新生淋巴管和异位类淋巴结——肾脏纤维化干预的新靶点？

The progression of renal interstitial fibrosis in CKD is a tough challenge for the whole world, and a radical cure for this condition has not yet been established.The current study suggest the number of interstitial inflammatory macrophages increase markedly and triggers a cascade of events leading to the development of fibrosis and the loss of renal cells.However, their details remain unclear.We found that macrophages infiltrated with the lymphangiogenesis and tertiary lymphoid neogenesis in renal interstitium in about 450 biopsies. The density of newly formed lymphatic vessel inversely correlated with the severity of tubular lesions and interstitial fibrosis It was also significantly associated with the amount of infiltrating macrophages, dendritic cells, lymphocytes and tertiary lymphoid tissues.According to the recent research and our job,we suppose that inflammatory macrophages contribute to lymphangiogenesis depending on the VEGF-C derived from the renal lesion microenvironment. The newly formed immature lymphatic vessels are not able to carry the infiltrated immune cells to the draining lymph node. We believe that such a relative defect in the lymphatic drainage of the inflamed tissue is a trigger for the cascade of events leading to the development of tertiary lymphoid neogenesis which maintain chronic inflammatory disorders. In the future,we will perform a animal model to identify the detailed mechanism of lymphangiogenesis and tertiary lymphoid neogenesis.Our destination is to promote the lymphatic vessels drainining more infiltrated immune cells and finally diminish or elicit tertiary lymphoid tissues. Thus there will be a new strategy to weaken the chronic inflammation and renal fibrosis.

如何抑制慢性肾脏病（CKD）肾脏纤维化的进展，是全世界肾脏病工作者面临的难题。近年来研究发现，肾脏炎症性巨噬细胞在肾脏炎症损伤和肾纤维化进展中起核心作用，但其机制尚不明了。我们在450例肾穿组织标本中发现，CKD患者肾脏纤维化区域巨噬细胞浸润伴有淋巴管新生和异位类淋巴结形成。新生淋巴管密度与肾间质纤维化程度、浸润的炎症细胞以及类淋巴结的密度显著相关。结合最新研究以及本课题组前期研究，我们提出假说：炎症性巨噬细胞在肾脏病变微环境来源的VEGF-C的作用下生成淋巴管，但新生淋巴管引流功能缺陷，导致通过其转运的炎症细胞在原位聚集形成异位类淋巴结，导致慢性炎症的维持和肾脏纤维化的进展。我们建立动物模型，进一步明确淋巴管新生、转运能力缺陷以及异位类淋巴结结构形成的确切机制，寻找促进新生淋巴管引流功能成熟，清除异位类淋巴结有效措施，从而为肾脏纤维化的治疗提供新的策略。

有关慢性肾脏病中肾脏淋巴管新生和异位淋巴结形成的研究是在最近几年受到了越来越多的关注。但是它们在慢性肾脏病中特别是IgAN 中的确切角色还不清楚，为此我们首先设计了前瞻性的实验，来明确肾脏淋巴管新生和异位淋巴结形成与肾脏病变和预后的关系。我们发现IgAN 患者，新生淋巴管参与CD68+, DC-SIGN+,CD4+, CD8+, CD20+细胞不同类型炎症细胞的转运，且淋巴管密度与上述炎症细胞的密度密切相关。新生淋巴管的密度与血肌酐、蛋白尿以及间质炎症细胞评分、小管萎缩/间质纤维化评分、小血管内膜增厚、小血管玻璃样变程度关系密切。多元回归分析显示肾间质淋巴管密度高是IgAN 患者血肌酐进展的独立危险因素。故IgAN 患者肾脏新生淋巴管和异位淋巴结的出现反映了肾脏局部的炎症反应的活化状态，它们可能参与IgAN 患者肾脏损伤和进展。然后，我们也在小鼠体内外进行了一系列相关实验，探讨肾间质中淋巴管新生与纤维化和巨噬细胞浸润的关系，以及巨噬细胞参与淋巴管新生机制。研究发现在不同纤维化模型中均存在巨噬细胞浸润、淋巴管新生和肾脏纤维化，且淋巴管新生与纤维化程度和巨噬细胞浸润呈正相关。同时我们发现M1比M和M0巨噬细胞更可能分化为淋巴管内皮细胞（LEC），且VEGF-C可以促进M1分化，转分化为LEC潜能增加；抑制VEGF-C/VEGFR3通路后，可以逆转此效应。而VEGF-C能够抑制巨噬细胞自噬，抑制VEGF-C/VEGFR3通路增加巨噬细胞自噬。自噬诱导剂雷帕霉素也会削弱巨噬细胞向M1分化，降低其分化为LEC潜能。综上所述，肾纤维化中VEGF-C通过下调巨噬细胞自噬，使之向M1分化增加，进一步增强转分化为LEC潜能，促进淋巴管新生。