Juan Yung-Shun, Lee Yi-Lun, Long Cheng-Yu, Wong Jhen-Hong, Jang Mei-Yu, Lu Jian-He, Wu Wen-Jeng, Huang Yen-Shun, Chang Wei-Chiao, Chuang Shu-Mien
Department of Urology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan; Department of Urology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
Graduate Institute of Medical Science, Kaohsiung Medical University, Kaohsiung, Taiwan.
Am J Pathol. 2015 Aug;185(8):2269-85. doi: 10.1016/j.ajpath.2015.04.020. Epub 2015 Jun 12.
The number of ketamine abusers has increased significantly recently. Ketamine abusers exhibit urinary frequency, urgency, and at times urinary incontinence. Our aim was to investigate the role of transcription factor NF-κB and cyclooxygenase (COX)-2 in ketamine-induced cystitis. Sprague-Dawley rats were distributed into three groups, which received saline or treatment with ketamine or ketamine combined with a Cox-2 inhibitor (parecoxib). In addition, the toxic effect of ketamine and its metabolites were examined by primary urothelial cell culture. The ketamine-treated group displayed bladder hyperactivity and decreased bladder capacity. Treatment with ketamine + COX-2 inhibitor prevented these bladder dysfunctions. These bladder dysfunctions were accompanied by increases in the expression of NF-κB and COX-2 at the protein and mRNA levels. Ketamine treatment also enhanced bladder interstitial fibrosis, whereas ketamine + Cox-2 inhibitor decreased the intensity of fibrosis. Treatment of primary urothelial cells in vitro with ketamine or urine obtained from ketamine-treated rats stimulated the expression of NF-κB p65 and COX-2. Ketamine also initiated NF-κB translocation from cell cytoplasm to nucleus. Treatment with NF-κB inhibitor suppressed Cox-2 mRNA expression. Promoter-deletion analysis revealed that NF-κB was a necessary transcription factor for COX-2 gene (Ptgs2) activation. These results demonstrate that the regulation of COX-2 via the NF-κB pathway is involved in the inflammatory signaling of ketamine-induced cystitis in rat urinary bladder.
近年来，氯胺酮滥用者的数量显著增加。氯胺酮滥用者表现出尿频、尿急，有时还会出现尿失禁。我们的目的是研究转录因子NF-κB和环氧化酶（COX）-2在氯胺酮诱导的膀胱炎中的作用。将Sprague-Dawley大鼠分为三组，分别给予生理盐水或氯胺酮治疗或氯胺酮与COX-2抑制剂（帕瑞昔布）联合治疗。此外，通过原代尿路上皮细胞培养检测氯胺酮及其代谢产物的毒性作用。氯胺酮治疗组表现出膀胱活动亢进和膀胱容量减小。氯胺酮+COX-2抑制剂治疗可预防这些膀胱功能障碍。这些膀胱功能障碍伴随着NF-κB和COX-2在蛋白质和mRNA水平的表达增加。氯胺酮治疗还增强了膀胱间质纤维化，而氯胺酮+COX-2抑制剂降低了纤维化程度。用氯胺酮或从氯胺酮治疗大鼠获得的尿液体外处理原代尿路上皮细胞可刺激NF-κB p65和COX-2的表达。氯胺酮还引发了NF-κB从细胞质向细胞核的转位。用NF-κB抑制剂治疗可抑制COX-2 mRNA表达。启动子缺失分析表明，NF-κB是COX-2基因（Ptgs-2）激活所必需的转录因子。这些结果表明，通过NF-κB途径对COX-2的调节参与了大鼠膀胱中氯胺酮诱导的膀胱炎的炎症信号传导。
