Inhibition of Neutrophil Apoptosis by PAI-1

Am J Physiol Lung Cell Mol Physiol. 2011 Aug;301(2):L247-54. doi: 10.1152/ajplung.00075.2011. Epub 2011 May 27.

Abstract

Increased circulating and tissue levels of plasminogen activator inhibitor 1 (PAI-1) are often present in severe inflammatory states associated with neutrophil activation and accumulation and correlate with poor clinical outcome from many of these conditions. The mechanisms by which PAI-1 contributes to inflammation have not been fully delineated. In the present experiments, we found that addition of PAI-1 to neutrophil cultures diminished the rate of spontaneous and TNF-related apoptosis-inducing ligand-induced apoptotic cell death. The effects of PAI-1 on cell viability were associated with activation of antiapoptotic signaling pathways, including upregulation of PKB/Akt, Mcl-1, and Bcl-x(L). Although urokinase-plasminogen activator receptor, lipoprotein receptor-related protein, and vitronectin are primary ligands for PAI-1, these molecules were not involved in mediating its antiapoptotic properties. In contrast, blocking pertussis toxin-sensitive G protein-coupled receptors and selective inhibition of phosphatidylinositide 3-kinase reversed the ability of PAI-1 to extend neutrophil viability. The antiapoptotic effects of PAI-1 were also evident under in vivo conditions during LPS-induced acute lung injury, where enhanced apoptosis was present among neutrophils accumulating in the lungs of PAI-1(-/-) compared with PAI-1(+/+) mice. These results demonstrate a novel antiapoptotic role for PAI-1 that may contribute to its participation in neutrophil-associated inflammatory responses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / classification
  • Acute Lung Injury / pathology
  • Acute Lung Injury / physiopathology
  • Animals
  • Apoptosis / drug effects*
  • Cells, Cultured
  • Enzyme Activation
  • GTP-Binding Proteins / metabolism
  • Lipopolysaccharides
  • Lung / pathology
  • Lung / physiopathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophils / physiology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Plasminogen Activator Inhibitor 1 / deficiency
  • Plasminogen Activator Inhibitor 1 / metabolism*
  • Plasminogen Activator Inhibitor 1 / pharmacology*
  • Receptors, Cell Surface / metabolism
  • Receptors, LDL / metabolism
  • Receptors, Urokinase Plasminogen Activator / metabolism
  • Recombinant Proteins / pharmacology
  • TNF-Related Apoptosis-Inducing Ligand / metabolism
  • Vitronectin / metabolism

Substances

  • Lipopolysaccharides
  • Plasminogen Activator Inhibitor 1
  • Receptors, Cell Surface
  • Receptors, LDL
  • Receptors, Urokinase Plasminogen Activator
  • Recombinant Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • Vitronectin
  • Phosphatidylinositol 3-Kinases
  • GTP-Binding Proteins