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Hepatology. 2001 Apr;33(4):925-37.

Effect of nitric oxide on shock-induced hepatic heme oxygenase-1 expression in the rat.

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Department of Anesthesiology and Critical Care Medicine, University of Freiburg, Germany.


Recent evidence suggests that the hepatic expression of heme oxygenase-1 (HO-1) may preserve hepatocellular integrity after hemorrhagic shock and resuscitation (HR). Because nitric oxide (NO) has been shown to modulate HO-1 expression in cultured cells in vitro, we determined its potential role in the regulation of HO-1 expression after HR in the rat liver in vivo. HO-1 mRNA and protein were highly induced and HO enzyme activity was higher after HR when compared with time-matched sham controls. Administration of the NO donor, molsidomine (MOL) (3 mg. kg(-1)), during resuscitation attenuated the accumulation of HO-1 mRNA and protein and the rise in HO activity. In addition, MOL prevented the shock-induced increase in DNA binding activity of the transcription factor, activator protein-1 (AP-1), but did not alter the activity of nuclear factor-erythroid 2 related factor (Nrf-2), nuclear transcription factor-kappaB (NF-kappaB), and hypoxia-inducible factor-1 (HIF-1). The suppressing action of MOL was not confined to HO-1, because the hepatic expression of the 70-kd major heat shock protein (HSP) in response to HR was also diminished. Moreover, MOL prevented the HR-induced increase in the serum activity of alanine transaminase (ALT) and alpha-glutathione-S-transferase (alpha-GST) that could otherwise be observed after HR. In contrast, the NO synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME) (1, had either no or only minor effects on the primary experimental endpoints. These findings would be consistent with a reduction of shock-induced liver damage by exogenous NO, which in turn prevents the subsequent activation of injury-sensitive transcription factors, thus attenuating the expression of stress-inducible proteins such as HO-1.

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