Schulze Sarah, Keshvari Sahar, Miller Gregory C, Bridle Kim R, Hume David A, Irvine Katharine M
Translational Research Institute, Mater Research Institute-The University of Queensland, Brisbane 4102, Queensland, Australia.
Envoi Pathology, Envoi Pathology, Brisbane 4000, Queensland, Australia.
World J Gastroenterol. 2025 Jun 28;31(24):108234. doi: 10.3748/wjg.v31.i24.108234.
In 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. Macrophages can drive inflammation in response to injury, but they can also promote liver growth and resolution of chronic liver injury and fibrosis. In chronic liver injury models in mice, macrophage colony stimulating factor (CSF)1 stimulates pro-regenerative macrophages.
To determine whether stimulation of macrophages with macrophage CSF could promote liver repair after I/R injury.
We 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 hours, 48 hours and 7 days post reperfusion in rats. Circulating and liver tissue monocyte and macrophage subsets in the ischaemic and oxygenated lobes were assessed using quantitative PCR and flow cytometry.
CSF1-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 (ILs), and peri-necrotic zone localization in the IL. CSF1-Fc treatment also promoted liver growth, associated with increased parenchymal and non-parenchymal cell proliferation. 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.
This 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.
在肝胆及肝移植手术中，缺血再灌注（I/R）损伤可能因器官血流的暂时中断，随后对再灌注产生潜在的有害炎症反应而发生。巨噬细胞可对损伤产生炎症反应，但它们也能促进肝脏生长以及慢性肝损伤和纤维化的消退。在小鼠慢性肝损伤模型中，巨噬细胞集落刺激因子（CSF）1可刺激促再生巨噬细胞。
确定用巨噬细胞CSF刺激巨噬细胞是否能促进I/R损伤后的肝脏修复。
我们研究了在大鼠再灌注后6小时、48小时和7天，用长效循环CSF1-Fc偶联物进行围手术期治疗对70%缺血60分钟后的肝损伤和肝细胞增殖的影响。使用定量PCR和流式细胞术评估缺血和氧合叶中的循环及肝组织单核细胞和巨噬细胞亚群。
血清转氨酶表明，CSF1-Fc治疗不影响再灌注后肝细胞损伤的程度。在术后48小时，CSF1-Fc治疗的大鼠肝I/R损伤，尤其是坏死面积减少。这与氧合叶和缺血叶（IL）中巨噬细胞积累增加以及IL中坏死周围区域定位有关。CSF1-Fc治疗还促进肝脏生长，这与实质细胞和非实质细胞增殖增加有关。CSF1-Fc增加了CD43+非经典单核细胞的丰度，这与CSF1信号在单核细胞成熟中的作用一致，并增加了成熟巨噬细胞上CD163的表达。
本研究表明CSF1刺激可促使单核细胞/巨噬细胞产生促再生反应，围手术期CSF1治疗可能增强肝切除患者的肝脏再生。
