The efficacy of N-acetylcysteine as a hepatoprotective agent in liver transplantation

Thies, Jochen; Teklote, J.; Clauer, U.; Töx, U.; Klar, E.; Hofmann, Walter; Herfarth, Christian; Otto, Gerd

doi:10.1007/s001470050505

Cited by 44 publications

(22 citation statements)

References 6 publications

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“…Multiple studies have shown partial protection to hepatic I/R using antioxidants (44), with variable clinical outcomes (45, 46). Complicating the picture, oxidative stress and inflammation are highly intertwined.…”

Section: Discussionmentioning

confidence: 99%

Sirtuin 1 Stimulation Attenuates Ischemic Liver Injury and Enhances Mitochondrial Recovery and Autophagy

Khader¹,

Yang²,

Godwin

et al. 2016

Critical Care Medicine

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Objective Hepatic ischemia-reperfusion (I/R) is a major clinical problem with limited treatment options. The pathophysiology of hepatic I/R is characterized by mitochondrial dysfunction and cellular energy deficits. Sirtuin 1 (Sirt1) is an energy-sensing enzyme known to modulate mitochondrial biogenesis. We hypothesized that pharmacologic activation of Sirt1 is protective after hepatic I/R injury. Design Animal study. Setting University-based experimental laboratory. Subjects Wild-type C57BL/6 mice. Interventions C57BL/6 mice were subjected to 60-min partial hepatic I/R and post-treated with Sirt1 activator, SRT1720 (20 mg/kg), or vehicle. Blood and liver were collected at 24 h after I/R for analyses of hepatic injury, ATP levels, mitochondrial mass, autophagy, inflammation, and oxidative stress. H4IIE hepatoma cells and rat primary hepatocytes were incubated with oxyrase to induce hypoxia followed by reoxygenation (H/R) in the presence or absence of SRT1720 for assessment of mitochondrial mass, mitochondrial membrane potential, and autophagy. Measurements and Main Results SRT1720 restored the reduction in mitochondrial mass, enhanced autophagy, and preserved ATP levels in the liver after I/R, which was associated with a decrease in I/R-induced hepatic injury, apoptosis, and necrosis. I/R-induced inflammation was also significantly reduced by SRT1720 as measured by systemic and hepatic cytokine and chemokine levels as well as a decrease in neutrophil infiltration to the liver. Further, oxidative stress was markedly attenuated in the SRT1720-treated mice, compared to the vehicle. SRT1720 treatment increased ATP levels and survival of cultured hepatocytes after H/R. SRT1720 not only increased the mitochondrial mass but also increased mitochondrial membrane potential per cell in cultured hepatocytes after H/R. Moreover, SRT1720 prevented the H/R-induced mitochondrial depolarization and resulted in an enhancement of autophagy in cultured hepatocytes after H/R. Conclusions Pharmacologic stimulation of Sirt1 attenuates liver injury after hepatic I/R by restoring mitochondrial mass and membrane potential, which is associated with the enhancement of autophagy.

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Section: Discussionmentioning

confidence: 99%

Sirtuin 1 Stimulation Attenuates Ischemic Liver Injury and Enhances Mitochondrial Recovery and Autophagy

Khader¹,

Yang²,

Godwin

et al. 2016

Critical Care Medicine

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“…In rabbit models, intravenous NAC administration improved tissue oxygenation, microcirculation, alanine aminotransferase activity, and indocyanine green clearance [41]. Clinical trials of intravenous NAC have also had equivocal results, but three studies did document improved liver function, decreased liver injury, less graft dysfunction, less reject, and/or decreased hospital stay [13, 162, 175] (Table 3). …”

Section: Implication For Future Interventionsmentioning

confidence: 99%

Nitric Oxide and Redox Regulation in the Liver: Part II. Redox Biology in Pathologic Hepatocytes and Implications for Intervention

Diesen¹,

Kuo²

2011

Journal of Surgical Research

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Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are created in normal hepatocytes and are critical for normal physiological processes including oxidative respiration, growth, regeneration, apoptosis, and microsomal defense. When the levels of oxidation products exceed the capacity of normal antioxidant systems, oxidative stress occurs. This type of stress, in the form of ROS and RNS, can be damaging to all liver cells, including hepatocytes, Kupffer cells, stellate cells, and endothelial cells, through induction of inflammation, ischemia, fibrosis, necrosis, apoptosis, or through malignant transformation by damaging lipids, proteins, and/or DNA. In part I of this review, we will discuss basic redox biology in the liver, including a review of ROS, RNS, and antioxidants, with a focus on nitric oxide as a common source of RNS. We will then review the evidence for oxidative stress as a mechanism of liver injury in hepatitis (alcoholic, viral, nonalcoholic). In part II of this review, we will review oxidative stress in common pathophysiological conditions including ischemia/reperfusion injury, fibrosis, hepatocellular carcinoma, iron overload, Wilson's disease, sepsis and acetaminophen overdose. Finally, biomarkers, proteomic, and antioxidant therapies will be discussed as areas for future therapeutic interventions.

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“…Steib et al used higher maintenance doses of NAC but found no differences at all between the groups [7]. The most recently published study by Thies et al, however, demonstrated attenuated reperfusion injury as histologically graded, significantly increased flow in the portal vein, improved liver synthesis function, and prevention of primary graft non-function in NAC-treated liver graft recipients [6]. Since the dosing regimen of the two latter studies differs only in an additional rinsing of the graft with NAC containing solution (Thies et al), the divergence of the results may be attributable to the high interpatient variability in orthotopic liver transplantation.…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, NAC has been evaluated as a hepatoprotective agent in clinical OLT and has shown favourable results in a recent study [6], whereas other studies did not demonstrate clinical benefit [7,8]. More detailed investigations with NAC treatment in OLT are needed [7].…”

Section: Introductionmentioning

confidence: 99%

N-acetylcysteine induces shedding of selectins from liver and intestine during orthotopic liver transplantation

Taut¹,

Schmidt²,

Zapletal

et al. 2001

Clinical and Experimental Immunology

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SUMMARYIn orthotopic liver transplantation (OLT), N-acetylcysteine (NAC) reduces ischaemia/reperfusion (I/R) injury, improves liver synthesis function and prevents primary nonfunction of the graft. To further elucidate the mechanisms of these beneficial effects of NAC, we investigated influence of high-dose NAC therapy on the pattern of adhesion molecule release from liver and intestine during OLT. Nine patients receiving allograft OLT were treated with 150 mg NAC/kg during the first hour after reperfusion; 10 patients received the carrier only. One hour after reperfusion, samples of arterial, portal venous and hepatic venous plasma were taken and blood flow in the hepatic artery and the portal vein was measured. Absolute concentrations of sICAM-1, sVCAM-1, sP-selectin and sE-selectin were not markedly different. However, balance calculations showed release of selectins from NAC-treated livers as opposed to net uptake in controls (P # 0´02 for sP-selectin). This shedding of selectins might be a contributing factor to the decrease in leucocyte adherence and improved haemodynamics found experimentally with NAC-treatment.

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The efficacy of N-acetylcysteine as a hepatoprotective agent in liver transplantation

Cited by 44 publications

References 6 publications

Sirtuin 1 Stimulation Attenuates Ischemic Liver Injury and Enhances Mitochondrial Recovery and Autophagy

Sirtuin 1 Stimulation Attenuates Ischemic Liver Injury and Enhances Mitochondrial Recovery and Autophagy

Nitric Oxide and Redox Regulation in the Liver: Part II. Redox Biology in Pathologic Hepatocytes and Implications for Intervention

N-acetylcysteine induces shedding of selectins from liver and intestine during orthotopic liver transplantation

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