Abstract
IntroductionHeme oxygenase-1 (HO-1) is a stress response enzyme, which catalyses the breakdown of heme into biliverdin-IX alpha, carbon monoxide and ferrous iron. Under situations of oxidative stress, heat stress, ischemia/reperfusion injury or endotoxemia, HO-1 has been shown to be induced and to elicit a protective effect. The mechanism of how this protective effect is executed is unknown.ResultsHO-1 induction with cobalt protoporphorin (Co-PP) dose-dependently protected against apoptotic cell death as well as neutrophil-mediated oncosis in the galactosamine/endotoxin (Gal/ET) shock model. Induction of HO-1 with Co-PP dose-dependently protected against neutrophil-mediated oncosis as indicated by attenuated ALT release and TNF-mediated apoptotic cell death as indicated by reduced caspase-3 activation. HO-1 induction did not attenuate Gal/ET-induced TNF-alpha formation. Furthermore, a similar protective effect with the high dose of Co-PP was observed when animals were treated with Gal/TNF-alpha.ConclusionsHO-1 induction attenuates apoptosis and neutrophil-mediated oncosis in the Gal/ET shock model. However, the protective effect is not due to the reduction of TNF-alpha release or the attenuation of neutrophil accumulation in the liver sinusoids.
Highlights
Heme oxygenase-1 (HO-1) is a stress response enzyme, which catalyses the breakdown of heme into biliverdin-IX alpha, carbon monoxide and ferrous iron
Among the three isoenzymes cloned to date, only heme oxygenase-1 (HO-1) can be induced by a variety of disparate stimuli, most of which are linked by their ability to provoke oxidative stress [1]
Western blot and immunohistochemical analysis indicated that cobalt protoporphyrin (Co-PP) dose-dependently induced HO-1 expression in hepatocytes and nonparenchymal cells, especially Kupffer cells
Summary
Heme oxygenase-1 (HO-1) is a stress response enzyme, which catalyses the breakdown of heme into biliverdin-IX alpha, carbon monoxide and ferrous iron. Under situations of oxidative stress, heat stress, ischemia/reperfusion injury or endotoxemia, HO-1 has been shown to be induced and to elicit a protective effect. Heme oxygenase (HO) catalyzes the oxidative cleavage of Fe-protoporphyrin-IX yielding equimolar amounts of biliverdin-IX alpha, free divalent iron, and carbon monoxide (CO) [1]. Induction of HO-1 may protect the cell against oxidative injury by a) controlling intracellular levels of "free" heme (a prooxidant), b) producing biliverdin (an antioxidant), c) improving nutritive perfusion via CO release, and d) fostering the synthesis of the Fe-binding protein ferritin [1]. HO-1 induction protected against ischemia/reperfusion injury [2,3] and endotoxemia [4]. It is (page number not for citation purposes)
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