| Autor: |
MULLARKY, I.K., SZABA, F.M., WINCHEL, C.G., PARENT, M.A., KUMMER, L.W., MACKMAN, N., JOHNSON, L.L., SMILEY, S.T. |
| Zdroj: |
Journal of Thrombosis and Haemostasis; July 2006, Vol. 4 Issue: 7 p1580-1587, 8p |
| Abstrakt: |
Background: Inflammatory cytokines potently impact hemostatic pathways during infection, but the tissue‐specific regulation of coagulation and fibrinolysis complicates studies of the underlying mechanisms. Methods and Results: Here, we describe assays that quantitatively measuring prothrombinase (PTase), protein C‐ase (PCase) and plasminogen activator (PA) activities in situ, thereby facilitating studies of tissue‐specific hemostasis. Using these assays, we investigate the mechanisms regulating hepatic fibrin deposition during murine toxoplasmosis and the means by which interferon‐gamma (IFN‐γ) suppresses infection‐stimulated fibrin deposition. We demonstrate that Toxoplasmainfection upregulates hepatic PTase, PCase, and PA activity. Wild type and gene‐targeted IFN‐γ‐deficient mice exhibit similar levels of infection‐stimulated PTase activity. By contrast, IFN‐γ‐deficiency is associated with increased PCase activity and reduced PA activity during infection. Parallel analyses of hepatic gene expression reveal that IFN‐γ‐deficiency is associated with increased expression of thrombomodulin (TM), a key component of the PCase, increased expression of thrombin‐activatable fibrinolysis inhibitor (TAFI), a PC substrate, and reduced expression of urokinase PA (u‐PA). Conclusions: These findings suggest that IFN‐γsuppresses infection‐stimulated hepatic fibrin deposition by suppressing TM‐mediated activation of TAFI, thereby destabilizing fibrin deposits, and concomitantly increasing hepatic u‐PA activity, thereby promoting fibrinolysis. We anticipate that further application of these in situassays will improve our understanding of tissue‐specific hemostasis, its regulation by cytokines, and its dysregulation during coagulopathy. |
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