Impact of N-Acetylcysteine on the Hepatic Microcirculation After Orthotopic Liver Transplantation1

Abstract

Recent observations showed an improvement of hepatic macro- and microhemodynamics as well as survival rates after warm ischemia of the liver following treatment with N-acetylcysteine (NAC). In this study we assessed the influence of NAC on the hepatic microcirculation after orthotopic liver transplantation (OLT) using intravital fluorescence microscopy. OLT with simultaneous arterialization was performed in 16 male Lewis rats following cold storage in University of Wisconsin solution for 24 hr. Within the experimental group (n = 8) donors received NAC (400 mg/kg) 25 min before hepatectomy. In addition, high-dose treatment of recipients with NAC (400 mg/kg) was started with reperfusion. Control animals (n = 8) received an equivalent amount of Ringer's solution. Intravital fluorescence microscopy was performed 30-90 min after reperfusion assessing acinar and sinusoidal perfusion, leukocyte-endothelium interaction, and phagocytic activity. Treatment with NAC reduced the number of nonperfused sinusoid from 52.4 +/- 0.8% to 15.7 +/- 0.5% (p = 0.0001) (mean +/- SEM). Furthermore, we achieved a significant reduction of leukocytes adhering to sinusoidal endothelium (per mm2 liver surface) from 351.9 +/- 13.0 in controls to 83.6 +/- 4.2 in the experimental group (P = 0.0001). In postsinusoidal venules, treatment with NAC decreased the number of sticking leukocytes (per mm2 endothelium) from 1098.5 +/- 59.6 to 425.9 +/- 37.7 (P = 0.0001). Moreover, bile flow was significantly increased after therapy with NAC (4.3 +/- 1.2 vs. 2.2 +/- 0.7 ml/90 min x 100g liver) (P < 0.05). Phagocytic activity was not influenced by application of NAC. We conclude that high-dose therapy with NAC in OLT attenuates manifestations of microvascular perfusion failure early after reperfusion and should be considered as a means to reduce reperfusion injury.

Role of free radicals in liver diseases

“…Since antioxidants can inhibit ROS, various studies have aimed at modulating the severity of IR damage utilizing different mechanisms, including pharmacological allopurinol [58,59], a-tocopherol [60], N-acethylcysteine [61], and enzymatic catalase [62,63] and SOD [57]. Endogenous antioxidant concentrations decrease significantly during reperfusion [60,64]; thus, administration of antioxidants, especially in the early stages of reperfusion, may significantly diminish IR injury in transplanted livers.…”

Grape seed protects cholestatic rats liver from ischemia/reperfusion injury

“…Hepatic GSH production decreases during normothermic ischemia, and discharge of ROS during reperfusion phase causes rapid consumption of GSH 19,20 . These two mechanisms cause decreases in both intracellular and extracellular GSH levels, which causes oxidation and degration of important structures in the cell such as proteins, lipids, or double strand structure of DNA 20 .…”

Bucillamine, a thiol antioxidant, prevents transplantation-associated reperfusion injury

“…The antioxidant enzyme superoxide dismutase had variable effectiveness in previous studies and has been most impressive when administered by gene therapy with viral vectors, an as-yet-unproven technology (12). N-acetylcysteine, especially at high doses, has been successful in preserving microcirculatory function in some studies but has been ineffective in others (28,(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45). In a pilot clinical study, it also seemed to improve outcomes in patients (46).…”