The lysophosphatidic acid receptor LPA 1 promotes epithelial cell apoptosis after lung injury

Manuela Funke, Zhenwen Zhao, Yan Xu, Jerold Chun, Andrew M. Tager

Research output: Contribution to journalArticle

74 Scopus citations

Abstract

Increasedepithelial cell apoptosis in response to lung injury hasbeen 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. Wenowshowthat 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 wildtype 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 apoptosismay therefore contribute to the capacity of this signaling pathway to regulate the development of pulmonary fibrosis after lung injury.

Original languageEnglish (US)
Pages (from-to)355-364
Number of pages10
JournalAmerican journal of respiratory cell and molecular biology
Volume46
Issue number3
DOIs
StatePublished - Mar 1 2012

Keywords

  • Apoptosis
  • Epithelial cells, lysophosphatidic acid
  • LPA
  • Pulmonary fibrosis

ASJC Scopus subject areas

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

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