Investigation of the effects of lipoxin a4 on liver cell regeneration and immune response during liver fibrosis

Aim: An anti-inflammatory lipid mediator lipoxin A4 (LXA4) regulates leukocyte cellular activity and activates gene transcription to activate intracellular enzyme activity by binding to a G-protein receptor. In our investigation we aimed to observe the effect of LXA4 on liver fibrosis and immune system after systemic administration of LXA4 to TAA induced liver fibrosis mice. Materials and Methods: LXA4 administered via intraperitoneally to BALB/c mice with TAA induced liver fibrosis and serum liver enzymes, IFN-, TNF-, IL-2, IL-17, IL-23, IL-4 and IL-10 levels measured, immunophenotyping on spleen cells performed, expression levels of genes responsible from degeneration and regeneration of liver analyzed and histo-pathological investigations performed by Knodell scoring. Results: According to our results, an elevation on liver enzymes ALT, AST during liver fibrosis together with a significant reduction on TNF-, IFN- and IL-2 levels observed after LXA4 injection. In cellular sense; TAA induced liver fibrosis increases the percentage of activated cytotoxic T-lymphocyte population. LXA4 administration significantly reduced that elevation. Despite that; LXA4 administration during liver fibrosis significantly reduced TGF-1 expression. MKK4 gene expression which is expected to be reduced during liver cell regeneration, highly expressed during fibrosis, however it is significantly reduced in LXA4 administered liver fibrosis group subjects. We did not observe a statistical difference on other genes ATF2, MKK7 expression. Accordingly; bridging fibrosis and leukocyte infiltration have been observed in TAA group. According to Trichrom staining connective tissue formation has been observed in TAA group. LXA4 administration during liver fibrosis significantly reduced infiltration of leukocytes, bridged fibrosis formation disappeared and connective tissue formation significantly reduced. According to PAS staining; LXA4 administration significantly reduced physiologic activation on liver cells. Conclusion: LXA4 can be used in the treatment of liver fibrosis and may be a molecule that may potentially cause liver regeneration.