Hepatic organ protection: From basic science to clinical practice

Abstract

Hepatic ischemia and reperfusion (I/R) injury during liver surgery is still the main cause of postoperative liver failure and the subsequent rise of mortality in these patients. During the last few years, a multitude of underlying mechanisms have been extensively characterized and many different protective approaches have been evaluated under experimental conditions. Some of them have already found their way into small sized clinical trials. In this Topic Highlight series of articles, we present recent insights into promising protective concepts including the regulation and optimization of hepatic blood flow, molecular mechanisms of preconditioning and pharmacological approaches with the aim of limiting hepatic I/R injury. Leading international experts present the latest experimental evidence in their fields stressing clinically relevant ideas, which are now on the edge of entering clinical practice.

Key Words: Heme oxygenase-1, Hepatectomy, Hepatic organ protection, Ischemia/reperfusion injury, Liver blood flow, Liver transplantation, Preconditioning

TEXT

The sequence of hepatic ischemia and reperfusion (I/R) is frequently associated with the destruction of liver cells thus contributing to postoperative liver failure and increased mortality. In liver transplantation, up to 30% of delayed graft function are caused by the consequences of hepatic I/R injury[1]. Intermittent clamping of hepatic blood inflow (e.g. Pringle’s maneuver), an established technique to reduce blood loss during major liver resection, could have similar adverse effects by I/R mediated mechanisms. Furthermore, van der Bilt and colleagues demonstrated that I/R induced by vascular clamping is a strong stimulus that promotes the outgrowth of micrometastasis in the liver[2]. Therefore, the development of therapeutic concepts to prevent hepatic I/R injury has become the focus of intensive research efforts during the last few years. In this Topic Highlight series, we have put together a group of international experts providing an update on the latest achievements in their fields stressing clinically relevant ideas with the aim of protecting the liver against I/R injury. The maintenance of macro- and microvascular perfusion after hepatic ischemia plays a crucial role in the prevention of liver cell injury. In the first article of the present review series, Eipel et al[3] discuss recent insights into the regulation of hepatic blood flow and in particular the relevance of the “hepatic arterial buffer response”, an important intrinsic mechanism of the hepatic artery to produce compensatory flow changes in response to changes in portal venous flow. The authors present detailed experimental and clinical information stressing the crucial importance of the hepatic arterial buffer response as a regulatory mechanism to maintain adequate liver function and metabolic homeostasis. The second contribution focuses on preconditioning, an important phenomenon mediating cytoprotection in many different organs including the liver. Alchera et al[4] provide an interesting overview on the molecular mechanisms of liver preconditioning with special emphasis on the development of pharmacological approaches aimed at activating intrinsic protective systems in patients undergoing liver surgery. The next review concentrates on one of the most powerful inducible enzymes known today: heme oxygenase-1 (HO-1). HO-1 metabolizes heme into iron, carbon monoxide, and biliverdin, which is subsequently converted to bilirubin. Upregulation of HO-1 and administration of each of its reaction products has been shown to play a pivotal role in the maintenance of cellular function after sublethal stress in nearly all organ systems including the liver. However, the development of therapeutic strategies that utilize the protective effect of HO-1 induction is hampered by the fact that most pharmacological inducers of this enzyme perturb organ function by themselves and that gene therapy for upregulation of HO-1 has potential negative side effects, which currently preclude its clinical application under these conditions. Hence, most substances used for upregulation of HO-1 under experimental conditions are not available for use in patients because of their toxicity and undesirable or unknown side effects[5]. During the last years, a few non-toxic HO-1 inducing compounds have been identified in animal experiments including the β₁-agonist dobutamine, the phosphodiesterase-III-inhibitor olprinone, and the volatile anesthetics isoflurane and sevoflurane. Isoflurane has been shown to profoundly protect the liver against I/R injury by upregulation of HO-1 gene expression under experimental conditions[6,7]. As a consequence, volatile anesthetics are currently being evaluated for their potential to induce HO-1 and protect the liver against I/R in humans. In the present series of reviews, Richards et al[8] summarize HO-1 mediated protective effects within the liver and point to its therapeutic potential in detail. The protective role of nitric oxide (NO) in the context of hepatic I/R injury is then nicely presented by Siriussawakul and coworkers in their contribution[9]. The authors discuss the influence of endogenous NO on hepatic I/R injury and the potential therapeutic role of inhaled NO, nitrite and other NO donors in ameliorating hepatic I/R injury. Next, Mathes systematically describes the current knowledge on the antioxidant and other protective actions of melatonin in the liver. Melatonin, the “hormone of darkness”, has recently been shown to exert abundant hepatoprotective effects in a multitude of experimental studies. Mathes illustrates this topic in depth and highlights possible approaches for its beneficial use in patients[10]. Finally, Gurusamy et al[11] present the currently available clinical data concerning protective strategies in liver surgery and review the significance of these studies in an evidence-based approach.

The present Topic Highlight series “Hepatic organ protection: From basic science to clinical practice” is far from being a complete reference of all experimental evidence concerning liver protection. It presents fascinating clinically relevant experimental concepts aimed at the identification of surgical techniques and pharmacological compounds, which now have to be validated in large randomized clinical trials.