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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
26
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pubmed:dateCreated |
2011-6-27
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pubmed:abstractText |
Urokinase plasminogen activator (uPA) and PA inhibitor type 1 (PAI-1) are elevated in acute lung injury, which is characterized by a loss of endothelial barrier function and the development of pulmonary edema. Two-chain uPA and uPA-PAI-1 complexes (1-20 nM) increased the permeability of monolayers of human pulmonary microvascular endothelial cells (PMVECs) in vitro and lung permeability in vivo. The effects of uPA-PAI-1 were abrogated by the nitric-oxide synthase (NOS) inhibitor L-NAME (N(D)-nitro-L-arginine methyl ester). Two-chain uPA (1-20 nM) and uPA-PAI-1 induced phosphorylation of endothelial NOS-Ser(1177) in PMVECs, which was followed by generation of NO and the nitrosylation and dissociation of ?-catenin from VE-cadherin. uPA-induced phosphorylation of eNOS was decreased by anti-low density lipoprotein receptor-related protein-1 (LRP) antibody and an LRP antagonist, receptor-associated protein (RAP), and when binding to the uPA receptor was blocked by the isolated growth factor-like domain of uPA. uPA-induced phosphorylation of eNOS was also inhibited by the protein kinase A (PKA) inhibitor, myristoylated PKI, but was not dependent on PI3K-Akt signaling. LRP blockade and inhibition of PKA prevented uPA- and uPA-PAI-1-induced permeability of PMVEC monolayers in vitro and uPA-induced lung permeability in vivo. These studies identify a novel pathway involved in regulating PMVEC permeability and suggest the utility of uPA-based approaches that attenuate untoward permeability following acute lung injury while preserving its salutary effects on fibrinolysis and airway remodeling.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Cyclic AMP-Dependent Protein Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Low Density Lipoprotein...,
http://linkedlifedata.com/resource/pubmed/chemical/NG-Nitroarginine Methyl Ester,
http://linkedlifedata.com/resource/pubmed/chemical/Nitric Oxide Synthase Type III,
http://linkedlifedata.com/resource/pubmed/chemical/Nos3 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Plasminogen Activator Inhibitor 1,
http://linkedlifedata.com/resource/pubmed/chemical/SERPINE1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Serpin E2,
http://linkedlifedata.com/resource/pubmed/chemical/Serpine2 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Urokinase-Type Plasminogen Activator
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pubmed:status |
MEDLINE
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pubmed:month |
Jul
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pubmed:issn |
1083-351X
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
1
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pubmed:volume |
286
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
23044-53
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pubmed:dateRevised |
2011-11-17
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pubmed:meshHeading |
pubmed-meshheading:21540184-Acute Lung Injury,
pubmed-meshheading:21540184-Animals,
pubmed-meshheading:21540184-Blood-Air Barrier,
pubmed-meshheading:21540184-Capillary Permeability,
pubmed-meshheading:21540184-Cell Line,
pubmed-meshheading:21540184-Cyclic AMP-Dependent Protein Kinases,
pubmed-meshheading:21540184-Enzyme Inhibitors,
pubmed-meshheading:21540184-Fibrinolysis,
pubmed-meshheading:21540184-Humans,
pubmed-meshheading:21540184-Low Density Lipoprotein Receptor-Related Protein-1,
pubmed-meshheading:21540184-Mice,
pubmed-meshheading:21540184-Mice, Knockout,
pubmed-meshheading:21540184-NG-Nitroarginine Methyl Ester,
pubmed-meshheading:21540184-Nitric Oxide Synthase Type III,
pubmed-meshheading:21540184-Phosphorylation,
pubmed-meshheading:21540184-Plasminogen Activator Inhibitor 1,
pubmed-meshheading:21540184-Pulmonary Edema,
pubmed-meshheading:21540184-Respiratory Mucosa,
pubmed-meshheading:21540184-Serpin E2,
pubmed-meshheading:21540184-Urokinase-Type Plasminogen Activator
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pubmed:year |
2011
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pubmed:articleTitle |
Urokinase-type plasminogen activator (uPA) induces pulmonary microvascular endothelial permeability through low density lipoprotein receptor-related protein (LRP)-dependent activation of endothelial nitric-oxide synthase.
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pubmed:affiliation |
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
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pubmed:publicationType |
Journal Article,
Research Support, N.I.H., Extramural
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