title: Regulation of lipopolysaccharide-induced lung inflammation by plasminogen activator Inhibitor-1 through a JNK-mediated pathway.
abstract: The neutrophil is of undoubted importance in lung inflammation after exposure to LPS. We have shown recently that systemic inhibition of JNK decreased neutrophil recruitment to the lung after exposure to LPS, although the mechanisms underlying this inhibition are incompletely understood. As plasminogen activator inhibitor-1 (PAI-1) accentuates cell migration, with JNK activation recently shown to up-regulate PAI-1 expression, this suggested that systemic JNK inhibition may down-regulate LPS-induced pulmonary neutrophil recruitment through a decrease in PAI-1 expression. We show in this study that exposure of mice to aerosolized LPS increased PAI-1 expression in the lung and alveolar compartment, which was decreased by pretreatment with the JNK inhibitor SP600125. Exogenous, intratracheally administered PAI-1 prevented the inhibition of pulmonary neutrophil recruitment in the setting of systemic JNK inhibition, thereby suggesting a role for PAI-1 in the JNK-mediated pathway regulating LPS-induced neutrophil recruitment. In addition, PAI-1(-/-) mice had a decrease in neutrophil recruitment to the alveolar compartment after exposure to LPS, compared with wild-type controls, further suggesting a role for PAI-1 in LPS-induced lung inflammation. An increase in the intravascular level of KC is a likely mechanism for the inhibition of pulmonary neutrophil recruitment after LPS exposure in the setting of decreased PAI-1 expression, as systemic KC levels after exposure to LPS were increased in PAI-1-deficient mice and in mice pretreated with SP600125, with augmentation of intravascular KC levels inhibiting neutrophil recruitment to the lung after exposure to LPS.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO 80206, USA. Patrick.Arndt@UCHSC.edu
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Arndt
authors.forename: Scott K
authors.initials: SK
authors.lastname: Young
authors.forename: G Scott
authors.initials: GS
authors.lastname: Worthen
mesh_terms: D000818:Animals; D002460:Cell Line; D002634:Chemotaxis, Leukocyte; D005260:Female; D007249:Inflammation / Q000139:chemically induced*; D016209:Interleukin-8 / Q000097:blood; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D016209:Interleukin-8; D008070:Lipopolysaccharides; D017395:Plasminogen Activator Inhibitor 1; D047428:Protein Kinase Inhibitors; D048031:JNK Mitogen-Activated Protein Kinases