How ischaemic preconditioning protects small liver grafts

Abstract

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.

Role of ischaemic preconditioning in liver regeneration following major liver resection and transplantation

“…Previous studies have shown that the release of IL-1 is potentially influenced by NO during IRI in a variety of cell types [157][158][159] . In IPC-treated rats that underwent reduced size liver transplantation, an increase in IL-1α levels were noted following NO synthesis inhibition [150] . This practice abolished the benefits of IPC on hepatic IRI, oxidative stress and liver regeneration [3,150] .…”

“…In IPC-treated rats that underwent reduced size liver transplantation, an increase in IL-1α levels were noted following NO synthesis inhibition [150] . This practice abolished the benefits of IPC on hepatic IRI, oxidative stress and liver regeneration [3,150] . Further more, the detrimental effects of NO inhibition were not observed when rats subjected to this treatment were subsequently treated with an IL-1 receptor antagonist (IL-1-RA) [150] .…”

“…IL-1β delays and inhibits hepatocyte proliferation in both culture models [149] and following partial hepatectomy in rats [148] . Other investigators have implicated IL-1α as a mediator of IRI and an inhibitor of liver regeneration [150] . Besides antagonizing the stimulatory effects of growth factors such as HGF [150] , IL-1 strongly inhibits hepatocyte DNA synthesis leading to impaired liver regeneration in primary culture models [149] .…”

“…Other investigators have implicated IL-1α as a mediator of IRI and an inhibitor of liver regeneration [150] . Besides antagonizing the stimulatory effects of growth factors such as HGF [150] , IL-1 strongly inhibits hepatocyte DNA synthesis leading to impaired liver regeneration in primary culture models [149] . TGF-β is another inhibitor of hepatocyte DNA synthesis [151][152][153] and antagonizes the stimulatory effects of HGF during liver regeneration in both in vitro and experimental hepatectomy models [152,154] .…”

“…This practice abolished the benefits of IPC on hepatic IRI, oxidative stress and liver regeneration [3,150] . Further more, the detrimental effects of NO inhibition were not observed when rats subjected to this treatment were subsequently treated with an IL-1 receptor antagonist (IL-1-RA) [150] . IL-1α has also been shown to be involved in pulmonary injury following liver IRI.…”