Molecular mechanisms of liver preconditioning

Abstract

Ischemia/reperfusion (I/R) injury still represents an important cause of morbidity following hepatic surgery and limits the use of marginal livers in hepatic transplantation. Transient blood flow interruption followed by reperfusion protects tissues against damage induced by subsequent I/R. This process known as ischemic preconditioning (IP) depends upon intrinsic cytoprotective systems whose activation can inhibit the progression of irreversible tissue damage. Compared to other organs, liver IP has additional features as it reduces inflammation and promotes hepatic regeneration. Our present understanding of the molecular mechanisms involved in liver IP is still largely incomplete. Experimental studies have shown that the protective effects of liver IP are triggered by the release of adenosine and nitric oxide and the subsequent activation of signal networks involving protein kinases such as phosphatidylinositol 3-kinase, protein kinase C δ/ε and p38 MAP kinase, and transcription factors such as signal transducer and activator of transcription 3, nuclear factor-κB and hypoxia-inducible factor 1. This article offers an overview of the molecular events underlying the preconditioning effects in the liver and points to the possibility of developing pharmacological approaches aimed at activating the intrinsic protective systems in patients undergoing liver surgery.

Figure 1

Signalling pathways involved in the development of ischemic preconditioning in rat hepatocytes. Adenosine triphosphate (ATP), adenosine and nitric oxide (NO) act as inductors of hepatocyte preconditioning by modulating a network of constitutive and newly synthesized signal mediators. Some of these mediators play a common central role in hepatocyte cytoprotection. p38 MAP kinase (p38 MAPK) is a mediator of the cytoprotective effects of all three preconditioning stimuli. Phosphatidylinositol 3-kinase (PI3K) mediates both adenosine and NO early resistance to hypoxia. PI3K together with protein kinase C (PKC) δ and ε, also induces hepatocyte late resistance to hypoxia contributing to the normoxic activation of hypoxia-inducible factor 1 (HIF-1). Diacylglycerol kinase theta (DGKθ) and the phosphatase tensin-homologues-deleted from chromosome 10 (PTEN) which metabolize diacyglycerol and phosphatidylinositol, respectively, are inhibited during preconditioning to sustain activation of the diacylglycerol (DAG)-dependent PKC δ and ε and the PI3K-dependent signals. See text and Refs[21,25,27,28,32,35,37,43]. P2YR: Purinergic P2Y receptors; A2aR: Adenosine 2A receptors; S-CG: Soluble guanylate cyclase; cGMP: Cyclic guanosine monophosphate; cGK: cGMP-dependent kinase; AC: Adenylate cyclase; cAMP: Cyclic adenosine monophosphate; PIP3: Phosphatidylinositol-3-phosphate; PKA: Protein kinase A; CAIX: Carbonic anhydrase IX; PLC: Phospholipase C; PA: Phosphatidic acid.

Figure 2

Na⁺-dependent mechanisms involved in hepatocyte damage by hypoxia and their modulation by ischemic preconditioning. Hypoxia-induced adenosine triphosphate (ATP) depletion causes intracellular acidification, leading to inhibition of Na⁺/K⁺ ATPase and the activation of acid buffering systems (Na⁺/H⁺ exchanger). This leads to an increase in intracellular Na⁺ that precipitates irreversible hepatocyte damage. ATP-dependent signalling through purinergic P2Y receptors prevents Na⁺ accumulation by inhibiting the ERK 1/2-dependent activation of the Na⁺/H⁺ exchanger. Adenosine and nitric oxide (NO) activate the vacuolar proton ATPase that maintains intracellular pH avoiding activation of the Na⁺/H⁺ exchanger. Adenosine also induces the hypoxia-inducible factor 1 (HIF-1) target gene, carbonic anhydrase IX (CAIX), which converts CO₂ into bicarbonate, that once transported into the hepatocytes through the Cl^-/HCO₃^- exchanger, neutralizes the intracellular pH and prevents Na⁺ accumulation. See text and Refs[20,21,25,27,28,43,52,53,58]. P38 MAPK: p38 MAP kinase; PI3-kinase: Phosphatidylinositol 3-kinase; PKC: Protein kinase C.