title: Acute systemic inflammation enhances endothelium-dependent tissue plasminogen activator release in men.
abstract: OBJECTIVE
  The purpose of this study was to investigate in vivo the effects of acute systemic inflammation on the endogenous fibrinolytic capacity in men.
  
  
  BACKGROUND
  Systemic inflammation and endogenous fibrinolysis play a major role in the pathogenesis of coronary artery disease. Although previous studies have shown impaired endothelium-dependent vasomotor function, the effects of inflammation on the endothelial release of the fibrinolytic factor tissue plasminogen activator (t-PA) are unknown.
  
  
  METHODS
  In a double-blind randomized placebo-controlled crossover trial, we administered a mild inflammatory stimulus, Salmonella typhi vaccine, or saline placebo to eight healthy men on two separate occasions. Six hours after vaccination, blood flow and plasma fibrinolytic variables were measured in both arms during intrabrachial infusions of bradykinin (40 to 1,000 pmol/min), acetylcholine (5 to 20 microg/min), and sodium nitroprusside (2 to 8 microg/min).
  
  
  RESULTS
  Compared with placebo, the S. typhi vaccination caused a rise in white cell count (11.1 +/- 0.5 x10(9)/l vs. 7.9 +/- 0.8 x10(9)/l; p = 0.004) and plasma interleukin-6 concentrations (6.9 +/- 1.4 pg/ml vs. 1.6 +/- 0.4 pg/ml; p = 0.01) in addition to a significant augmentation of t-PA antigen (45 +/- 9 ng/100 ml/min at peak dose vs. 24 +/- 8 ng/100 ml/min at peak dose; p = 0.016, analysis of variance) and activity (104 +/- 15 IU/100 ml/min vs. 54 +/- 12 IU/100 ml/min; p = 0.006, analysis of variance) release during bradykinin infusion. Forearm blood flow increased in a dose-dependent manner after bradykinin, acetylcholine and sodium nitroprusside infusions (p < 0.001), but this was unaffected by vaccination.
  
  
  CONCLUSIONS
  Our results showed that acute systemic inflammation augmented local forearm t-PA release in men, which suggests that acute inflammation may invoke a protective response by enhancing the acute endogenous fibrinolytic capacity in healthy men. Further studies are needed to clarify whether this response is impaired in patients with cardiovascular disease.
authors.affiliation: Cardiovascular Research, University of Edinburgh, Royal Infirmary of Edinburgh, United Kingdom. schia@ed.ac.uk
authors.forename: Stanley
authors.initials: S
authors.lastname: Chia
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ludlam
authors.forename: Keith A A
authors.initials: KA
authors.lastname: Fox
authors.forename: David E
authors.initials: DE
authors.lastname: Newby
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D001916:Brachial Artery / Q000187:drug effects / Q000378:metabolism; D001920:Bradykinin / Q000494:pharmacology*; D003324:Coronary Artery Disease / Q000276:immunology*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood* / Q000276:immunology; D012039:Regional Blood Flow; D010959:Tissue Plasminogen Activator / Q000097:blood* / Q000276:immunology; D014436:Typhoid-Paratyphoid Vaccines / Q000008:administration & dosage*
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D014436:Typhoid-Paratyphoid Vaccines; D009599:Nitroprusside; D010959:Tissue Plasminogen Activator; D000109:Acetylcholine; D001920:Bradykinin