title: Urokinase-type plasminogen activator potentiates lipopolysaccharide-induced neutrophil activation.
abstract: Urokinase plasminogen activator (uPA) is a serine protease that catalyzes the conversion of plasminogen to plasmin. Although increased circulating levels of uPA are present in endotoxemia and sepsis, conditions in which activated neutrophils contribute to the development of acute organ dysfunction, the ability of uPA to participate directly in LPS-induced neutrophil activation has not been examined. In the present experiments, we show that uPA can enhance activation of neutrophils exposed to submaximal stimulatory doses of LPS. In particular, uPA increased LPS-induced activation of intracellular signaling pathways, including Akt and c-Jun N-terminal kinase, nuclear translocation of the transcriptional regulatory factor NF-kappa B, and expression of proinflammatory cytokines, including IL-1 beta, macrophage-inflammatory protein-2, and TNF-alpha. There was no effect of uPA on LPS-induced activation of p38 mitogen-activated protein kinase in neutrophils. Transgenic mice unable to produce uPA (uPA(-/-)) were protected from endotoxemia-induced lung injury, as determined by development of lung edema, pulmonary neutrophil accumulation, lung IL-1 beta, macrophage-inflammatory protein-2, and TNF-alpha cytokine levels. These results demonstrate that uPA can potentiate LPS-induced neutrophil responses and also suggest that such effects are sufficiently important in vivo to play a major contributory role in neutrophil-mediated inflammatory responses, such as the development of acute lung injury.
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA. edward.abraham@uchsc.edu
authors.forename: Edward
authors.initials: E
authors.lastname: Abraham
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Gyetko
authors.forename: Katherine
authors.initials: K
authors.lastname: Kuhn
authors.forename: John
authors.initials: J
authors.lastname: Arcaroli
authors.forename: Derek
authors.initials: D
authors.lastname: Strassheim
authors.forename: Jong Sung
authors.initials: JS
authors.lastname: Park
authors.forename: Sreerama
authors.initials: S
authors.lastname: Shetty
authors.forename: Steven
authors.initials: S
authors.lastname: Idell
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics / Q000276:immunology; D000208:Acute Disease; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D004357:Drug Synergism; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D018375:Neutrophil Activation / Q000235:genetics / Q000276:immunology*; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D014568:Urokinase-Type Plasminogen Activator / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D014568:Urokinase-Type Plasminogen Activator