Gastroenterology

Gastroenterology

Volume 125, Issue 3, September 2003, Pages 917-936
Gastroenterology

Special reports and review
Protective strategies against ischemic injury of the liver☆

https://doi.org/10.1016/S0016-5085(03)01048-5Get rights and content

Abstract

This article summarizes strategies to protect the liver from injuries caused by ischemia and reperfusion. Three different sections (i.e., surgical and pharmacologic strategies and gene therapy) present approaches to enhance the survival and viability of the liver in various surgical procedures including liver transplantation. The first section reviews approaches using surgical interventions such as ischemic preconditioning and intermittent clamping. Their protective effects are discussed with respect to the mechanism of injury. In the second section, pharmacologic agents targeting microcirculation, oxidative stress, proteases, and inflammation are described. Mechanisms of injury and their suppression by a wide variety of drugs are discussed. The third section focuses on gene therapy. Potential target genes have been identified (e.g., superoxide dismutase or heme oxygenase). Animal experiments in which the liver injury is reduced successfully may pave the way to novel strategies applied to different liver diseases in humans.

Section snippets

Should we differentiate different types of ischemic injury of the liver?

The liver can be subjected to 3 forms of ischemia, namely cold (or hypothermic), warm (or normothermic), and rewarming.3 Cold ischemia occurs almost exclusively in the transplant setting where it is applied intentionally to reduce metabolic activities of the graft while the organ awaits implantation. Warm ischemia occurs in a variety of situations including transplantation, trauma, shock, and liver surgery, when hepatic inflow occlusion (Pringle maneuver) or inflow and outflow (total vascular

How can we protect the liver against ischemic injury?

Many protective strategies have been proposed, which can be classified in different ways. For example, from a practical perspective, protective strategies can be divided into 3 different categories: (1) surgical interventions, (2) the use of pharmacologic agents, and (3) gene therapy. Another possibility is to present the strategies based on the protective mechanisms: (1) strategies aimed at a preemptive induction of tolerance against ischemic injury, which can be covered by the concept of

Surgical strategies

Today, 2 powerful strategies are in clinical use, ischemic preconditioning and intermittent clamping (Figure 4). Other protocols that have shown protection in animal models include preconditioning by hyperthermia56, 57, 58, 59, 60, 61 and application of a portosystemic shunt during the hepatic inflow occlusion,23 but these approaches never made the transition into clinical practice outside of case reports.

Pharmacologic strategies

A large number of pharmacologic agents were shown to confer protection against ischemic injury in the liver. They either blocked the injurious pathways directly or they subjected the liver to preconditioning (i.e., they induced a low level of stress to the liver cells that initiated cellular defense mechanisms against a subsequent stronger insult). A nonexhaustive list of all these agents is presented in Table 1. A number of these agents mentioned later have been identified during studies on

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    ☆

    Supported by a grant from the National Institutes of Health (DK54048) and from the Swiss National Science Foundation (SNF3200–061411) (to P.-A.C.).

    1

    N.S. and H.R. contributed equally to this work.

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