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CLINICAL STUDY: ENDOTHELIAL FUNCTION

Acute systemic inflammation enhances endothelium-dependent tissue plasminogen activator release in men

Stanley Chia, MB, ChB (Hons), MRCP^*,*, Christopher A. Ludlam, MB, ChB, PhD, FRCP, FRCPath, Keith A. A. Fox, BSc (Hons), MB, ChB, FRCP, FESC^* and David E. Newby, BA, BSc (Hons), PhD, BM, DM, MRCP^*

^* Cardiovascular Research, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom
Department of Haematology, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom

Manuscript received June 5, 2002; revised manuscript received September 16, 2002, accepted September 20, 2002.

^* Reprint requests and correspondence: Dr. Stanley Chia, Cardiovascular Research, Department of Cardiology, Royal Infirmary of Edinburgh, Lauriston Place, Edinburgh EH3 9YW, United Kingdom.
schia{at}ed.ac.uk

OBJECTIVES: 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 µg/min), and sodium nitroprusside (2 to 8 µg/min).

RESULTS: Compared with placebo, the S. typhi vaccination caused a rise in white cell count (11.1 ± 0.5 x10⁹/l vs. 7.9 ± 0.8 x10⁹/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.

Abbreviations and Acronyms   ANOVA   analysis of variance   CRP   C-reactive protein   FBF   forearm blood flow   IL-6   interleukin-6   PAI-1   plasminogen activator inhibitor type 1   t-PA   tissue-type plasminogen activator

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