title: Inhibition of neutrophil apoptosis by PAI-1.
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.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294-0012, USA.
authors.forename: Jaroslaw W
authors.initials: JW
authors.lastname: Zmijewski
authors.forename: Hong-Beom
authors.initials: HB
authors.lastname: Bae
authors.forename: Jessy S
authors.initials: JS
authors.lastname: Deshane
authors.forename: Cynthia B
authors.initials: CB
authors.lastname: Peterson
authors.forename: David D
authors.initials: DD
authors.lastname: Chaplin
authors.forename: Edward
authors.initials: E
authors.lastname: Abraham
mesh_terms: D055371:Acute Lung Injury / Q000145:classification / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000378:metabolism; D008070:Lipopolysaccharides; D008168:Lung / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D019096:Vitronectin / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D017395:Plasminogen Activator Inhibitor 1; D011956:Receptors, Cell Surface; D011973:Receptors, LDL; D055293:Receptors, Urokinase Plasminogen Activator; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D019096:Vitronectin; D019869:Phosphatidylinositol 3-Kinases; D019204:GTP-Binding Proteins