Effect of ascorbate on fibrinolytic factors in septic mouse skeletal muscle.
Plugging of the capillary bed in tissues correlates with organ failure during sepsis. In septic mouse skeletal muscle, we showed that blood in capillaries becomes hypercoagulable and that ascorbate injection inhibits capillary plugging. In the present study, we hypothesized that ascorbate promotes fibrinolysis, reversing this plugging. Sepsis in mice was induced by fecal injection into peritoneum. Mice were injected intravenously with a bolus of streptokinase (fibrinolytic agent) or ascorbate at 5-6 h. Both agents reversed capillary plugging in muscle at 7 h. Sepsis increased mRNA expression of urokinase plasminogen activator (u-PA) (profibrinolytic) and plasminogen activator inhibitor 1 (PAI-1) (antifibrinolytic) in muscle and liver homogenates at 7 h. Ascorbate did not affect u-PA mRNA in either tissue, but it inhibited PAI-1 mRNA in muscle, suggesting enhanced fibrinolysis in this tissue. However, ascorbate did not affect increased PAI-1 mRNA in the liver (dominant source of soluble PAI-1 in systemic blood). Consistently, ascorbate affected neither elevated PAI-1 protein/enzymatic activity in septic liver nor lowered plasmin antiplasmin level in septic blood. Furthermore, hypocoagulability of septic blood revealed by thrombelastography and thrombin-induced PAI-1 release from isolated platelets (ex-vivo model of sepsis) were not affected by ascorbate. Based on the PAI-1 protein data, the present study does not support the hypothesis that ascorbate promotes fibrinolysis in sepsis.
aCritical Illness Research, Lawson Health Research Institute, London, Ontario bDepartment of Physiology and Pharmacology cDepartment of Medical Biophysics dDepartment of Anesthesia and Perioperative Medicine, Critical Care Western, University of Western Ontario, London eDepartment of Medicine, Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada fDepartment of Exercise and Nutrition Sciences, University at Buffalo, Buffalo, New York, USA.
Scott
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Swarbreck
Dan
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Secor
Fuyan
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Li
Peter L
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Gross
Christopher G
CG
Ellis
Michael D
MD
Sharpe
John X
JX
Wilson
Karel
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D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology*; D005342:Fibrinolysis / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018805:Sepsis / Q000097:blood* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D058258:Serpin E2 / Q000235:genetics / Q000378:metabolism; D013916:Thrombelastography / Q000379:methods; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism
D012333:RNA, Messenger; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D001205:Ascorbic Acid