The nitric oxide pathway – evidence and mechanisms for protection against liver ischaemia reperfusion injury

Authors

  • Mahmoud Abu-Amara,

    1. Liver Transplantation and Hepatobiliary Unit, Royal Free Hospital, London, UK
    2. Division of Surgery & Interventional Science, University College London, London, UK
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  • Shi Yu Yang,

    1. Division of Surgery & Interventional Science, University College London, London, UK
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  • Alexander Seifalian,

    1. Division of Surgery & Interventional Science, University College London, London, UK
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  • Brian Davidson,

    1. Liver Transplantation and Hepatobiliary Unit, Royal Free Hospital, London, UK
    2. Division of Surgery & Interventional Science, University College London, London, UK
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  • Barry Fuller

    Corresponding author
    1. Division of Surgery & Interventional Science, University College London, London, UK
    • Liver Transplantation and Hepatobiliary Unit, Royal Free Hospital, London, UK
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Correspondence

Professor Barry Fuller, Division of Surgery & Interventional Science, University College London, 9th Floor, Royal Free Hospital, Pond Street, London, NW3 2QG, UK

Tel: ++44 20 7472 6111

Fax: ++44 20 7830 2688

e-mail: b.fuller@medsch.ucl.ac.uk

Abstract

Ischaemia reperfusion (IR) injury is a clinical entity with a major contribution to the morbidity and mortality of liver surgery and transplantation. A central pathway of protection against IR injury utilizes nitric oxide (NO). Nitric oxide synthase (NOS) enzymes manufacture NO from L-arginine. NO generated by the endothelial NOS (eNOS) isoform protects against liver IR injury, whereas inducible NOS (iNOS)-derived NO may have either a protective or a deleterious effect during the early phase of IR injury, depending on the length of ischaemia, length of reperfusion and experimental model. In late phase hepatic IR injury, iNOS-derived NO plays a protective role. In addition to NOS consumption of L-arginine during NO synthesis, this amino acid may also be metabolized by arginase, an enzyme whose release is increased during prolonged ischaemia, and therefore diverts L-arginine away from NOS metabolism leading to a drop in the rate of NO synthesis. NO most commonly acts through the soluble guanylyl cyclase-cyclic GMP- protein kinase G pathway to ameliorate hepatic IR injury. Both endogenously generated and exogenously administered NO donors protect against liver IR injury. The beneficial effects of NO on liver IR are not, however, universal, and certain conditions, such as steatosis, may influence the protective effects of NO. In this review, the evidence for, and mechanisms of these protective actions of NO are discussed, and areas in need of further research are highlighted.

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