Keywords: Liver regeneration, Partial hepatectomy, Complement system, C5a, C3H/HeJ mice Following partial hepatectomy (PH), gut derived LPS acts as a signal for LPS/TLR4 and Complement pathways. Complement activation leads to... [ view full abstract ]
Keywords: Liver regeneration, Partial hepatectomy, Complement system, C5a, C3H/HeJ mice
Following partial hepatectomy (PH), gut derived LPS acts as a signal for LPS/TLR4 and Complement pathways. Complement activation leads to the generation of C3a and C5a components which prime the hepatocyte proliferation and regulate cytokine release and consequent induction of transcription factors required for regeneration. In the current investigation, we compared the effect of C5a-receptor blockade on liver regeneration after 70% PH in wildtype C3H/HeN (HeN) and the tlr4 mutant C3H/HeJ (HeJ) mice.
8-12 week old HeN and HeJ mice receivedeither a specific C5aR-antagonist PMX53 (1 mg/kg i.p.), or vehicle 45 min prior to undergoing 70% PH and daily until sacrifice (n = 4-6 per group). Plasma TNF-α and IL-6 levels were measured by magnetic bead ELISA. Hepatocyte proliferation was quantified by counting mitotic figures and by Ki67 immunohistochemistry. STAT3and Cyclin D1 mRNA levels in regenerating liver were quantified by RT-PCR.
The HeJ mice showed delayed regeneration compared to the HeN mice (Fig 1). PMX53 treatment further decreased liver mass restoration, Ki67 positive nuclei and mitotic figures. In the HeJ mouse, the treatment highly abrogated liver restoration by day 7. Plasma IL-6 and TNF-α were elevated at 3 hours post PH in both strains, with and without PMX53. However, in HeJ mice and both strains of treated mice, the elevation was suppressed compared to untreated HeN.
Conclusions: Our results show that simultaneous lack of functional TLR4 and Complement signalling highly inhibits liver regeneration after partial hepatectomy in mice.
