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INFLAMMATION/IMMUNITY/MEDIATORS
1Departments of Medicine, 2Biochemistry and Biophysics, and 3Cell Biology and Anatomy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7032
Submitted 22 January 2003 ; accepted in final form 21 May 2003
Recent evidence indicates that angiotensin II (ANG II) plays an important
role in liver fibrogenesis. However, the underlying mechanisms are largely
unknown. In advanced chronic liver diseases, circulating levels of ANG II are
frequently elevated. We investigated the hepatic effects of prolonged systemic
infusion of ANG II in normal rats. Saline or ANG II at subpressor and pressor
doses (15 and 50
ng·kg-1·min-1,
respectively) were infused to normal rats for 4 wk through a subcutaneous
osmotic pump. Infusion of ANG II resulted in liver injury, as assessed by
elevated serum liver enzymes. Livers from ANG II-perfused rats showed
activation of JNK and ERK as well as increased NF-
B and activating
protein-1 DNA-binding activity. Moreover, ANG II perfusion induced oxidative
stress, increased concentration of proinflammatory cytokines, and upregulated
the inflammatory proteins inducible nitric oxide synthase and
cyclooxygenase-2. Histological examination of the livers from ANG II-infused
rats showed mild portal inflammation as well as thickening and thrombosis of
small hepatic vessels. ANG II-treated livers showed accumulation of
CD43-positive inflammatory cells and activated hepatic stellate cells (HSCs)
at the pericentral areas. A slight increase in collagen synthesis was
observed, as assessed by Sirius red staining and hepatic hydroxyproline. All
of these effects were observed when ANG II was perfused at subpressor and
pressor doses. ANG II also accelerated the activation of primary cultured rat
HSCs. In conclusion, increased systemic ANG II can induce liver injury by
promoting proinflammatory events and vascular damage. ANG II-induced hepatic
effects are not dependent on increase in arterial pressure.
hepatic inflammation; renin-angiotensin system; cytokines
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