Benefit of Kupffer cell modulation with glycine versus Kupffer cell depletion after liver transplantation in the rat: effects on postischemic reperfusion injury, apoptotic cell death graft regeneration and survival*

Abstract

Summary Inhibition or destruction of Kupffer cells (KC) may protect against ischemia‐reperfusion (IR) induced primary graft nonfunction (PNF) in liver transplantation. Besides KC activation, PNF is characterized by microvascular perfusion failure, intrahepatic leukocyte accumulation, cell death and hepatocellular dysfunction. KCs can be inactivated by different agents including gadolinium chloride (GdCl3), methyl palmitate (MP) and glycine. The effects of three KC inactivators on IR‐injury after rat liver transplantation were compared in the present study. Lewis liver donors were treated with GdCl3, MP, glycine or saline (control). Liver grafts were transplanted following 24 h storage (UW solution). KC populations and IR damage were assessed by histologic analysis, quantitative real‐time polymerase chain reaction (RT‐PCR) and intravital microscopy. The number of hepatic ED‐1 positive macrophages was diminished after GdCl3 (114.8 ± 4.4/mm2 liver tissue) and MP treatment (176.0 ± 5.0), versus the glycine (263.9 ± 5.5) and control (272.1 ± 5.6) groups. All three treatment modalities downregulated phagocytic activity for latex particles, paralleled by reduced microvascular injury (acinar perfusion index, GdCl3: 0.75 ± 0.03; MP: 0.83 ± .03; glycine: 0.84 ± 0.03; 0.63 ± 0.03). Quantitative RT‐PCR revealed elevated myeloperoxidase mRNA after glycine versus GdCl3 and MP pretreatment (3.2‐ and 3.4‐fold, P = 0.011, respectively), without difference to controls (2.9‐fold of glycine). TNFα‐mRNA was reduced after glycine‐ (5.2‐fold), GdCl3‐ (19.7‐fold), MP‐treatment (39.5‐fold) compared with controls. However, profound prevention of intrahepatic cell death and liver graft failure was solely achieved with glycine preconditioning. Different than GdCl3 and MP, glycine modulates rather than destroys KCs. Glycine appears to preserve cell viability and to TNFα/leukocyte dependent organ regeneration capacity, which is related to increase graft survival following liver transplantation.

The effect of dietary glycine on the hepatic tumor promoting activity of polychlorinated biphenyls (PCBs) in rats

“…For this, we examined the ability of dietary glycine to inhibit PCB-induced tumor promotion, since several studies have shown that glycine decreases the production of superoxide and TNF-α by Kupffer cells (Ikejima et al 1996;Rose et al 1999a;Rose et al 1997a;Rusyn et al 1999). The inhibition by glycine of TNF-α production by Kupffer cells is not as strong as using agents such as gadolinium chloride or methyl palmitate, but that may be an advantage for a therapeutic agent (Rentsch et al 2005). Kupffer cell inhibition by glycine has also been shown to affect lipid metabolism in the liver (Neyrinck 2004).…”

Different Protection Mechanisms after Pretreatment with Glycine or α-Lipoic Acid in a Rat Model of Warm Hepatic Ischemia

“…Previous experimental and clinical studies have shown that glycine minimizes reperfusion injury due to organ manipulation during harvest and liver transplantation [18] . In addition, it was shown that glycine modulates Kupffer cell and TNF ␣ activation and prevents apoptosis in a model of cold ischemia [19] . Our findings of reduced TNF ␣ content in liver tissue might favor the assumption that glycine prevents Kupffer cell activation after warm liver ischemia, as described previously in a model of cold ischemia [6] .…”

Tacrolimus Preconditioning of Rat Liver Allografts Impacts Glutathione Homeostasis and Early Reperfusion Injury

“…KC were blocked upon reperfusion [20,37,38], or when antioxidants were given at various time points during liver transplantation [11,29,39]. This suggests that ROS, either released intracellulary or in the sinusoidal space, might be a target for tacrolimus action [32,40].…”