Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, CA 94117, USA.
MRC Centre for Reproductive Health, University of Edinburgh, Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK Clinical Sciences, Imperial College London, London W12 0NN, UK.
Mol Hum Reprod. 2014 Jun;20(6):579-89. doi: 10.1093/molehr/gau019. Epub 2014 Mar 12.
Preterm birth (PTB) is a major public health problem, with a global prevalence of 9.6% and over a million annual neonatal deaths. In a mouse model of preterm labor (PTL) induced by intravaginal administration of a subclinical dose of lipopolysaccharide (LPS), we previously demonstrated that LPS ascends to the cervix, inducing complement activation, cervical remodeling and PTL. Here we show that complement activation also plays a role in myometrial contractions during PTL in this model. Increased levels of C5a were detected in the myometrium of LPS-treated mice but not in age-matched control or term myometrium. Human and mouse myometrium incubated with C5a showed increased frequency of contractions and expression of connexin 43, suggesting that C5a is an uterotonic molecule. Statins, which showed beneficial effects in preventing complement-mediated pregnancy complications, prevented cervical remodeling, myometrial contractions and PTL in the LPS model. The protective effects of statins in PTL were associated with increased synthesis, expression and activity of heme oxygenase (HO-1) in myometrium and cervix. Coadministration of HO-1 inhibitor tin-protoporphyrin-IX with pravastatin abrogated the protective effects of pravastatin on cervical remodeling and myometrial contractions leading to PTB. In addition, pravastatin inhibited complement activation in the cervix by increasing the synthesis and expression of complement inhibitor decay-accelerating factor. This study in mice suggests that statins might be useful to prevent PTL in humans. Clinical trials in humans are needed and if these results are confirmed, they may form the basis for a new clinical approach to prevent PTB.
早产 (PTB) 是一个主要的公共卫生问题，全球发病率为 9.6%，每年有超过 100 万新生儿死亡。在我们之前通过阴道内给予亚临床剂量脂多糖 (LPS) 诱导早产 (PTL) 的小鼠模型中，我们证明 LPS 上升到宫颈，诱导补体激活、宫颈重塑和 PTL。在这里，我们表明补体激活在该模型的 PTL 期间的子宫收缩中也起作用。在 LPS 处理的小鼠的子宫肌中检测到 C5a 水平升高，但在年龄匹配的对照或足月子宫肌中未检测到。与人及鼠子宫肌孵育 C5a 显示收缩频率增加和连接蛋白 43 的表达增加，表明 C5a 是一种子宫收缩分子。他汀类药物在预防补体介导的妊娠并发症方面显示出有益作用，可预防 LPS 模型中的宫颈重塑、子宫收缩和 PTL。他汀类药物在 PTL 中的保护作用与子宫肌和子宫颈中血红素加氧酶 (HO-1) 的合成、表达和活性增加有关。HO-1 抑制剂 tin-protoporphyrin-IX 与 pravastatin 联合给药可消除 pravastatin 对宫颈重塑和子宫收缩导致 PTB 的保护作用。此外，pravastatin 通过增加补体抑制剂衰变加速因子的合成和表达来抑制宫颈中的补体激活。这项在小鼠中的研究表明，他汀类药物可能对预防人类 PTL 有用。需要进行人类临床试验，如果这些结果得到证实，它们可能为预防 PTL 的新临床方法奠定基础。
