Department of Pediatrics, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taiwan.
Toxicol Sci. 2013 Jan;131(1):302-10. doi: 10.1093/toxsci/kfs270. Epub 2012 Sep 7.
Hemorrhagic cystitis is a common complication in children receiving cyclophosphamide, a chemotherapeutic alkylating agent. Acrolein is a urinary metabolite from cyclophosphamide and can induce hemorrhagic cystitis. Here, we investigated the effects and mechanisms of acrolein by intravesical instillation on urinary bladder muscle contractions and pathological alterations in rats. Acrolein instillation significantly increased the muscle contractions of rat bladder detrusor after 1 and 6 h but markedly decreased detrusor contractions after 24 h. Acrolein increased phosphorylated protein kinase C (pan-PKC) expressions in bladders after 1 and 6 h but inhibited it after 24 h. Inducible nitric oxide (NO) synthase (iNOS) protein expressions were markedly induced in bladders 24 h after acrolein treatment. Twenty-four-hour acrolein instillation increased the levels of nitrite/nitrate and interleukin-6 (IL-6) in the urinary bladder. The iNOS inhibitors significantly inhibited the acrolein-increased nitrite/nitrate levels, but not IL-6 levels. IL-6-neutralizing antibodies effectively inhibited the acrolein-increased NOx levels. The increased detrusor contractions by 1-h acrolein treatment were significantly reversed by the PKC inhibitor RO32-0432, and the decreased detrusor contractions by 24-h acrolein treatment were significantly reversed by the iNOS inhibitor and IL-6-neutralizing antibody. Both the iNOS inhibitor and IL-6-neutralizing antibody effectively reversed the increased iNOS expression, decreased PKC phosphorylation, increased bladder weight, and hemorrhagic cystitis in rats 24 h after acrolein treatment. Taken together, these results suggest that an IL-6-regulated iNOS/NO signaling pathway participates in the acrolein-triggered detrusor contraction inhibition and hemorrhagic cystitis. These findings may help us to find a new strategy to treat cyclophosphamide-induced hemorrhagic cystitis.
出血性膀胱炎是接受环磷酰胺（一种化学治疗烷化剂）治疗的儿童的常见并发症。丙烯醛是环磷酰胺的尿代谢物，可诱导出血性膀胱炎。在这里，我们通过膀胱内灌注研究了丙烯醛对大鼠膀胱逼尿肌收缩和病理改变的影响及其机制。丙烯醛灌注后 1 和 6 小时明显增加了大鼠膀胱逼尿肌的肌肉收缩，但 24 小时后明显降低了逼尿肌收缩。丙烯醛在 1 和 6 小时后增加了膀胱中磷酸化蛋白激酶 C（pan-PKC）的表达，但在 24 小时后抑制了它。诱导型一氧化氮合酶（iNOS）蛋白表达在丙烯醛处理后 24 小时明显诱导。24 小时丙烯醛灌注增加了膀胱中硝酸盐/亚硝酸盐和白细胞介素-6（IL-6）的水平。iNOS 抑制剂显著抑制了丙烯醛增加的硝酸盐/亚硝酸盐水平，但不抑制 IL-6 水平。IL-6 中和抗体有效抑制了丙烯醛增加的 NOx 水平。1 小时丙烯醛处理引起的逼尿肌收缩增加被 PKC 抑制剂 RO32-0432 显著逆转，24 小时丙烯醛处理引起的逼尿肌收缩减少被 iNOS 抑制剂和 IL-6 中和抗体显著逆转。iNOS 抑制剂和 IL-6 中和抗体均有效逆转了丙烯醛处理后 24 小时大鼠逼尿肌中 iNOS 表达增加、PKC 磷酸化减少、膀胱重量增加和出血性膀胱炎。总之，这些结果表明，IL-6 调节的 iNOS/NO 信号通路参与了丙烯醛触发的逼尿肌收缩抑制和出血性膀胱炎。这些发现可能有助于我们找到治疗环磷酰胺诱导的出血性膀胱炎的新策略。
