环氧合酶-2抑制剂对尿毒症大鼠腹膜淋巴管形成及腹膜功能的影响

The effects of cyclooxygenase-2 inhibitors on peritoneal lymphangiogenesis and peritoneal function in uremic rats

目的探讨环氧合酶-2（COX-2）抑制剂（塞来昔布）对尿毒症腹膜透析（腹透）大鼠腹膜淋巴管形成及腹膜功能的影响。方法检测塞来昔布干预的尿毒症腹透大鼠的腹膜，从腹膜的结构与功能、腹膜组织淋巴管密度（LVD）及COX-2、血管内皮生长因子-C（VEGF—C）、淋巴管内皮透明质酸受体-1（LYVE-1）mRNA及蛋白表达水平，观察塞来昔布对尿毒症腹透大鼠腹膜淋巴管形成及腹膜功能的影响。结果随着透析时间的延长，尿毒症大鼠腹膜厚度增加，炎性细胞浸润明显，腹膜平衡试验（PET）显示超滤量明显下降，葡萄糖转运量上升，但塞来昔布干预组可提高超滤量，减少葡萄糖转运量（P〈0．05）。5组动物的腹膜组织LVD及COX-2、VEGF—C、LVE-1mRNA和蛋白表达的检测发现：与正常组相比，尿毒症组和腹透组均明显升高（P〈0．05）；而腹透＋塞来昔布干预组较腹透组均明显降低（P〈0．05）。相关性分析显示，腹透组蛋白水平上COX-2的表达量与LVD（r=0．847，P〈0．05）、VEGF．C（r=0．910，P〈0．05）呈正相关，VEGF—C的表达量与LVD呈正相关（r=0．975，P〈0．05）。腹透＋塞来昔布干预组蛋白水平上COX-2的表达量与LVD（r=0．970，P〈0．05）、VEGF-C（r=0．927，P〈0．05）呈正相关，VEGF—C的表达量与LVD呈正相关（r=0．919，P〈0．05）。结论大鼠体内高糖透析液与尿毒症环境的刺激可以促进腹膜组织COX-2、VEGF—C、LYVE-1基因和蛋白的表达水平上调及新生淋巴管数量增多。COX-2抑制剂可缓解长期腹透导致的腹膜组织形态结构和功能的改变，并能抑制新生淋巴管的形成，可能是通过COX-2依赖的途径下调VEGF—C的产生而发挥作用的。

Objective To investigate the effects of cyclooxygenase-2 （COX-2） inhibitor on peritoneal lymphangiogenesis and peritoneum function in uremic rat. Methods Uremic rats treated by peritoneal dialysis were intragastric administration celecoxib. Structures of peritoneum, peritoneal function, peritoneal lymphatic vessel density （LVD） were detected in every group. The mRNA of vascular endothelial growth factor-C （ VEGF-C）, lymphatic vessel endothelial hyluronan receptor-1 （ LYVE-1 ） and COX-2 were tested by RT-PCR. The protein expressions of LYVE-1, VEGF-C, COX-2 were tested by western blot. Results With the extension of the duration of dialysis, the peritoneum thickness was increasing, inflammatory cell infiltrated obviously, uhrafiltration volume decreased significantly. But the celecoxib could increase uhrafiltration volume and reduce the glucose transport rate （P 〈 0. 05 ）. Compared with the normal group, the levels of LVD, COX-2, VEGF-C, and LYVE-1 mRNA and protein were significantly up-regulated in uremic and dialysis groups （P 〈 0.05）. Compared with the uremic dialysis group, the levels of LVD, COX-2, VEGF- C and LYVE-1 mRNA and protein were significantly down-regulated in the celecoxib group. There was a positive correlation between COX-2 and VEGF-C, LVD in protein levels, as well as VEGF-C and LVD （all P values 〈 0. 05 ）. Conclusions Hyper glucose dialysis solution and uremic condition could up-regulate the expression of COX-2, VEGF-C, LYVE-1 in gene and protein level and stimulate lymphangiogenesis. COX-2 inhibitor could delay the change of peritoneal structures and function. COX-2 inhibitor could prevent the lymphangiogenesis in uremic rat treated by peritoneal dialysis, which might down-regulate the expression of VEGF-C by COX-2 depended manner.