A mouse model for interstitial cystitis/painful bladder syndrome based on APF inhibition of bladder epithelial repair: a pilot study.
A mouse model for interstitial cystitis/painful bladder syndrome based on APF inhibition of bladder epithelial repair: a pilot study.
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DOI：
10.1186/1471-2490-12-17
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发表时间：
2012-06-08
期刊：
影响因子：
2
通讯作者：
Johnson D
中科院分区：
文献类型：
--
作者：
Keay S;Leitzell S;Ochrzcin A;Clements G;Zhan M;Johnson D
间质性膀胱炎/膀胱疼痛综合征（IC/PBS）是一种慢性膀胱疾病，伴有膀胱上皮变薄或溃疡、疼痛、尿频和尿急。对于IC/PBS没有可靠有效的疗法，并且对于可以测试潜在疗法的病症没有普遍接受的动物模型。来自IC/PBS患者的膀胱上皮细胞产生小的糖肽抗增殖因子或“APF”，其抑制增殖，降低紧密连接蛋白表达，增加细胞旁通透性，并诱导体外膀胱上皮细胞的基因表达变化，其模拟体内IC/PBS患者活检标本中的异常。因此，我们确定了合成的APF衍生物抑制小鼠膀胱上皮修复的能力。通过经尿道输注3%乙酸剥离雌性CBA/J小鼠的膀胱上皮，随后每天用三种膀胱内治疗[合成的as-APF、无活性的非糖基化对照肽或磷酸盐缓冲盐水载体（PBS）]中的一种治疗小鼠1-21天。固定的膀胱切片用苏木精和伊红染色，通过图像分析确定上皮面积，或与抗尿斑蛋白III（UPIII）或抗闭锁小带1型（ZO-1）抗体孵育，用于免疫荧光显微镜检查。通过双向方差分析（ANOVA）分析上皮测量数据;使用Tukey-Kramer方法进行多组的事后比较。在第3-21天，与对照小鼠相比，经as-APF处理的小鼠的膀胱上皮修复显著减弱（p < 0.05）;通过事后分析，经as-APF处理的小鼠的平均上皮/总面积也显著低于任一对照组的小鼠（两种比较均为p < 0.0001）。与对照组小鼠相比，在第7天（UPIII）或第14天（ZO-1），经as-APF处理的小鼠中UPIII和ZO-1表达也降低。该模型证明了as-APF的体内作用，其在CBA/J小鼠中在经尿道乙酸输注后消除膀胱上皮修复和UPIII和ZO-1的表达。由于膀胱上皮变薄、UPIII表达降低和ZO-1表达降低是IC/PBS患者活检的组织病理学特征，因此该模型可用于研究IC/PBS的病理生理学和潜在治疗的效果。
Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic bladder disorder with bladder epithelial thinning or ulceration, pain, urinary frequency and urgency. There is no reliably effective therapy for IC/PBS, and no generally accepted animal model for the disorder in which potential therapies can be tested. Bladder epithelial cells from IC/PBS patients make a small glycopeptide antiproliferative factor or "APF" that inhibits proliferation, decreases tight junction protein expression, increases paracellular permeability, and induces changes in gene expression of bladder epithelial cells in vitro that mimic abnormalities in IC/PBS patient biopsy specimens in vivo. We therefore determined the ability of a synthetic APF derivative to inhibit bladder epithelial repair in mice. The bladder epithelium of female CBA/J mice was stripped by transurethral infusion of 3% acetic acid, and mice were subsequently treated daily with one of three intravesical treatments [synthetic as-APF, inactive unglycosylated control peptide, or phosphate buffered saline carrier (PBS)] for 1–21 days. Fixed bladder sections were either stained with haematoxylin and eosin for determination of epithelial area by image analysis, or incubated with anti-uroplakin III (UPIII) or anti-zonula occludens type 1 (ZO-1) antibodies for immunofluorescence microscopy. Epithelial measurement data were analyzed by a two-way analysis of variance (ANOVA); post hoc comparisons of multiple groups were carried out using the Tukey-Kramer method. Bladder epithelial repair was significantly attenuated in as-APF-treated mice as compared to control mice on days 3–21 (p < 0.05); the mean epithelial/total area over all measured days was also significantly lower in as-APF-treated mice vs. mice in either control group by post hoc analysis (p < 0.0001 for both comparisons). UPIII and ZO-1 expression was also decreased in as-APF-treated mice as compared to mice in either control group by day 7 (UPIII) or day 14 (ZO-1). This model demonstrates in vivo effects of as-APF which abrogates bladder epithelial repair and expression of UPIII and ZO-1 in CBA/J mice following transurethral acetic acid infusion. As bladder epithelial thinning, decreased UPIII expression, and decreased ZO-1 expression are histopathologic features of IC/PBS patient biopsies, this model may be useful for studying the pathophysiology of IC/PBS and the effect of potential therapies.
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