title: Plasmin-dependent proteolysis of tissue factor pathway inhibitor in a mouse model of endotoxemia.
abstract: BACKGROUND
  The development of a procoagulant state in sepsis, owing to aberrant expression of tissue factor (TF) and a sharp decrease in the level of its major inhibitor, TF pathway inhibitor (TFPI), could lead to microthrombotic organ failure. The mechanism for the decline in TFPI activity in the lung could involve plasmin-mediated cleavage of the inhibitor.
  
  
  OBJECTIVE
  To investigate the effect of plasmin generation on lung-associated TFPI activity, in normal conditions and during infusion of endotoxin (lipopolysaccharide [LPS]) in mice.
  
  
  METHODS
  Plasmin generation and TFPI activity were assayed in the lungs of mice deficient in tissue-type plasminogen (Plg) activator (t-PA) or Plg, at 2 h after LPS or saline injection.
  
  
  RESULTS
  The sharp loss of lung-associated TFPI activity at 2 h after LPS challenge paralleled the abrupt increase in plasmin generation. TFPI activity was significantly retained in both t-PA(-/-) and Plg(-/-) mice, which are unable to generate plasmin.
  
  
  CONCLUSIONS
  The increased plasmin generation during the early stages of sepsis could cleave/inactivate TFPI and thus lead to thrombotic complications.
authors.affiliation: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors.forename: C
authors.initials: C
authors.lastname: Lupu
authors.forename: O
authors.initials: O
authors.lastname: Herlea
authors.forename: H
authors.initials: H
authors.lastname: Tang
authors.forename: R H
authors.initials: RH
authors.lastname: Lijnen
authors.forename: F
authors.initials: F
authors.lastname: Lupu
mesh_terms: D000818:Animals; D001777:Blood Coagulation; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D019446:Endotoxemia / Q000097:blood* / Q000139:chemically induced / Q000150:complications / Q000235:genetics; D004731:Endotoxins; D005260:Female; D005341:Fibrinolysin / Q000378:metabolism*; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010958:Plasminogen / Q000172:deficiency / Q000235:genetics; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013927:Thrombosis / Q000097:blood / Q000209:etiology; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000172:deficiency / Q000235:genetics; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D004731:Endotoxins; D008074:Lipoproteins; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; C051928:lipoprotein-associated coagulation inhibitor; C044101:endotoxin, Escherichia coli; D010958:Plasminogen; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin