The endothelin/nitric oxide balance determines small-for-size liver injury after reduced-size rat liver transplantation

Abstract

Small-for-size (SFS) liver graft injury is probably related to microcirculatory disorders due to an imbalance of vasoconstricting, e.g. endothelin (ET)-1, and vasorelaxing mediators, e.g. nitric oxide (NO). We studied the role of ET-1/NO balance and the effect of an endothelin A receptor (ETAR) antagonist on SFS injury after liver resection and reduced-size liver transplantation (RSLT). One hundred twenty-six Lewis rats were divided into five groups: (I) 70% liver resection, (II) 70% liver resection treated with the ETAR antagonist LU 135252 (1 mg/kg b.w. i.v.), (III) RSLT (30% residual liver volume), (IV) RSLT treated with the ETAR antagonist, (V) sham operation. Liver microcirculation was measured by intravital microscopy. ET-1, ETAR, endothelial NO-synthase (eNOS), activation of Kupffer cells (KCs) and parenchymal injury were studied by immunohistology. Survival and liver function were followed up to 14 days. RSLT led to increased ET-1, ETAR and decreased eNOS protein expression, accompanied by activation of KC, reduced perfusion rate, vasoconstriction and elevated sinusoidal blood flow, as well as hepatocellular damage, impaired liver function and impaired survival. ETAR blockade (groups II + IV) improved the ET-1/NO balance, attenuated microcirculatory disorders and improved hepatocellular apoptosis and liver function. Microcirculatory disorders related to an ET-1/NO imbalance may contribute to SFS liver injury. Maintenance of ET-1/NO balance by blocking ETAR reduces SFS injury by protecting liver microcirculation, thus reducing hepatocellular damage.

Molecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis

“…In particular, hepatocyte growth factor as well as the cytokines IL-6 (Aldeguer et al, 2002) and TNF-␣ (Kirillova et al, 1999;Abshagen et al, 2007) provided by Kupffer cells and endothelial cells stimulate hepatocyte proliferation by triggering hepatocytic DNA replication via NF-〉 (Seto et al, 1998;Armbrust et al, 2002;Bruun et al, 2002;Lalani et al, 2005;Bastard et al, 2006;Wang et al, 2006a;Simons et al, 2007). In addition, Kupffer cells seem to be involved in maintenance of adequate perfusion during liver cell proliferation-a function that could be related to Kupffer cell-derived cytokines or Kupffer cell-mediated effects on nitric oxide metabolism, which apparently plays an important role in hepatic microcirculation, particularly after liver injury (Rolfe et al, 1997;West et al, 1999;Holden et al, 2000;Meijer et al, 2000, Abshagen et al, 2008Palmes et al, 2005;Schuett et al, 2007).…”

Nitric oxide reduces organ injury and enhances regeneration of reduced-size livers by increasing hepatic arterial flow

“…Thus, the positive effects of decreasing blood flow and thus shear stress during surgery might actually be achieved at the expense of regenerative capacity. As imbalance of vasorelaxing and vasoconstricting mediators is considered to be an important pathogenetic feature in reduced-size livers 22 , the present authors aimed to establish a counterbalancing strategy by augmenting the vasodilatory response via substitution of nitric oxide. Animals treated with the nitric oxide donor molsidomine had less liver damage together with higher regeneration and improved liver function compared with resected controls.…”

“…In addition, others have demonstrated an imbalance of vasoactive mediators in reduced-size livers, with decreased expression of endothelial nitric oxide synthase (eNOS) 22 . The lack of vasodilating nitric oxide with impairment of the hepatic haemodynamics could be of fundamental importance in the development of small-for-size syndrome.…”

A Novel Organ Preservation for Small Partial Liver Transplantations in Rats: Venous Systemic Oxygen Persufflation With Nitric Oxide Gas

“…Small partial liver graft injuries are related to microcirculatory disorders due to an imbalance of vasoconstricting and vasorelaxing mediators such as endothelin-1/NO (11,19). Because e-NOS-derived NO prevents hepatic IRI (20), endogenous e-NOS activation and e-NOS-derived NO may be a promising approach to limiting organ injury.…”