Role for macrophage migration inhibitory factor in peritoneal fibrosis

MIF被认为是一种促炎细胞因子，最近的研究揭示了该细胞因子在细胞增殖、纤维化和血管生成中的多功能特性。我们通过研究MIF敲除（MIF-/-）小鼠的PF实验模型来研究MIF在PF中的作用。方法。在Balb/c来源的野生型（WT）或MIF-/-小鼠腹膜内灌注葡萄糖酸氯己定（CG）诱导PF。给药后1 ~ 4周处死小鼠，进行组织学检查。我们还试图阐明腹腔注射抗MIF抗体是否能减弱PF，并通过免疫组化检测MIF、TNF-α的表达和巨噬细胞的浸润。结果。注射CG后，WT腹膜呈进行性增厚。从第2周开始，与WT相比，MIF-/-小鼠腹膜增厚明显受到抑制，抗MIF抗体治疗也能抑制腹膜增厚。WT腹膜增厚，可见F4/80抗原阳性巨噬细胞大量浸润。在MIF-/-小鼠中，浸润明显受到抑制。超微结构WT显示间皮细胞形状退行性改变，微绒毛稀疏。相比之下，MIF-/-小鼠的间皮细胞表现出正常形状和广泛形成的厚微绒毛。免疫组织化学分析显示，WT间皮细胞和间皮下致密区在第1周时MIF表达增加。第3周，在被认为是再生上皮的间皮层中表达进一步增加。TNF-α与MIF在WT间皮和致密区强共表达；然而，MIF-/-小鼠TNF-α表达明显降低。结论。我们的数据表明，MIF在PF中发挥重要作用，抑制MIF可能通过抗炎作用和抑制间皮损伤来保护PF的进展。

MIF is known as a pro-inflammatory cytokine and recent studies have revealed multi-functional property of this cytokine in cell proliferation, fibrosis and angiogenesis. We investigated MIF' s role in PF by studying an experimental model of PF in MIF-knockout (MIF-/-) mice. Methods. PF was induced by intra-peritoneal infusion of chlorhexidine gluconate (CG) in wild type (WT) or MIF-/-mice from Balb/c origin. The mice were sacrificed at weeks 1-4 from the start of infusion and examined histologically. We also attempted to clarify whether an intraperitoneal injection of anti-MIF antibody could attenuate PF. The expression of MIF, TNF-α and the macrophage infiltration were examined by immunohistochemistry. Results. The peritoneum in WT showed progressive thickening by CG infusion. From week 2, peritoneal thickening was significantly inhibited in MIF-/-mice as compared with WT. The thickening was also inhibited by anti-MIF antibody treatment. Thickened peritoneum in WT showed massive infiltration of macrophages positive for F4/80 antigen. In MIF-/-mice, the infiltration is significantly inhibited. Ultrastructurally WT demonstrated mesothelial cells showing degenerative changes of the shape and sparse microvilli. In contrast, mesothelial cells in MIF-/-mice exhibited normal-shaped and extensive formation of thick microvilli. By immunohistochemical analysis, mesothelial cells and submesothelial compact zone in WT showed an increase in MIF expression at week 1. The expression further increased in the mesothelial layer supposed to be regenerated epithelium at week 3. TNF-α was strongly co-expressed with MIF in the mesothelium and compact zone in WT; however, the MIF-/- mice showed a significant decrease in TNF-α expression. Conclusions. Our data suggest that MIF plays important roles in PF. MIF inhibition may protect the progression of PF by the anti-inflammatory effect and also by the inhibition of mesothelial damage.