The effects of selective cyclooxygenase-2 inhibitor on fetal ductus arteriosus and kidney

背景：最近的研究表明，选择性COX-2抑制剂作为非特异性COX抑制剂，如吲哚美辛(IND)，可抑制胎儿动脉导管(DA)的收缩。我们以前曾报道过母体给药引起胎鼠肾组织损伤。目的：评价母体给予选择性环氧合酶-2抑制剂塞来昔布是否会导致胎鼠肾脏的形态损伤，并探讨其与胎儿DA收缩的关系。方法：孕鼠于妊娠第20天经口给予健得丸(10 mg/kg)、塞来昔布(10~60 mg/kg)及赋形剂。24小时后取出胎儿，并分为两个研究组。在DA收缩研究中，采用快速全身冷冻法测定DA与主肺动脉内径的比值(DA/PA)。在形态学研究中，取出肾脏并进行组织病理学检查。数据采用非参数分析进行统计学比较。结果：塞来昔布呈剂量依赖性收缩胎儿DA(10 mg：0.92±0.02、20 mg：0.65±0.12、30 mg：0.35±0.08、40 mg：0.31±0.11、50 mg：0.17±0.10、60 mg：0.11±0.04)。塞来昔布在胎儿肾脏的远端和近端肾小管中引起多种皮质髓坏死和塌陷。IND产生了类似的但更严重的形态损伤。结论：选择性COX-2抑制剂塞来昔布可引起胎鼠形态组织损伤，如吲哚美辛，且这些损伤与胎儿DA收缩无关。

Background : Recent studies demonstrated that selective COX-2 inhibitors constrict the fetal ducus arteriosus (DA) as non-specific COX inhibitors, like indomethacin (IND). We previously reported renal tissue damage in fetal rats induced by maternally administered IND. To evaluate whether a maternally administered selective COX-2 inhibitor, celecoxib, causes morphological renal damages in fetal rats and to evaluate the relation to the fetal DA constriction. Methods : JND (10mg/kg), celecoxibs (10-60mg/kg) and vehicles were administered orally to the pregnant rats on the 20^<th> day of gestation. The fetuses were removed 24 hours after and were divided into two study groups. In the DA constriction study, rapid whole body freezing method was used to obtain the inner diameter ratio of the DA to the main pulmonary artery (DA/PA). In morphological study, the kidneys were removed and examined histopathologically. The data was statistically compared by non-parametric analysis. Result : Celecoxibs constricted the fetal DA dose-dependently (10 mg: 0.92 ± 0.02、20 mg: 0.65 ± 0.12、30 mg: 0.35 ± 0.08、40 mg: 0.31 ± 0.11、50mg: 0.17 ± 0.10、 60 mg: 0.11 ± 0.04). Celecoxibs produced a variety of corticomedullary necrosis and of collapse in distal and proximal tubules in the fetal kidney. IND produced the similar but more severe morphological damages. Conclusion : These data suggested that a selective COX-2 inhibitor, celecoxib, causes morphological tissue damages in fetal rats, like indomethacin, and that these damages are indepen of the fetal DA constriction.