-akt
Phosphorylation
Endothelial cells
Capillary Permeability
p38 Mitogen-Activated Protein Kinases
sphingosine 1-phosphate
sphingosine 1-phosphate lyase (aldolase)
Small Interfering RNA
Blood Vessels
Interleukin-6
Edema
Animals
Down-Regulation

Keywords

  • Acute lung injury
  • IL-6
  • Intracellular sphingosine-1-phosphate
  • Sphingosine-1-phosphate lyase
  • Transendothelial resistance

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Protection of LPS-induced murine acute lung injury by sphingosine-1- phosphate lyase suppression. / Zhao, Yutong; Gorshkova, Irina A.; Berdyshev, Evgeny; He, Donghong; Fu, Panfeng; Ma, Wenli; Su, Yanlin; Usatyuk, Peter V.; Pendyala, Srikanth; Oskouian, Babak; Saba, Julie D.; Garcia, Joe GN; Natarajan, Viswanathan.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 45, No. 2, 01.08.2011, p. 426-435.

Research output: Contribution to journalArticle

Zhao, Y, Gorshkova, IA, Berdyshev, E, He, D, Fu, P, Ma, W, Su, Y, Usatyuk, PV, Pendyala, S, Oskouian, B, Saba, JD, Garcia, JGN & Natarajan, V 2011, 'Protection of LPS-induced murine acute lung injury by sphingosine-1- phosphate lyase suppression', American Journal of Respiratory Cell and Molecular Biology, vol. 45, no. 2, pp. 426-435. https://doi.org/10.1165/rcmb.2010-0422OC
Zhao, Yutong ; Gorshkova, Irina A. ; Berdyshev, Evgeny ; He, Donghong ; Fu, Panfeng ; Ma, Wenli ; Su, Yanlin ; Usatyuk, Peter V. ; Pendyala, Srikanth ; Oskouian, Babak ; Saba, Julie D. ; Garcia, Joe GN ; Natarajan, Viswanathan. / Protection of LPS-induced murine acute lung injury by sphingosine-1- phosphate lyase suppression. In: American Journal of Respiratory Cell and Molecular Biology. 2011 ; Vol. 45, No. 2. pp. 426-435.
@article{1b17d61920024085a3c4e008f2b3e22b,
title = "Protection of LPS-induced murine acute lung injury by sphingosine-1- phosphate lyase suppression",
abstract = "A defining feature of acute lung injury (ALI) is the increased lung vascular permeability and alveolar flooding, which leads to associated morbidity and mortality. Specific therapies to alleviate the unremitting vascular leak in ALI are not currently clinically available; however, our prior studies indicate a protective role for sphingosine-1-phosphate (S1P) in animal models of ALI with reductions in lung edema. As S1P levels are tightly regulated by synthesis and degradation, we tested the hypothesis that inhibition of S1P lyase (S1PL), the enzyme that irreversibly degrades S1P via cleavage, could ameliorate ALI. Intratracheal instillation of LPS to mice enhanced S1PL expression, decreased S1P levels in lung tissue, and induced lung inflammation and injury. LPS challenge of wild-type mice receiving 2-acetyl-4(5)-[1(R),2(S),3(R),4- tetrahydroxybutyl]-imidazole to inhibit S1PL or S1PL+/- mice resulted in increased S1P levels in lung tissue and bronchoalveolar lavage fluids and reduced lung injury and inflammation. Moreover, down-regulation of S1PL expression by short interfering RNA (siRNA) in primary human lung microvascular endothelial cells increased S1P levels, and attenuated LPS-mediated phosphorylation of p38 mitogen-activated protein kinase and I-κB, IL-6 secretion, and endothelial barrier disruption via Rac1 activation. These results identify a novel role for intracellularly generated S1P in protection against ALI and suggest S1PL as a potential therapeutic target.",
keywords = "Acute lung injury, IL-6, Intracellular sphingosine-1-phosphate, Sphingosine-1-phosphate lyase, Transendothelial resistance",
author = "Yutong Zhao and Gorshkova, {Irina A.} and Evgeny Berdyshev and Donghong He and Panfeng Fu and Wenli Ma and Yanlin Su and Usatyuk, {Peter V.} and Srikanth Pendyala and Babak Oskouian and Saba, {Julie D.} and Garcia, {Joe GN} and Viswanathan Natarajan",
year = "2011",
month = "8",
day = "1",
doi = "10.1165/rcmb.2010-0422OC",
language = "English (US)",
volume = "45",
pages = "426--435",
journal = "American Journal of Respiratory Cell and Molecular Biology",
issn = "1044-1549",
publisher = "American Thoracic Society",
number = "2",

}

TY - JOUR

T1 - Protection of LPS-induced murine acute lung injury by sphingosine-1- phosphate lyase suppression

AU - Zhao, Yutong

AU - Gorshkova, Irina A.

AU - Berdyshev, Evgeny

AU - He, Donghong

AU - Fu, Panfeng

AU - Ma, Wenli

AU - Su, Yanlin

AU - Usatyuk, Peter V.

AU - Pendyala, Srikanth

AU - Oskouian, Babak

AU - Saba, Julie D.

AU - Garcia, Joe GN

AU - Natarajan, Viswanathan

PY - 2011/8/1

Y1 - 2011/8/1

N2 - A defining feature of acute lung injury (ALI) is the increased lung vascular permeability and alveolar flooding, which leads to associated morbidity and mortality. Specific therapies to alleviate the unremitting vascular leak in ALI are not currently clinically available; however, our prior studies indicate a protective role for sphingosine-1-phosphate (S1P) in animal models of ALI with reductions in lung edema. As S1P levels are tightly regulated by synthesis and degradation, we tested the hypothesis that inhibition of S1P lyase (S1PL), the enzyme that irreversibly degrades S1P via cleavage, could ameliorate ALI. Intratracheal instillation of LPS to mice enhanced S1PL expression, decreased S1P levels in lung tissue, and induced lung inflammation and injury. LPS challenge of wild-type mice receiving 2-acetyl-4(5)-[1(R),2(S),3(R),4- tetrahydroxybutyl]-imidazole to inhibit S1PL or S1PL+/- mice resulted in increased S1P levels in lung tissue and bronchoalveolar lavage fluids and reduced lung injury and inflammation. Moreover, down-regulation of S1PL expression by short interfering RNA (siRNA) in primary human lung microvascular endothelial cells increased S1P levels, and attenuated LPS-mediated phosphorylation of p38 mitogen-activated protein kinase and I-κB, IL-6 secretion, and endothelial barrier disruption via Rac1 activation. These results identify a novel role for intracellularly generated S1P in protection against ALI and suggest S1PL as a potential therapeutic target.

AB - A defining feature of acute lung injury (ALI) is the increased lung vascular permeability and alveolar flooding, which leads to associated morbidity and mortality. Specific therapies to alleviate the unremitting vascular leak in ALI are not currently clinically available; however, our prior studies indicate a protective role for sphingosine-1-phosphate (S1P) in animal models of ALI with reductions in lung edema. As S1P levels are tightly regulated by synthesis and degradation, we tested the hypothesis that inhibition of S1P lyase (S1PL), the enzyme that irreversibly degrades S1P via cleavage, could ameliorate ALI. Intratracheal instillation of LPS to mice enhanced S1PL expression, decreased S1P levels in lung tissue, and induced lung inflammation and injury. LPS challenge of wild-type mice receiving 2-acetyl-4(5)-[1(R),2(S),3(R),4- tetrahydroxybutyl]-imidazole to inhibit S1PL or S1PL+/- mice resulted in increased S1P levels in lung tissue and bronchoalveolar lavage fluids and reduced lung injury and inflammation. Moreover, down-regulation of S1PL expression by short interfering RNA (siRNA) in primary human lung microvascular endothelial cells increased S1P levels, and attenuated LPS-mediated phosphorylation of p38 mitogen-activated protein kinase and I-κB, IL-6 secretion, and endothelial barrier disruption via Rac1 activation. These results identify a novel role for intracellularly generated S1P in protection against ALI and suggest S1PL as a potential therapeutic target.

KW - Acute lung injury

KW - IL-6

KW - Intracellular sphingosine-1-phosphate

KW - Sphingosine-1-phosphate lyase

KW - Transendothelial resistance

UR - http://www.scopus.com/inward/record.url?scp=80051658461&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80051658461&partnerID=8YFLogxK

U2 - 10.1165/rcmb.2010-0422OC

DO - 10.1165/rcmb.2010-0422OC

M3 - Article

VL - 45

SP - 426

EP - 435

JO - American Journal of Respiratory Cell and Molecular Biology

JF - American Journal of Respiratory Cell and Molecular Biology

SN - 1044-1549

IS - 2

ER -