Author(s): Alexander Hoetzel, Daniel Leitz, Rene Schmidt, Eva Tritschler, Inge Bauer
HEPATIC reperfusion injury, e.g. , after transplantation, systemic low flow conditions, or disturbances of the hepatic microcirculation, is associated with high morbidity and mortality. To date, no pharmacologic strategy is clinically applicable that effectively prevents hepatic reperfusion injury and improves the outcome. The heme oxygenase (HO) pathway has been shown to limit reperfusion injury after experimental systemic and regional hepatic ischemia.1 Heme oxygenase 1 (HO-1) represents the inducible isoform of the microsomal HO family. HO-1 gene expression is up-regulated in response to a variety of stimuli and catalyzes the oxidation of heme to biliverdin-IXa, iron, and carbon monoxide. The HO system exerts major antioxidative, antiinflammatory, antiapoptotic, and vasodilatory characteristics.1,2 In that regard, preinduction of HO-1 and application of carbon monoxide have been shown to prevent reperfusion injury after liver transplantation or after systemic ischemia in several experimental studies.3 Therefore, the HO pathway seems to represent a promising candidate for reducing reperfusion injury in patients. Many efforts have been made to modulate or preinduce HO-1 and to optimize its protective potency against subsequent noxious stimuli. However, most inducers of HO-1 (e.g. , oxidative stress, hypoxia, hemin, cobalt chloride, radiation) have numerous side effects and therefore cannot be used in patients. Therefore, it is essential to identify substances or conditions that induce HO-1 without endangering the patient. We recently demonstrated that the volatile anesthetics isoflurane and sevoflurane are able to specifically up-regulate HO-1 gene expression.4 The mechanism of this inducing action remained unclear. However, characterization of the respective signal transduction pathway could help to establish new concepts aimed at modulating the HO system, furthermore expanding its protective function. In the current study, we investigated potential activating cascades and identified mechanisms of HO-1 regulation by the volatile anesthetic isoflurane.