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

Inhibition of neutrophil apoptosis by PAI-1.

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  • 1Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294-0012, USA.

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.

PMID:
21622848
[PubMed - indexed for MEDLINE]
PMCID:
PMC3154633
Free PMC Article
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