Chen Yung-Ming, Ng Yee-Yung, Lin Shuei-Liong, Chiang Wen-Chih, Lan Hui Y, Tsai Tun-Jun
Department of Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan.
Nephrol Dial Transplant. 2004 May;19(5):1106-15. doi: 10.1093/ndt/gfh127. Epub 2004 Feb 19.
Crescentic glomerulonephritis is a rapidly progressive form of glomerulonephritis, but treatment remains non-specific. The methylxanthine derivative pentoxifylline (PTX) is a clinically available phosphodiesterase inhibitor with anti-inflammatory and immunoregulatory activities. This study examined whether PTX has beneficial effects in a rat model of anti-glomerular basement membrane (GBM) crescentic glomerulonephritis.
Experimental crescentic glomerulonephritis was induced in Wistar rats by intravenous injection of rabbit anti-rat GBM serum and treated with either vehicle (phosphate-buffered saline) or PTX (0.1 g/kg/day) intravenously on a daily basis. Groups of six animals were euthanized at days 3, 7, 14 or 28 after induction of disease. Effects of PTX on renal function, histology and expression of cytokines, chemokines and adhesion molecules were determined.
Compared with the vehicle-treated nephritic rats, PTX treatment beginning at the start of the nephritis significantly suppressed mRNA expression of tumour necrosis factor (TNF)-alpha, but not interleukin-1 beta, throughout the course of nephritis. Moreover, PTX decreased renal mRNAs for intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1), regulated on activation, normal T-cell expressed and secreted (RANTES) and osteopontin (OPN) at all time points examined. These effects were associated with a significant inhibition of macrophage and T-cell infiltration, a reduction of 24-h urinary protein excretion (50-75%, P<0.05), an improvement of histological damage including glomerular crescent formation (60-70%, P<0.01) and a decrease of cortical mRNAs for type I (alpha 1) collagen and fibronectin. The efficacy of PTX could also be seen, though to a lesser extent, in rats with established nephritis.
PTX is an effective anti-inflammatory and immunomodulatory agent capable of suppressing rat crescentic glomerulonephritis. Inhibition of renal TNF-alpha, ICAM-1, RANTES, MCP-1 and OPN expression may be a mechanism whereby PTX suppresses progressive renal injury in rat crescentic glomerulonephritis.
新月体性肾小球肾炎是一种快速进展的肾小球肾炎形式，但治疗方法仍缺乏特异性。甲基黄嘌呤衍生物己酮可可碱（PTX）是一种临床上可用的磷酸二酯酶抑制剂，具有抗炎和免疫调节活性。本研究检测了PTX在抗肾小球基底膜（GBM）新月体性肾小球肾炎大鼠模型中是否具有有益作用。
通过静脉注射兔抗大鼠GBM血清在Wistar大鼠中诱导实验性新月体性肾小球肾炎，并每天静脉注射赋形剂（磷酸盐缓冲盐水）或PTX（0.1 g/kg/天）进行治疗。在疾病诱导后的第3、7、14或28天对每组6只动物实施安乐死。测定PTX对肾功能、组织学以及细胞因子、趋化因子和黏附分子表达的影响。
与接受赋形剂治疗的肾炎大鼠相比，从肾炎开始时就进行PTX治疗在整个肾炎病程中均显著抑制肿瘤坏死因子（TNF）-α的mRNA表达，但对白细胞介素-1β无此作用。此外，在所有检测时间点，PTX均降低了细胞间黏附分子-1（ICAM-1）、单核细胞趋化蛋白-1（MCP-1）、活化调节正常T细胞表达和分泌因子（RANTES）以及骨桥蛋白（OPN）的肾mRNA水平。这些作用与巨噬细胞和T细胞浸润的显著抑制、24小时尿蛋白排泄减少（50-75%，P<0.05）、包括肾小球新月体形成在内的组织学损伤改善（60-70%，P<0.01）以及I型（α1）胶原和纤连蛋白的皮质mRNA水平降低相关。在已患肾炎的大鼠中也能观察到PTX的疗效，尽管程度较轻。
PTX是一种有效的抗炎和免疫调节剂，能够抑制大鼠新月体性肾小球肾炎。抑制肾TNF-α、ICAM-1、RANTES、MCP-1和OPN表达可能是PTX抑制大鼠新月体性肾小球肾炎进行性肾损伤的一种机制。
