How ischaemic preconditioning protects small liver grafts.
Interleukin-1 (IL-1) and transforming growth factor-beta (TGFbeta) are key inhibitors of hepatocyte proliferation after hepatectomy. IL-1 inhibition by heat shock proteins (HSPs) has been reported in inflammatory processes. A recent study indicated the benefits of ischaemic preconditioning in reduced-size orthotopic liver transplantation (ROLT). The present study examined: (a) the effect of ischaemic preconditioning on IL-1 and TGFbeta in ROLT; (b) whether preconditioning protects small liver grafts through HSP induction; and (c) whether the potential benefits of preconditioning on HSP is related to IL-1 inhibition. Our results, obtained with an IL-1 receptor antagonist, indicated the injurious effects of IL-1 in ischaemia-reperfusion (I/R) injury and established a relationship between IL-1 and growth factors. Thus, IL-1 reduced hepatocyte growth factor (HGF) and promoted TGFbeta release, thus contributing to the impaired liver regeneration associated with ROLT. Preconditioning inhibited IL-1 through nitric oxide (NO), thereby protecting against the injurious effects of IL-1. In addition, by another pathway independent of NO, preconditioning induced HSP70 and haem-oxygenase-1 (HO-1). HO-1 protected against I/R injury and liver regeneration, whereas the benefits resulting from HSP70 were mainly related to hepatocyte proliferation. These results suggest a mechanism that explains the effectiveness of preconditioning in ROLT. They suggest, too, that other strategies, in addition to preconditioning, that modulate IL-1 and/or HSPs could be considered in clinical situations requiring liver regeneration such as small liver grafts.
Franco-Gou
R
R
Experimental Hepatology Unit, Instituto de Investigaciones Biomédicas de Barcelona -CSIC, Institut d'Investigacions Biomédiques August Pi i Sunyer, Barcelona, Spain.
Roselló-Catafau
J
J
Casillas-Ramirez
A
A
Massip-Salcedo
M
M
Rimola
A
A
Calvo
N
N
Bartrons
R
R
Peralta
C
C
D000818:Animals; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology; D018841:HSP90 Heat-Shock Proteins / Q000276:immunology; D006360:Heat-Shock Proteins / Q000276:immunology; D051547:Heme Oxygenase-1 / Q000276:immunology; D022781:Hepatocytes / Q000276:immunology / Q000473:pathology; D007150:Immunohistochemistry / Q000379:methods; D007375:Interleukin-1 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000276:immunology; D019194:Ischemic Preconditioning / Q000379:methods*; D008099:Liver / Q000098:blood supply / Q000473:pathology; D008115:Liver Regeneration / Q000276:immunology; D016031:Liver Transplantation / Q000379:methods*; D008297:Male; D008565:Membrane Proteins / Q000276:immunology; D019331:NG-Nitroarginine Methyl Ester / Q000276:immunology; D009336:Necrosis; D009569:Nitric Oxide / Q000276:immunology; D018384:Oxidative Stress / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000276:immunology / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000276:immunology
D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D007375:Interleukin-1; D008565:Membrane Proteins; D016212:Transforming Growth Factor beta; D009569:Nitric Oxide; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D019331:NG-Nitroarginine Methyl Ester