Decreased cervical epithelial sensitivity to nonoxynol-9 (N-9) after four daily applications in a murine model of topical vaginal microbicide safety.
Decreased cervical epithelial sensitivity to nonoxynol-9 (N-9) after four daily applications in a murine model of topical vaginal microbicide safety.
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DOI：
10.1186/2050-6511-13-9
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发表时间：
2012-10-01
影响因子：
2.9
通讯作者：
Krebs FC
中科院分区：
文献类型：
--
作者：
Lozenski K;Ownbey R;Wigdahl B;Kish-Catalone T;Krebs FC
五种局部阴道杀微生物剂令人失望的临床失败为影响杀微生物剂安全性和有效性的因素提供了新的见解。具体而言，与多次使用含壬苯醇醚-9（N-9）的产品相关的人类免疫缺陷病毒1型（HIV-1）感染风险更高，这突出了应用频率作为临床前杀微生物剂开发期间变量的重要性，特别是在动物模型研究中。为了评价施用频率和N-9毒性之间的关联，使用宫颈阴道杀微生物剂安全性的小鼠模型进行实验。在该模型系统中，在单次和多次暴露于N-9后评估宫颈和阴道上皮完整性、细胞因子释放和免疫细胞浸润的变化。在首次应用N-9（水性，1%）后，早在暴露后10 min和暴露后8 h就观察到宫颈上皮（但不是阴道上皮）的相当大的损伤。随后的每日暴露（长达4天）的特征是相对于相同持续时间的单次暴露，宫颈毒性降低。释放到宫颈阴道腔的促炎细胞因子水平和宫颈上皮近端CD 14阳性免疫细胞浸润的程度也取决于N-9暴露的次数。重复应用N-9的特征在于对N-9相关毒性的敏感性降低和免疫细胞募集水平降低，而不是引起累积性宫颈上皮损伤。这些结果为N-9基杀微生物剂的失败提供了新的见解，并说明了在临床前杀微生物剂开发策略中考虑多次暴露方案的重要性。
The disappointing clinical failures of five topical vaginal microbicides have provided new insights into factors that impact microbicide safety and efficacy. Specifically, the greater risk for human immunodeficiency virus type 1 (HIV-1) acquisition associated with multiple uses of a nonoxynol-9 (N-9)-containing product has highlighted the importance of application frequency as a variable during pre-clinical microbicide development, particularly in animal model studies. To evaluate an association between application frequency and N-9 toxicity, experiments were performed using a mouse model of cervicovaginal microbicide safety. In this model system, changes in cervical and vaginal epithelial integrity, cytokine release, and immune cell infiltration were assessed after single and multiple exposures to N-9. After the initial application of N-9 (aqueous, 1%), considerable damage to the cervical epithelium (but not the vaginal epithelium) was observed as early as 10 min post-exposure and up to 8 h post-exposure. Subsequent daily exposures (up to 4 days) were characterized by diminished cervical toxicity relative to single exposures of like duration. Levels of pro-inflammatory cytokines released into the cervicovaginal lumen and the degree of CD14-positive immune cell infiltration proximal to the cervical epithelium were also dependent on the number of N-9 exposures. Rather than causing cumulative cervical epithelial damage, repeated applications of N-9 were characterized by decreased sensitivity to N-9-associated toxicity and lower levels of immune cell recruitment. These results provide new insights into the failure of N-9-based microbicides and illustrate the importance of considering multiple exposure protocols in pre-clinical microbicide development strategies.
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影响因子：
4.9
作者：
KELLY, JP;REYNOLDS, RB;ALEXANDER, WJ
通讯作者：
ALEXANDER, WJ
影响因子：
3.7
作者：
Milligan, GN;Bernstein, DI
通讯作者：
Bernstein, DI
影响因子：
7.6
作者：
Krebs, FC;Miller, SR;Wigdahl, B
通讯作者：
Wigdahl, B
影响因子：
4.9
作者：
BENES, S;MCCORMACK, WM
通讯作者：
MCCORMACK, WM
影响因子：
4.3
作者：
KAMINSKY, M;SZIVOS, MM;WILLIGAN, DA
通讯作者：
WILLIGAN, DA