Selective cyclooxygenase-2 inhibition impairs glomerular capillary healing in experimental glomerulonephritis
Selective cyclooxygenase-2 inhibition impairs glomerular capillary healing in experimental glomerulonephritis
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DOI：
10.1681/asn.v1351261
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发表时间：
2002-05-01
影响因子：
13.6
通讯作者：
Floege, J
中科院分区：
文献类型：
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作者：
Kitahara, M;Eitner, F;Floege, J
选择性环氧合酶-2（考克斯-2）抑制剂具有抗炎活性，可减少实验性膜性肾小球肾炎的蛋白尿。最近报道了考克斯-2抑制剂的抗血管生成特性。研究了这些特性是否与炎症性肾小球疾病的肾小球愈合过程有关。为了评价选择性考克斯-2抑制剂对系膜增生性肾小球肾炎（由抗Thy 1.1抗体诱导）大鼠模型中肾小球愈合过程的作用，从疾病诱导后第1天开始每天施用选择性考克斯-2抑制剂（罗非昔布或塞来昔布）或载体，直到第6天安乐死。从第1天至第10天，用罗非昔布或载体处理另外的肾炎大鼠，并监测至第28天。选择性考克斯-2抑制导致第2天和第6天系膜溶解显著增加（高达+71%），第6天白蛋白尿显著增加（高达3.1倍）。肾小球毛细血管损伤的加剧与肾小球内皮细胞的稀疏有关，而系膜细胞的增殖和活化不受影响。在第2天，未观察到对多形核中性粒细胞的肾小球内流或单核细胞/巨噬细胞的浸润和增殖的显著影响。这些影响与全身血流动力学特征无关，因为罗非昔布在第2天或第5天不影响收缩压。用罗非昔布治疗10天的肾病大鼠在第28天表现出持续的肾小球损伤，如蛋白尿增加（10倍）和系膜IV型胶原沉积（+24%）所示。在正常大鼠中，5天的罗非昔布给药未能诱导蛋白尿或形态学肾损害。总之，选择性考克斯-2抑制剂损害抗Thy 1.1肾小球肾炎大鼠系膜溶解后的肾小球毛细血管修复。这些数据表明，选择性考克斯-2抑制剂应谨慎使用的患者与炎症毛细血管内肾小球疾病。
Selective cyclooxygenase-2 (COX-2) inhibitors have anti-inflammatory activity and reduce proteinuria in experimental membranous glomerulonephritis. Antiangiogenic properties of COX-2 inhibitors were recently reported. Whether these properties are relevant to the glomerular healing process in inflammatory glomerular diseases was investigated. For evaluation of the effects of selective COX-2 inhibitors on the glomerular healing process in a rat model of mesangioproliferative glomerulonephritis (induced by anti-Thy 1.1 antibody), a selective COX-2 inhibitor (rofecoxib or celecoxib) or vehicle was administered daily from day I after disease induction until euthanasia on day 6. Additional nephritic rats were treated with rofecoxib or vehicle from day 1 to day 10 and were monitored until day 28. Selective COX-2 inhibition led to significant increases in mesangiolysis (up to +71%) on days 2 and 6 and in albuminuria (up to 3.1-fold) on day 6. This augmentation of glomerular capillary damage was associated with rarefaction of glomerular endothelial cells, whereas the proliferation and activation of mesangial cells were not affected. No significant effects on the glomerular influx of polymorphonuclear neutrophils or the infiltration and proliferation of monocytes/macrophages at day 2 were noted. These effects were independent of systemic hemodynamic features, because rofecoxib did not affect systolic BP on day 2 or 5. Nephritic rats treated with rofecoxib for 10 d demonstrated persistent glomerular injury at day 28, as indicated by increased albuminuria (10-fold) and mesangial type IV collagen deposition (+24%). In normal rats, 5-d administration of rofecoxib failed to induce albuminuria or morphologic renal damage. In conclusion, selective COX-2 inhibitors impair glomerular capillary repair after mesangiolysis in rats with anti-Thy 1.1 glomerulonephritis. These data suggest that selective COX-2 inhibitors should be used with caution among patients with inflammatory endocapillary glomerular disorders.