Interleukin IL-1, IL-6, and IL-8 predict mucosal toxicity of vaginal microbicidal contraceptives
Interleukin IL-1, IL-6, and IL-8 predict mucosal toxicity of vaginal microbicidal contraceptives
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DOI：
10.1095/biolreprod.104.029603
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发表时间：
2004-09-01
影响因子：
3.6
通讯作者：
Doncel, GF
中科院分区：
文献类型：
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作者：
Fichorova, RN;Bajpai, M;Doncel, GF
女性生殖道的炎症增加了对HIV-1和其他病毒感染的易感性，因此，它成为阴道产品的严重负担。促炎细胞因子的过度释放可能改变组织破坏和修复之间的粘膜平衡，并与化学损伤后病毒病原体的渗透和复制增强有关。本研究评估了四种表面活性杀菌剂候选物壬氧醇-9 （N-9）、苯扎氯铵（BZK）、十二烷基硫酸钠和单月月酸钠对人类精子和HIV的活性，以及它们在人类阴道上皮细胞和兔阴道粘膜上诱导炎症反应的能力。杀精和杀病毒评价将N-9列为最有效的化合物，但无法预测该化合物对阴道细胞活力的影响。白细胞介素-1的体外释放更准确地反映了它们的细胞毒性特征。此外，阴道洗液中IL-1浓度与单次和多次使用后的累积粘膜刺激评分相关（P < 0.01），表明BZK是对阴道粘膜损伤最大的剂。BZK诱导细胞快速死亡、IL-1释放和IL-6分泌。其他化合物需要更长时间或反复与阴道上皮接触才能引起显著的炎症反应。经多次应用后，体内IL-8水平升高，确定的累积粘膜毒性最高的化合物（P < 0.01）。综上所述，阴道分泌物中IL-1、IL-6和IL-8是化合物诱导粘膜毒性的敏感指标。所描述的评价系统是一个有价值的工具，在识别新的阴道避孕杀菌剂，选择出候选人，可能加强，而不是减少，艾滋病毒传播。
Inflammation of the female reproductive tract increases susceptibility to HIV-1 and other viral infections and, thus, it becomes a serious liability for vaginal products. Excessive release of proinflammatory cytokines may alter the mucosal balance between tissue destruction and repair and be linked to enhanced penetration and replication of viral pathogens upon chemical insult. The present study evaluates four surface-active microbicide candidates, nonoxynol-9 (N-9), benzalkonium chloride (BZK), sodium dodecyl sulfate, and sodium monolaurate for their activity against human sperm and HIV, and their capacity to induce an inflammatory response on human vaginal epithelial cells and by the rabbit vaginal mucosa. Spermicidal and virucidal evaluations ranked N-9 as the most potent compound but were unable to predict the impact of the compounds on vaginal cell viability. Interleukin (IL)-1 release in vitro reflected their cytotoxicity profiles more accurately. Furthermore, IL-1 concentrations in vaginal washings correlated with cumulative mucosal irritation scores after single and multiple applications (P < 0.01), showing BZK as the most damaging agent for the vaginal mucosa. BZK induced rapid cell death, IL-1 release, and IL-6 secretion. The other compounds required either more prolonged or repeated contact with the vaginal epithelium to induce a significant inflammatory reaction. Increased IL-8 levels after multiple applications in vivo identified compounds with the highest cumulative mucosal toxicity (P < 0.01). In conclusion, IL-1, IL-6, and IL-8 in the vaginal secretions are sensitive indicators of compound-induced mucosal toxicity. The described evaluation system is a valuable tool in identifying novel vaginal contraceptive microbicides, selecting out candidates that may enhance, rather than decrease, HIV transmission.