Perisurgical Colony Stimulating Factor 1 (CSF1) treatment ameliorates liver 1 ischaemia/reperfusion injury in rats

BackgroundIn the context of hepatobiliary and liver transplant surgery, ischemia-reperfusion (I/R) injury can occur due to temporary interruption of blood flow to the organ followed by a potentially damaging inflammatory response to reperfusion. As macrophages can promote liver growth and contribute to resolution of chronic liver injury and fibrosis, we tested the hypothesis that stimulation of monocytes and macrophages with Colony Stimulating Factor 1 (CSF1) could have a beneficial impact on liver repair after I/R injury. MethodsWe investigated the impact of perisurgical treatment with a long-circulating CSF1-Fc conjugate on liver injury and hepatocyte proliferation after 70% ischemia for 60 minutes at 6 h, 48 h and 7 days post reperfusion in male rats. Changes in the circulating and liver tissue monocyte and macrophage subsets in the ischaemic and oxygenated lobes were assessed using quantitative PCR and flow cytometry. ResultsCSF1-Fc treatment did not affect the extent of hepatocellular injury post-reperfusion, as indicated by serum transaminases. Liver I/R injury, especially necrotic area, was reduced in CSF1-Fc-treated rats 48 h post-surgery. This was associated with increased accumulation of macrophages in both the oxygenated and ischemic lobes, and localization to necrotic tissue in the ischemic lobe. CSF1-Fc treatment also promoted liver growth, associated with increased parenchymal and non-parenchymal cell proliferation. Flow cytometry and gene expression analysis demonstrated increased monocyte infiltration in ischemic compared to oxygenated lobes. CSF1-Fc increased the abundance of CD43+ non-classical monocytes, consistent with the role of CSF1 signaling in monocyte maturation, and increased CD163 expression on mature macrophages. ConclusionThis study suggests CSF1 stimulation drives monocytes/macrophages towards a pro-regenerative response and perisurgical CSF1 treatment might augment liver regeneration in patients undergoing liver resection. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/642926v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@181eb0borg.highwire.dtl.DTLVardef@6e3370org.highwire.dtl.DTLVardef@f32022org.highwire.dtl.DTLVardef@1c2c1b3_HPS_FORMAT_FIGEXP M_FIG C_FIG