The role of tubulointerstitial inflammation.
The role of tubulointerstitial inflammation.
复制标题
DOI：
10.1111/j.1523-1755.2005.09423.x
复制
发表时间：
2005-04
期刊：
影响因子：
--
通讯作者：
G. Zheng;Yiping Wang;D. Mahajan;X. Qin;Ying Wang;Yuanmin Wang;S. Alexander;D. Harris
中科院分区：
文献类型：
--
作者：
G. Zheng;Yiping Wang;D. Mahajan;X. Qin;Ying Wang;Yuanmin Wang;S. Alexander;D. Harris
探索肾小管间质炎症在实验性慢性肾脏病（CRD）中的作用是理解和发现人类CRD新治疗方法的重要一步。阿霉素肾病（AN）是人类局灶性肾小球硬化和肾小管间质炎症的实验性类似物。方法利用小鼠和大鼠AN，我们系统地研究了趋化因子、共刺激分子和炎性细胞（如巨噬细胞、效应和调节性T淋巴细胞）的致病作用。在体外和体内研究了体液和细胞介质的概况。通过DNA疫苗接种、白细胞重建和耗竭、逆转录病毒转导和单克隆抗体阻断等方法研究了各种因素的致病意义。结果肾皮质和肾小管细胞CC趋化因子，包括MCP-1、RANTES和MIP-1 α，通过NF κ B介导上调，并通过吸引炎性细胞进入肾小管而促进疾病的发生。这些趋化因子的作用通过DNA疫苗接种得到证实。CD 40-CD 40 L共刺激信号参与炎症浸润的扩张和活化，而PD-1信号具有抑制作用，CD 28-B7似乎具有中性作用。巨噬细胞和CD 8 + T细胞被证明是损伤的效应细胞，而CD 4 + CD 25+和γ δ T细胞作为调节细胞。FoxP 3转导能够将初始T细胞转化为CD 4 + CD 25+调节性T细胞。结论多种体液和细胞因子参与了实验性CRD的发病过程，其中一些因子是治疗CRD的潜在靶点。
BACKGROUND Exploration of the role of tubulointerstitial inflammation in experimental chronic renal disease (CRD) is an essential step to understanding and finding new treatments for human CRD. Adriamycin nephrosis (AN) is an experimental analogue of human focal glomerular sclerosis and tubulointerstitial inflammation. METHODS Using murine and rat AN, we have systematically investigated the pathogenic roles of chemokines, costimulatory molecules, and inflammatory cells, such as macrophages and effector and regulatory T lymphocytes. The profile of humoral and cellular mediators was studied in vitro and in vivo. The pathogenic significance of various factors was investigated by DNA vaccination, leukocyte reconstitution and depletion, retroviral transduction, and blockade with monoclonal antibodies. RESULTS Renal cortical and tubular cell CC-chemokines, including MCP-1, RANTES, and MIP-1alpha, were up-regulated via mediation of NFkappaB, and contributed to disease by attracting inflammatory cells into the interstitium. The role of these chemokines was confirmed by DNA vaccination. CD40-CD40L costimulation signals were involved in expansion and activation of the inflammatory infiltrate, whereas PD-1 signals were inhibitory, and CD28-B7 appeared to have a neutral effect. Macrophage and CD8+ T cells were shown to be effectors of injury, whereas CD4+CD25+ and gammadelta T cells acted as regulatory cells. FoxP3 transduction was able to convert naive T cells to CD4+CD25+ regulatory T cells. CONCLUSION There is a broad range of humoral and cellular factors involved in the pathogenesis of experimental CRD, some of which are potential targets for treatment of human CRD.