The lysophosphatidic acid receptor LPA1 promotes epithelial cell apoptosis after lung injury

Am J Respir Cell Mol Biol. 2012 Mar;46(3):355-64. doi: 10.1165/rcmb.2010-0155OC. Epub 2011 Oct 20.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

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


  • Lysophospholipids
  • Receptors, Lysophosphatidic Acid
  • Bleomycin
  • Casp3 protein, mouse
  • Caspase 3
  • lysophosphatidic acid