L-Selectin and P-Selectin Are Novel Biomarkers of Cervicovaginal Inflammation for Preclinical Mucosal Safety Assessment of Anti-HIV-1 Microbicide
L-Selectin and P-Selectin Are Novel Biomarkers of Cervicovaginal Inflammation for Preclinical Mucosal Safety Assessment of Anti-HIV-1 Microbicide
复制标题
L-选择素和 P-选择素是宫颈阴道炎症的新型生物标志物，用于抗 HIV-1 杀菌剂的临床前粘膜安全性评估
DOI：
10.1128/aac.05950-11
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发表时间：
2012-06-01
影响因子：
4.9
通讯作者：
Yan, Huimin
中科院分区：
文献类型：
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作者：
Zhong, Maohua;He, Benxia;Yan, Huimin
摘要阻碍杀微生物剂临床前开发的主要障碍是缺乏有效的宫颈阴道炎症生物标志物。因此，本研究的目的是确定新的非侵入性可溶性标记物在小鼠模型中用于评估杀微生物剂粘膜安全性。通过进行细胞因子抗体阵列分析，我们确定了两种粘附分子，L-选择素和P-选择素，当粘膜炎症被壬苯醇醚-9（N9）（一种抗HIV-1杀微生物剂候选物，临床试验失败）触发时，在一种药物诱导的宫颈阴道炎症的精制小鼠模型中，这两种粘附分子显著增加。我们发现，L-选择素和P-选择素的检测模式明显不同于先前定义的宫颈阴道炎症的两个生物标志物，单核细胞趋化蛋白1（MCP-1）和白细胞介素6（IL-6）。这两种可溶性选择素的水平与N9和两种批准的促炎化合物苯扎氯铵（BZK）和十二烷基硫酸钠（SDS）引发的粘膜炎症的持续时间和严重程度的相关性优于MCP-1和IL-6，但与两种非促炎化合物羧甲基纤维素（CMC;杀微生物剂赋形剂）和替诺福韦（TFV;杀微生物剂候选物）无关。这些数据表明，L-选择素和P-选择素可以作为额外的新型宫颈阴道炎症生物标志物，用于预防HIV和其他性传播病原体感染的候选杀微生物剂的临床前粘膜安全性评价。
ABSTRACT A major obstacle thwarting preclinical development of microbicides is the lack of a validated biomarker of cervicovaginal inflammation. Therefore, the present study aims to identify novel noninvasive soluble markers in a murine model for assessment of microbicide mucosal safety. By performing cytokine antibody array analysis, we identified two adhesion molecules, L-selectin and P-selectin, which significantly increased when mucosal inflammation was triggered by nonoxynol-9 (N9), an anti-HIV-1 microbicide candidate that failed clinical trials, in a refined murine model of agent-induced cervicovaginal inflammation. We found that patterns of detection of L-selectin and P-selectin were obviously different from those of the two previously defined biomarkers of cervicovaginal inflammation, monocyte chemotactic protein 1 (MCP-1) and interleukin 6 (IL-6). The levels of these two soluble selectins correlated better than those of MCP-1 and IL-6 with the duration and severity of mucosal inflammation triggered by N9 and two approved proinflammatory compounds, benzalkonium chloride (BZK) and sodium dodecyl sulfate (SDS), but not by two nonproinflammatory compounds, carboxymethyl celluose (CMC; microbicide excipients) and tenofovir (TFV; microbicide candidate). These data indicated that L-selectin and P-selectin can serve as additional novel cervicovaginal inflammation biomarkers for preclinical mucosal safety evaluation of candidate microbicides for the prevention of infection with HIV and other sexually transmitted pathogens.