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北京大学学报（医学版） ›› 2024, Vol. 56 ›› Issue (5): 908-912. doi: 10.19723/j.issn.1671-167X.2024.05.024

• 论著 • 上一篇    下一篇

优化环磷酰胺剂量在间质性膀胱炎/膀胱疼痛综合征啮齿动物模型中的应用

柯涵炜, 王起, 许克新*()   

  1. 北京大学人民医院泌尿外科，北京大学应用碎石研究所，北京 100044
  • 收稿日期:2024-03-11 出版日期:2024-10-18 发布日期:2024-10-16
  • 通讯作者: 许克新 E-mail:cavinx@yeah.net
  • 作者简介:第一联系人：

    *These authors contributed to this work equally

  • 基金资助:
    国家自然科学基金(81970660);北京大学人民医院研发基金(2147000692)

Optimization study of an animal model for interstitial cystitis/bladder pain syndrome based on the dose effect of cyclophosphamide

Hanwei KE, Qi WANG, Kexin XU*()   

  1. Department of Urology, Peking University Applied Liyhotripsy Institute, Peking University People's Hospital, Beijing 100044, China
  • Received:2024-03-11 Online:2024-10-18 Published:2024-10-16
  • Contact: Kexin XU E-mail:cavinx@yeah.net
  • Supported by:
    the the National Natural Science Foundation of China(81970660);Research and Development Fund of Peking University People's Hospital(2147000692)

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摘要：

目的: 评估不同剂量的环磷酰胺(cyclophosphamide，CYP)诱导的间质性膀胱炎/膀胱痛综合征(interstitial cystitis/bladder pain syndrome, IC/BPS)动物模型模拟疾病症状的准确性与可重复性，以期为IC/BPS的病理生理学研究和治疗策略评估提供实验模型依据。方法: 选用7周龄的Sprague-Dawley雌性大鼠28只分为a组(25 mg/kg CYP)、b组(75 mg/kg CYP)、c组(125 mg/kg CYP)和d组(对照组)4组，每组7只，通过腹腔注射CYP或生理盐水建立动物模型，评估指标包括尿斑实验、von Frey纤维触痛实验、尿动力学检查，以及组织学分析。结果: 25 mg/kg CYP剂量的大鼠在模拟IC/BPS膀胱功能障碍和炎症反应方面显著优于其他CYP剂量组，且对生理功能影响较小。所有剂量CYP处理的大鼠都表现出膀胱炎症，但25 mg/kg剂量的症状与IC/BPS临床特征更为一致。此外，25 mg/kg CYP剂量组大鼠膀胱顺应性降低，内脏疼痛增加，但未显著增加排尿频率，与IC/BPS患者表现相似。结论: 25 mg/kg的CYP剂量在模拟非溃疡性IC/BPS的关键特征方面表现出明显的优势，对未来IC/BPS的研究和治疗策略提供了重要参考。但尽管如此，由于IC/BPS的多因素性质，未来研究需要探索更多诱导手段，以复现疾病的复杂病理过程。

关键词: 环磷酰胺, 间质性膀胱炎, 膀胱痛综合征, 尿动力学, 动物模型

Abstract:

Objective: To evaluate the efficacy of cyclophosphamide (CYP) at different doses in replicating the symptoms of interstitial cystitis/bladder pain syndrome (IC/BPS) in an animal model, thereby providing an experimental basis for understanding the pathophysiology of IC/BPS and assessing treatment strategies. Methods: Twenty-eight female Sprague-Dawley rats aged seven weeks were divided into four groups: Group a (25 mg/kg CYP), group b (75 mg/kg CYP), group c (125 mg/kg CYP), and group d (a control group). The rats were injected intraperitoneally with either CYP or saline solution. Evaluations included urine spot tests, von Frey filament pain threshold tests, urodynamic examinations, and histological assessments. Results: The study found that the 25 mg/kg CYP dosage significantly outperformed higher doses in simulating bladder dysfunction and inflammatory responses while minimizing the impact on the rats' physiological functions. Specifically, urine spot area, group a showed a significant reduction in urine spot area compared with the control group (P < 0.05), while groups b and c did not show significant differences. Pain threshold: The von Frey filament test indicated increased visceral pain in group a, aligning closely with IC/BPS patient symptoms, without a significant increase in urination frequency. Urodynamic assessments: Group a exhibited decreased bladder compliance and reduced maximum bladder capacity (P < 0.05), with no significant differences in baseline bladder pressure and maximum detrusor pressure across all groups. Histological analysis: Hematoxylin-eosin (HE) staining revealed that bladder tissue in group a had moderate inflammatory reactions, whereas groups b and c showed severe inflammation and tissue damage, correlating with the higher doses of CYP. Furthermore, the urine spot tests and von frey filament tests provided quantitative data supporting the model's reliability, urine spot count, group a had an average urine spot count of (15±3) spots, significantly higher than the control group's (5±2) spots (P < 0.01). Nociceptive score: Group a nociceptive score increased to 0.5±0.1, indicating heightened pain sensitivity compared with the control group 0.10±0.05 (P < 0.01). Conclusion: The 25 mg/kg CYP demonstrated significant advantages in simulating the key features of non-ulcerative IC/BPS, summarizing the main aspects of the human condition, including persistent visceral pain and mild inflammatory reactions in bladder tissue. These findings offer substantial experimental support for drug development and treatment research in IC/BPS and provide new insights into the complex patho-physiology of the disease.

Key words: Cyclophosphamide, Interstitial Cystitis, Bladder Pain Syndrome, Urodynamics, Animal Model

中图分类号: 

  • R694.3

图1

造模后各组小鼠一般情况"

图2

各组大鼠造模后膀胱功能"

图3

各组大鼠HE染色结果"

1 Driscoll A , Teichman JMH . How do patients with interstitial cystitis present[J]. J Urol, 2001, 166 (6): 2118- 2120.
doi: 10.1016/S0022-5347(05)65517-6
2 Hanno PM , Erickson D , Moldwin R , et al. Diagnosis and treatment of interstitial cystitis/bladder pain syndrome: AUA guideline amendment[J]. J Urol, 2015, 193 (5): 1545- 1553.
doi: 10.1016/j.juro.2015.01.086
3 Parsons CL . The role of the urinary epithelium in the pathogenesis of interstitial cystitis/prostatitis/urethritis[J]. Urology, 2007, 69, S9- S16.
doi: 10.1016/j.urology.2006.03.084
4 van de Merwe JP . Interstitial cystitis and systemic autoimmune diseases[J]. Nat Clin Pract Urol, 2007, 4 (9): 484- 491.
doi: 10.1038/ncpuro0874
5 Cox PJ . Cyclophosphamide cystitis: Identification of acrolein as the causative agent[J]. Biochem Pharmacol, 1979, 28 (13): 2045- 2049.
doi: 10.1016/0006-2952(79)90222-3
6 Liu XY , Zhu MZ , Xie JP . Mutagenicity of acrolein and acrolein-induced DNA adducts[J]. Toxicol Mech Methods, 2010, 20 (1): 36- 44.
doi: 10.3109/15376510903530845
7 Vera PL , Iczkowski KA , Wang X , et al. Cyclophosphamide-induced cystitis increases bladder CXCR4 expression and CXCR4-macrophage migration inhibitory factor association[J]. PLoS One, 2008, 3 (12): e3898.
doi: 10.1371/journal.pone.0003898
8 Boucher M , Meen M , Codron JP , et al. Cyclophosphamide-induced cystitis in freely-moving conscious rats: Behavioral approach to a new model of visceral pain[J]. J Urol, 2000, 164 (1): 203- 208.
doi: 10.1016/S0022-5347(05)67495-2
9 Augé C , Chene G , Dubourdeau M , et al. Relevance of the cyclophosphamide-induced cystitis model for pharmacological studies targeting inflammation and pain of the bladder[J]. Eur J Pharmacol, 2013, 707 (1/2/3): 32- 40.
10 Augé C , Gamé X , Vergnolle N , et al. Characterization and validation of a chronic model of cyclophosphamide-induced interstitial cystitis/bladder pain syndrome in rats[J]. Front Pharmacol, 2020, 11, 1305.
doi: 10.3389/fphar.2020.01305
11 Gray KJ , Engelmann UH , Johnson EH , et al. Evaluation of misoprostol cytoprotection of the bladder with cyclophosphamide (Cytoxan) therapy[J]. J Urol, 1986, 136 (2): 497- 500.
doi: 10.1016/S0022-5347(17)44929-9
12 Hakimi Z , Houbiers J , Pedersini R , et al. The burden of bladder pain in five european countries: A cross-sectional study[J]. Urology, 2017, 99, 84- 91.
doi: 10.1016/j.urology.2016.08.038
13 Smaldone MC , Vodovotz Y , Tyagi V , et al. Multiplex analysis of urinary cytokine levels in rat model of cyclophosphamide-induced cystitis[J]. Urology, 2009, 73 (2): 421- 426.
doi: 10.1016/j.urology.2008.07.031
14 Arms L , Girard BM , Vizzard MA . Expression and function of CXCL12/CXCR4 in rat urinary bladder with cyclophosphamide-induced cystitis[J]. Am J Physiol Renal Physiol, 2010, 298 (3): F589- F600.
doi: 10.1152/ajprenal.00628.2009
15 May V , Vizzard MA . Bladder dysfunction and altered somatic sensitivity in PACAP-/-mice[J]. J Urol, 2010, 183 (2): 772- 779.
doi: 10.1016/j.juro.2009.09.077
16 Augé C , Basso L , Blanpied C , et al. Pain management in a model of interstitial cystitis/bladder pain syndrome by a vaccinal strategy[J]. Front Pain Res (Lausanne), 2021, 2, 642706.
doi: 10.3389/fpain.2021.642706
17 Koziol JA , Adams HP , Frutos A . Discrimination between the ulcerous and the nonulcerous forms of interstitial cystitis by noninvasive findings[J]. J Urol, 1996, 155 (1): 87- 90.
doi: 10.1016/S0022-5347(01)66551-0
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ISSN 1671-167X
CN 11-4691/R
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