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-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.

Mechanisms of Severe Acute Respiratory Syndrome Coronavirus-Induced Acute Lung Injury

“…Although we cannot absolutely ascribe this phenotype to elevation in the levels of fibrin and fibrin breakdown products, fluorescence-activated cell sorting (FACS) analysis shows significant increases in lung neutrophil counts, as a function of increasing SARS-CoV dose (data not shown). More recent studies have also shown that Serpine1 inhibits neutrophil apoptosis (53), suggesting that neutrophil recruitment and effector function likely contribute to more severe disease outcomes following SARS-CoV MA15 infection. Similar findings have been reported with highly pathogenic influenza viruses, including H5N1 and 1918 influenza viruses (54).…”

Novel concepts of acute lung injury and alveolar-capillary barrier dysfunction

“…Transgenic mouse models reveal that components of the coagulation cascade impact on neutrophil recruitment or their survival. Plasminogen activator inhibitor-1 (PAI-1) enhances neutrophil recruitment after P. aeruginosa infection and exerts antiapoptotic effects on neutrophils via phosphatidylinositol 3-kinase activation in a model of LPSinduced acute lung injury (80,277), increasing neutrophil load in the air spaces. Tissue plasminogen activator (tPA)-deficient mice are protected from lung ischemia-reperfusion injury through inhibition of neutrophil recruitment, which is mediated by the tPA/LDL receptor-related protein/NF-B signaling pathway and reduction in PECAM-1 expression (275).…”

The inflammasome in lung diseases

“…IL-1␤ also promotes the secretion of neutrophil-attracting CXC chemokines, which favor the influx of neutrophils and exacerbate the damage to epithelial cells, and PDGF, which further induces fibrosis. Finally, TGF-␤ and IL-1␤ can increase the expression of plasminogen activator inhibitor 1, which inhibits ECM degradation, promotes recruitment of more inflammatory cells (67), and suppresses the release of antifibrogenic growth factors (30). The initial proinflammatory scenario of inflammasome activation can rapidly progress to a profibrotic one, leading to the chronic and devastating disease.…”