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The lysophosphatidic acid receptor lpa(1) promotes epithelial cell apoptosis after lung injury

Academic Article
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Overview

authors

  • Funke, M.
  • Zhao, Z. W.
  • Xu, Y.
  • Chun, Jerold
  • Tager, A. M.

publication date

  • March 2012

journal

  • American Journal of Respiratory Cell and Molecular Biology  Journal

abstract

  • Increased epithelial cell apoptosis in response to lung injury has been implicated in the development of idiopathic pulmonary fibrosis (IPF), but the molecular pathways promoting epithelial cell apoptosis in this disease have yet to be fully identified. Lysophosphatidic acid (LPA), which we have previously demonstrated to mediate bleomycin lung injury-induced fibroblast recruitment and vascular leak in mice and fibroblast recruitment in patients with IPF, is an important regulator of survival and apoptosis in many cell types. We now show that LPA signaling through its receptor LPA(1) promotes epithelial cell apoptosis induced by bleomycin injury. The number of apoptotic cells present in the alveolar and bronchial epithelia of LPA(1)-deficient mice was significantly reduced compared with wild-type mice at Day 3 after bleomycin challenge, as was lung caspase-3 activity. Consistent with these in vivo results, we found that LPA signaling through LPA(1) induced apoptosis in normal human bronchial epithelial cells in culture. LPA-LPA(1) signaling appeared to specifically mediate anoikis, the apoptosis of anchorage-dependent cells induced by their detachment. Similarly, LPA negatively regulated attachment of R3/1 rat alveolar epithelial cell line cells. In contrast, LPA signaling through LPA(1) promoted the resistance of lung fibroblasts to apoptosis, which has also been implicated in IPF. The ability of LPA-LPA(1) signaling to promote epithelial cell apoptosis and fibroblast resistance to apoptosis may therefore contribute to the capacity of this signaling pathway to regulate the development of pulmonary fibrosis after lung injury.

subject areas

  • Animals
  • Anoikis
  • Apoptosis
  • Bleomycin
  • Caspase 3
  • Cell Adhesion
  • Cells, Cultured
  • Disease Models, Animal
  • Epithelial Cells
  • Fibroblasts
  • Humans
  • Lung
  • Lung Injury
  • Lysophospholipids
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pulmonary Fibrosis
  • Rats
  • Receptors, Lysophosphatidic Acid
  • Signal Transduction
  • Time Factors
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Research

keywords

  • LPA(1)
  • apoptosis
  • epithelial cells, lysophosphatidic acid
  • pulmonary fibrosis
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Identity

PubMed Central ID

  • PMC3326436

International Standard Serial Number (ISSN)

  • 1044-1549

Digital Object Identifier (DOI)

  • 10.1165/rcmb.2010-0155OC

PubMed ID

  • 22021336
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Additional Document Info

start page

  • 355

end page

  • 364

volume

  • 46

issue

  • 3

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