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Lysophosphatidic acid receptor 1 modulates lipopolysaccharide-induced inflammation in alveolar epithelial cells and murine lungs

Academic Article
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Overview

authors

  • Zhao, J.
  • He, D. H.
  • Su, Y. L.
  • Berdyshev, E.
  • Chun, Jerold
  • Natarajan, V.
  • Zhao, Y. T.

publication date

  • October 2011

journal

  • American Journal of Physiology-Lung Cellular and Molecular Physiology  Journal

abstract

  • Lysophosphatidic acid (LPA), a bioactive phospholipid, plays an important role in lung inflammation by inducing the release of chemokines and lipid mediators. Our previous studies have shown that LPA induces the secretion of interleukin-8 and prostaglandin E(2) in lung epithelial cells. Here, we demonstrate that LPA receptors contribute to lipopolysaccharide (LPS)-induced inflammation. Pretreatment with LPA receptor antagonist Ki16425 or downregulation of LPA receptor 1 (LPA(1)) by small-interfering RNA (siRNA) attenuated LPS-induced phosphorylation of p38 MAPK, I-κB kinase, and I-κB in MLE12 epithelial cells. In addition, the blocking of LPA(1) also suppressed LPS-induced IL-6 production. Furthermore, LPS treatment promoted interaction between LPA(1) and CD14, a LPS coreceptor, in a time- and dose-dependent manner. Disruption of lipid rafts attenuated the interaction between LPA(1) and CD14. Mice challenged with LPS increased plasma LPA levels and enhanced expression of LPA receptors in lung tissues. To further investigate the role of LPA receptors in LPS-induced inflammation, wild-type, or LPA(1)-deficient mice, or wild-type mice pretreated with Ki16425 were intratracheally challenged with LPS for 24 h. Knock down or inhibition of LPA(1) decreased LPS-induced IL-6 release in bronchoalveolar lavage (BAL) fluids and infiltration of cells into alveolar space compared with wild-type mice. However, no significant differences in total protein concentration in BAL fluids were observed. These results showed that knock down or inhibition of LPA(1) offered significant protection against LPS-induced lung inflammation but not against pulmonary leak as observed in the murine model for lung injury.

subject areas

  • Animals
  • Antigens, CD14
  • Bronchi
  • Bronchoalveolar Lavage Fluid
  • Cells, Cultured
  • Epithelial Cells
  • Gene Expression Regulation
  • Inflammation
  • Interleukin-6
  • Interleukin-8
  • Isoxazoles
  • Lipopolysaccharides
  • Lysophospholipids
  • Male
  • Membrane Microdomains
  • Mice
  • Mice, Knockout
  • NF-kappa B
  • Phosphorylation
  • Propionates
  • Pulmonary Alveoli
  • Receptor Cross-Talk
  • Receptors, Lysophosphatidic Acid
  • Signal Transduction
  • p38 Mitogen-Activated Protein Kinases
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Research

keywords

  • acute lung injury
  • inflammation
  • interleukin-6
  • lipopolysaccharide
  • lysophosphatidic acid receptor 1
  • lysophospholipid
  • signal transduction
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Identity

PubMed Central ID

  • PMC3191756

International Standard Serial Number (ISSN)

  • 1040-0605

Digital Object Identifier (DOI)

  • 10.1152/ajplung.00058.2011

PubMed ID

  • 21821728
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Additional Document Info

start page

  • L547

end page

  • L556

volume

  • 301

issue

  • 4

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