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

TitleProtection of LPS-induced murine acute lung injury by sphingosine-1-phosphate lyase suppression.
Publication TypeJournal Article
Year of Publication2011
AuthorsZhao 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
JournalAm J Respir Cell Mol Biol
Volume45
Issue2
Pagination426-35
Date Published2011 Aug
ISSN Number1535-4989
KeywordsAcute Lung Injury, Aldehyde-Lyases, Animals, Bronchoalveolar Lavage, Cells, Cultured, Endothelium, Vascular, Humans, Immunoblotting, Injections, Intraperitoneal, Interleukin-6, Lipopolysaccharides, Lysophospholipids, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-kappa B, p38 Mitogen-Activated Protein Kinases, Phosphorylation, Pneumonia, RNA, Small Interfering, Sphingosine, Tandem Mass Spectrometry
Abstract

<p>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.</p>

DOI10.1165/rcmb.2010-0422OC
Alternate JournalAm. J. Respir. Cell Mol. Biol.
PubMed ID21148740
PubMed Central IDPMC3175568
Grant ListR01 HL091916-02 / HL / NHLBI NIH HHS / United States
HL091916 / HL / NHLBI NIH HHS / United States
HL079396 / HL / NHLBI NIH HHS / United States
CA77528 / CA / NCI NIH HHS / United States
R01 HL091916 / HL / NHLBI NIH HHS / United States
P01 HL098050 / HL / NHLBI NIH HHS / United States