应激在子宫内膜异位症发生发展中的作用

The negative impact of chronic psychological stress on health is now well documented. Mounting evidence indicates that symptoms such as chronic, incapacitating pelvic pain and infertility negatively and substantially impact the physical and mental health status, health-related quality of life, and productivity on women with endometriosis. They are also reported to have elevated anxiety levels, elevated perceived stress levels and reduced quality of life. We preliminary data suggest that mice that were under stress one day after surgical induction of endometriosis for 2 weeks had their lesion size nearly doubled than those that received regular handling (no stress). In addition, β2-adrenergic receptor is found to be overexpressed in the ectopic endometrium in women with endometriosis. Despite these findings, the role of stress on the development of endometriosis has received scant attention. The purpose of this project is to investigate the impact of stress hormones, mostly epinephrine and norepinephrine, on cellular proliferation, invasiveness, angiogenesis, and the production of proinflammatory cytokines in endometriotic cells. In addition, the involvement of specific adrenergic receptors in endometriosis development will be validated through mouse models, which also will be used to determine as whether intervention through pharmacological means would be of any utility in mitigating or even eliminating the promoting effect of stress. We believe that a better understanding as how stress impacts on the development of endometriosis would shed new light into the pathogenesis of endometriosis, helping to develop more efficacious therapeutics for endometriosis.

慢性(精神)应激对健康的不良影响已为科学界公认。众多证据表明：子宫内膜异位症（内异症）患者由于饱受诸如慢性盆腔痛及不孕等症状的困扰，生活质量及工作效率下降，焦虑水平及自身感受到的应激水平上升。我们的前期研究表明：小鼠在手术建模1天后人为进行应激，其病灶相对于无应激组增加了近一倍，而内异症患者异位内膜中β2-肾上腺素受体的表达亦显著升高。但是，应激对内异症发生发展中作用的研究在国内外几乎是一个空白。本课题旨在研究应激激素在异位内膜细胞中对细胞增殖、侵袭、新生血管形成、炎症因子产生的分子生物学机制。此外，通过体内动物模型实验，进一步验证哪些肾上腺素受体在起作用，并确定是否可以通过药物手段（如β-阻断剂）干扰肾上腺素受体以期降低甚至去除应激对内异症的促进作用。我们相信，阐明应激在内异症发生发展中起重要促进作用的机制，可以进一步认识内异症的发生发展机制，为开发更有效的治疗内异症的药物奠定基础。

通过2种不同的应激模型，我们报道了应激可以加速内异症的发展，且表明这个促进作用是通过激活肾上腺素ADRB2受体信号通路，通过CERB，激活Akt，然后诱导VEGF表达，促进新生血管生成，最终导致病灶的增长。..我们还报道了手术作为应激源可以促进内异症的发展，并证实也是通过激活肾上腺素受体ADRB2信号通路导致病灶的发展。我们的临床流行病学研究也证实，的确具有手术史的妇女其患内异症的风险增加了2.6倍。..由于术后复发是临床上治疗内异症一个非常头痛的问题，我们觉得有必要在围手术期采取一定的措施，降低内异症的发病风险。我们据此首先建立了一个小鼠的内异症复发模型，并报道在围手术期干预可以有效降低内异症复发的风险。..在完成课题的过程中，我们意识到，肾上腺素及肾上腺素受体通路是通过自主神经来介导的。但是，在内异症病灶常常分泌一些因子排斥自主神经纤维但诱导感觉神经纤维的生长。的确，在深部内异症病灶附近，往往有许多神经丛，且常常有感觉神经过度再生。这启示我们感觉神经所分泌的一些神经肽有可能促进了病灶的加速发展。据此，我们迅速调整了研究方向，把研究重点放在了感觉神经细胞上。..我们研究了内异症病灶和感觉神经是否存在交互对话。我们发现，内异症间质细胞会分泌血栓素，促进感觉神经突触生长。随后，我们通过大量的动物实验，证明感觉神经所分泌的神经肽，如P物质，可以加速内异症病灶的发展。大量的体外实验也表明，P物质及CGRP可以促进内异症细胞的上皮-间质转化，成纤维细胞-肌成纤维细胞的转分化，及平滑肌化生，从而加速病灶纤维化。这就很好地解释了为什么深部内异症病灶要比其他类型的内异症病灶更有感觉神经过度再生，且往往具有结节状病灶（表现为平滑肌及纤维化）。..在这个基础上，我们建立了世界上第一个小鼠的深部内异症模型。据称，小鼠深部内异症模型尝试了20多年，均未成功。所以，我们现在对深部内异症的形成有了一个清晰的解释，也解释了为什么深部内异症和卵巢内膜样囊肿的区别。