Estrogen Affects the Glycosaminoglycan Layer of the Murine Bladder
Estrogen Affects the Glycosaminoglycan Layer of the Murine Bladder
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DOI：
10.1097/spv.0b013e31824b76bd
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发表时间：
2012-05-01
影响因子：
1.6
通讯作者：
Mysorekar, Indira U.
中科院分区：
文献类型：
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作者：
Anand, Mallika;Wang, Caihong;Mysorekar, Indira U.
目的：尿路感染（uti），通常由尿路致病性大肠杆菌（UPEC）引起，在绝经后妇女中具有显著的发病率。糖胺聚糖（GAGs）构成膀胱管腔表面的第一道防线。我们的目的是使用绝经小鼠模型来确定雌激素状态是否影响GAG层对UPEC感染的反应。方法：采用假手术（sham, n = 18）或卵巢切除术（OVX, n = 66）建立小鼠绝经模型。一组卵巢切除小鼠接受17a -雌二醇激素治疗（HT, n = 33）。用UPEC接种小鼠，在不同时间点处死；收集膀胱并在多个膀胱切片上评估GAG层厚度。每个膀胱测量16次。采用重复测量的双向方差分析来确定感染后时间和激素状况对GAG厚度的影响。我们还研究了GAG生物合成对雌激素状态和感染变化的反应的分子基础。结果：3种激素状态下胃粘膜瘤厚度差异无统计学意义；两组间胃粘膜厚度变化时间差异有统计学意义（P < 0.05）。OVX小鼠在感染后72小时表现出明显的厚度增加（P = 0.0001），而这种影响在添加HT后更早（感染后24小时）转移（P = 0.001）。在感染后2至4周，所有队列的GAG厚度与基线无显著差异。此外，定量逆转录-聚合酶链反应分析显示，GAG的生物合成受到基础水平雌激素水平和感染的影响。结论：尿路感染过程中GAG层发生动态变化。我们的数据表明，随着时间的推移，高温正调节GAG层的厚度，以及GAG的组成。此外，在UPEC感染反应中，GAG硫酸化状态可受雌激素水平的影响。GAG层在尿路感染中的保护作用可能是治疗和预防绝经后尿路感染的药理学靶点。
Objectives: Urinary tract infections (UTIs), commonly caused by uropathogenic Escherichia coli (UPEC), confer significant morbidity among postmenopausal women. Glycosaminoglycans (GAGs) comprise the first line of defense at the bladder's luminal surface. Our objective was to use a murine model of menopause to determine whether estrogen status affects the GAG layer in response to UPEC infection.Methods: Adult female mice underwent sham surgery (SHAM, n = 18) or oophorectomy (OVX, n = 66) to establish a murine model of menopause. A subset of oophorectomized mice underwent hormone therapy (HT, n = 33) with 17A-estradiol. Mice were inoculated with UPEC and killed at various time points; bladders were collected and GAG layer thickness was assessed in multiple bladder sections. Sixteen measurements were made per bladder. A repeated-measures 2-way analysis of variance was performed to determine the effect of time after infection and hormonal condition on GAG thickness. We also investigated the molecular underpinnings of GAG biosynthesis in response to alterations in estrogen status and infection.Results: We did not observe significant difference of GAG thickness among the 3 hormonal conditions; however, the time course of GAG thickness was significantly different (P < 0.05). The OVX mice demonstrated significantly greater thickness at 72 hours after infection (P = 0.0001), and this effect was shifted earlier (24 hours after infection) on the addition of HT (P = 0.001). At 2 to 4 weeks after infection, GAG thickness among all cohorts was not significantly different from baseline. In addition, quantitative reverse transcription-polymerase chain reaction analysis revealed that GAG biosynthesis is altered by estrogen status at basal level and on infection.Conclusions: The GAG layer is dynamically altered during the course of UTI. Our data show that HT positively regulates GAG layer thickness over time, as well as the composition of the GAGs. In addition, the GAG sulfation status can be influenced by estrogen levels in response to UPEC infection. The protective effects of the GAG layer in UTI may represent pharmacologic targets for the treatment and prevention of postmenopausal UTI.