Studies on the mechanism of action of cyclosporine on liver regeneration after 2/3 partial hepatectomy in rats

Hippokratia 1999, 3(2):86-87

I. Fouzas


The effect and the precise mechanism of action of cyclosporine (CsA) on the regenerative capacity of the liver has not been elucidated. Previous findings in the experimental model of 2/3 partial hepatectomy (PH 2/3), in the rat, support the theory that liver regeneration is controlled by specific immume mechanisms. Therefore, we considered worthwhile to dissect the possibility that CsA intervenes in the immune reaction to the regenerating liver through its influence to hepatocytes as antigen presenting cells (APCs), by studying a) the effect of CsA on liver regeneration, b) the effect of SC-19220 on the influence of CsA on liver regeneration and c) the expression of class I and II MHC molecules on regenerating hepatocytes. CsA (20 mg/Kgr, 4 days pre-op and 1 day post-op) augmented liver regeneration, 48h after PH 2/3, in wistar rats. This was proved by the increase of DNA synthesis in isolated hepatocytes (p<0.05), by flow cytometry after BrdUrd administration (2×50 mg tab, SC, at 18 and 42 h post-op), as well as of the number of mitosing hepatocytes / 50 HPFs (p<0.05). Moreover, it was found that CsA increases DNA synthesis in the sham operated animals (p<0.001), although there were no mitoses in the first 48 h post-op.The IP administration of SC-19220 (5 mg bolus and 20 mg by an osmotic minipump for 48 h), inhibited, very significantly, the augmenting action of CsA on DNA synthesis (p<0.001), labeling index (p<0.001) and number of mitosing hepatocytes / 50 HPFs (p<0.01).Flow cytometry analysis of the isolated normal rat hepatocytes showed medium grade expression of class I and very low but detectable expression of class II MHC molecules. PH 2/3 induced the expression of class I and II MHCs by the regenerating hepatocytes (p< 0.01) and this was reduced by CsA (p< 0.01), although there was only a small, not significant, increase in DNA synthesis (p> 0.05).PH 2/3 induced the levels of SGOT (p<0.001) which were reduced by CsA (p< 0.05). PH 2/3 increased the levels of alkaline phosphatase (p<0.01), blood urea nitrogen (BUN) (p<0.01) and serum creatinine (Scr) (p<0.001) and they were increased further by the administration of CsA. Total bilirubin levels were not affected by 2/3 partial hepatectomy, CsA or SC-19220. The administration of CsA increased, very significantly, the levels of glucose in the sham operated rats (p<0.001).In conclusion, the augmenting action of CsA on hepatocyte proliferation is indirect and can be attributed to an increase of PGE2 synthesis, through its action on EP1 receptor. CsA reduces, also, the immunogenicity of the regenerating liver by inhibiting the expression of class I and II MHCs by the regenerating hepatocytes, although this had no effect on DNA synthesis. At 48 hours after partial hepatectomy, it was probably too early for the cytotoxic immune response to have any impact on liver regeneration and its inhibition by CsA could not have any augmentive effect. This is supported by the fact that light microscopy showed no inflammatory infiltrate or necrosis in the liver lobules and portal tracts of the hepatectomized animals. The reduction of the levels of SGOT after PH 2/3 can be considered as an additional protective influence of CsA on the liver remnant.