Inhibition of neutrophil apoptosis by PAI-1
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 TNFrelated 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-xL. 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. © 2011 the American Physiological Society.
Publication Source (Journal or Book title)
American Journal of Physiology - Lung Cellular and Molecular Physiology
Zmijewski, J., Bae, H., Deshane, J., Peterson, C., Chaplin, D., & Abraham, E. (2011). Inhibition of neutrophil apoptosis by PAI-1. American Journal of Physiology - Lung Cellular and Molecular Physiology, 301 (2) https://doi.org/10.1152/ajplung.00075.2011