大鼠子宫内膜异位模型的建立与组织学观察

目的为开发诊治子宫内膜异位症(endometriosis,EMT)的新药研究提供理想的动物模型。方法取雌性未交配性成熟大鼠,术前雌激素诱导,麻醉开腹取部份右侧子宫,将内膜种植于左腹壁内,术后16周取出包块,进行组织形态学、组织化学观察。结果异位内膜在腹壁内生长,呈隆起囊状小包块,内有黏液,具有正常子宫内膜基本组织结构,囊腔较大。异位内膜中有糖原、RNA的存在。结论该手术方法建立的子宫异位内膜生长良好,术后一周就可摸及包块大小,为开发研究子宫内膜异位症的新药提供了方便。     

巨噬细胞迁移抑制因子拮抗剂对子宫内膜异位症的影响

目的：探讨巨噬细胞迁移抑制因子拮抗剂（ISO-1）对子宫内膜异位症的影响。方法：以裸鼠为研究对象,构建子宫内膜异位元症动物模型,应用巨噬细胞迁移抑制因子拮抗剂进行干预,观察子宫内膜异位症小鼠的成活率和体重变化;采用RT-PCR检测基质金属蛋白酶-2（MMP-2）,基质金属蛋白酶抑制剂-2（TIMP-2）,血管内皮细胞生长因子（VEGF）,TNF-αmRNA的表达,ELISA检测TNF-α蛋白的表达。结果：ISO-1对子宫内膜异位症小鼠的存活率无明显影响,但可增加其体重（P〈0.05）。ISO-1减少子宫内膜异位症小鼠受损组织中MMP-2、VEGF、TNF-α的表达（P〈0.05）,但对TIMP-2的表达无明显影响。结论：巨噬细胞迁移抑制因子被特异性阻断后,可明显抑制受损组织的重构、血管生成和炎症,最终影响子宫内膜异位症的组织生长及进一步恶化,这可能是临床治疗子宫内膜异位症的新策略。     

子宫内膜异位症动物模型研究进展

为研究子宫内膜异位症的病因、发病机制、治疗和预防对策,需要构建实验动物模型。本文通过分析各种模型的优点和缺点,为选择性应用动物模型提供指导,从而更利于对该病的研究。     

子宫内膜异位症大鼠模型的建立及其病理学改变

目的构建子宫内膜异位症（内异症）大鼠动物模型,为阐明内异位症发病机理以及寻找有效的治疗方法提供理想的动物模型。方法取性成熟雌性Sprague-Dawley（SD）大鼠30只,通过手术将大鼠自体子宫组织移植到子宫旁韧带上,建立诱发型内异症大鼠动物模型。术后8周,再次剖腹观察异位组织的存活情况、病灶大小、与周围组织的粘连程度以及病理学变化。结果25只大鼠有明显的异位病灶。所有病灶都与周围组织有不同程度的粘连,病灶外观呈囊泡状。光镜观察见大部分异位子宫内膜形态和结构与在位子宫内膜基本相同,但内膜细胞、间质细胞、腺体,与在位内膜相比较少。少数病灶只有上皮组织或只有问质组织。结论自体子宫移植法可成功建立内异症大鼠模型。     

改良大鼠子宫内膜异位症模型的建立及微血管密度观察

目的对皮下筋膜层与腹壁肌层之间移植自体子宫内膜制作的子宫内膜异位症（endometriosis,EMs）模型进行评估。方法取10只雌性未交配性成熟大鼠,术前雌激素诱导,手术开腹取右侧子宫,将自体子宫内膜种植于双侧皮下筋膜层与腹壁肌层之间,术后第29天取出异位组织,进行组织形态学观察,免疫组织化学染色观察微血管密度（Microvessel density,MVD）。结果异位内膜在腹壁内生长,呈隆起囊状小包块,内有黏液,具有正常子宫内膜基本组织结构。异位内膜中微血管密度较在位内膜和正常子宫内膜高。结论此手术方法建立的大鼠子宫内膜异位症模型异位内膜病理改变与EMs患者类似,可以作为子宫内膜异位研究的动物模型。     

雌激素受体β基因敲除小鼠子宫内膜异位症模型的建立

目的建立雌激素受体β基因敲除小鼠子宫内膜异位症模型,为进一步研究雌激素受体β基因在子宫内膜异位症发生发展过程中的作用提供平台。方法用外科手术方法对16只β基因敲除小鼠进行自体子宫移植,术后14d、21d取病灶组织进行光镜观察分析。结果建模成功率达95．8％,可形成明显囊肿,内含囊液,囊肿内壁有子宫内膜上皮细胞生长。结论应用本方法可建立稳定的子宫内膜异位症转基因小鼠模型,便于研究雌激素受体β亚型及其相关基因、蛋白在子宫内膜异位症发生发展过程中的作用机制。     

非编码RNA在子宫内膜异位症中的调控机制及应用的研究进展

子宫内膜异位症是一种良性妇科疾病,影响10%～15%的育龄妇女,其特征是在子宫体以外的部位发现有活性的子宫内膜腺体或间质。然而,由于其发病机制尚未明确,缺乏特异性症状和非侵入性检测方法,常需要外科干预用于诊断和治疗。因此,迫切需要更准确的非侵入性诊断工具和更有效的治疗方式。近年来研究表明,非编码RNA在子宫内膜异位症的发生发展中发挥着极其重要的作用,非编码RNA的异常表达很可能为子宫内膜异位症的早期诊断和病情评估提供理论依据,并为子宫内膜异位症的治疗提供潜在的靶点。现就近年来非编码RNA在子宫内膜异位症中的调控机制及应用的研究进展作一综述。     

子宫内膜异位症患者细胞因子的表达与抗体反应

目的:探究细胞因子的表达与抗体反应在子宫内膜异位症(EMS)发生中的作用及其作为诊断指标的可能性。方法:选取子宫内膜异位症患者70例与对照组50例,检测并比较两组患者血清肿瘤坏死因子-α(TNF-α)、白细胞介素(IL-6)、单核细胞趋化因子-1(MCP-1)、血管内皮生长因子(VEGF)的表达以及抗子宫内膜抗体(EM-Ab)和转铁蛋白抗体(TRF-Ab)的阳性率。分析以上细胞因子及抗体的表达与子宫内膜异位症临床分期的关系。结果:子宫内膜异位症组TNF-α、IL-6、MCP-1与VEGF均显著高于对照组,差异具有统计学意义(P0.05);子宫内膜异位症组抗子宫内膜抗体阳性率、转铁蛋白抗体阳性率以及两种抗体均为阳性的比例均显著高于对照组,差异具有统计学意义(P0.05);TNF-α、IL-6、MCP-1与VEGF细胞因子与子宫内膜异位症分期呈正相关,分期越高、EMS病情越重则细胞因子表达水平越高(P0.05)。结论:细胞因子的表达与相关抗体反应均参与了子宫内膜异位症的发生及发展,通过检测到相关细胞因子水平的升高与自身抗体转阳可以筛选与诊断子宫内膜异位症,初步判断其临床分期和病情程度。     

子宫内膜异位症患者凋亡相关基因TGF-β mRNA表达的研究

目的:探计TGF-β在子宫内膜异位症发病及发展中的分子生物学机制及与凋亡的相关性.方法:选取子宫内膜异位症患者12例为研究对象(EMS组),正常妇女正常子宫内膜12例(对照组),应用半定量逆转录-聚合酶链反应(RT-PCR)方法,测定TGF-β mRNA表达水平;运用western-blotting印迹法检测检测TGF-β蛋白的表达.同时用TUNEL染色对标本进行凋亡检测.结果:异位子宫内膜的凋亡率明显低于正常子宫内膜,且EMS组患者异位内膜的TGF-β mKNA和蛋白的表达水平上调.结论:患者子宫内膜中凋亡率的改变,在子宫内膜异位症的发生发展中起重要作用.异位的子宫内膜可能是由于TGF-β的表达上调增加了抗凋亡能力.     

子宫内膜异位症对小鼠生育能力的影响

目的建立子宫内膜异位症小鼠模型,观察子宫内膜异位症对模型小鼠妊娠能力的影响。方法通过"腹腔+皮下"同系异体子宫内膜注射法建立子宫内膜异位症小鼠模型,与假手术组、空白组比较,观察其妊娠率及活胎率,观察子宫内膜异位症对模型小鼠妊娠能力的影响。结果建模2周后,小鼠皮下和腹腔均见有子宫内膜异位病灶生成,模型组、假手术组和空白组,共三组。通过生育功能检测,三组妊娠率差异有显著性意义(P0.05)。三组的活胎数差异有显著性意义(P0.05)。结论成功建立子宫内膜异位症小鼠模型,并证实子宫内膜异位症可影响模型小鼠生育功能。     

ERβ对子宫内膜异位症小鼠模型的影响

目的通过建立子宫内膜异位症小鼠模型探讨雌激素β受体对子宫内膜异位症的影响。方法利用雌激素β基因敲除小鼠建立自体子宫内膜异位模型;应用人不同的组织在SCID小鼠建立子宫内膜异位症模型后,注射雌激素β受体激动剂WAY-200070,观察其对异位病灶生长的影响。结果比较30只雌激素β受体基因敲除小鼠及22只同源未敲除小鼠异位病灶生长及组织细胞形态无明显差异（P〉0.05）;雌激素β受体激动剂WAY-200070对不同类型的SCID小鼠内异症病灶生长影响无明显差异（P〉0.1）。结论雌激素β受体对子宫内膜异位病灶的形成影响作用微弱。     

Mouse model of surgically-induced endometriosis by auto-transplantation of uterine tissue

Endometriosis is a chronic, painful disease whose etiology remains unknown. Furthermore, treatment of endometriosis can require laparoscopic removal of lesions, and/or chronic pharmaceutical management of pain and infertility symptoms. The cost associated with endometriosis has been estimated at 22 billion dollars per year in the United States. To further our understanding of mechanisms underlying this enigmatic disease, animal models have been employed. Primates spontaneously develop endometriosis and therefore primate models most closely resemble the disease in women. Rodent models, however, are more cost effective and readily available. The model that we describe here involves an autologous transfer of uterine tissue to the intestinal mesentery (Figure 1) and was first developed in the rat and later transferred to the mouse. The goal of the autologous rodent model of surgically-induced endometriosis is to mimic the disease in women. We and others have previously shown that the altered gene expression pattern observed in endometriotic lesions from mice or rats mirrors that observed in women with the disease. One advantage of performing the surgery in the mouse is that the abundance of transgenic mouse strains available can aid researchers in determining the role of specific components important in the establishment and growth of endometriosis. An alternative model in which excised human endometrial fragments are introduced to the peritoneum of immunocompromised mice is also widely used but is limited by the lack of a normal immune system which is thought to be important in endometriosis. Importantly, the mouse model of surgically induced endometriosis is a versatile model that has been used to study how the immune system, hormones and environmental factors affect endometriosis as well as the effects of endometriosis on fertility and pain.     

Record review of baboons with histologically confirmed endometriosis in a large established colony

Spontaneous endometriosis was diagnosed in 43 baboons over a 14-year period. Thirty-seven have died; five remain alive; one was sold and lost to follow-up. The average age at diagnosis was 17.2 years; 29 (67%) were between 12 and 21 years of age. Fifteen (35%) were diagnosed by biopsy and received surgical excision of the endometriotic tissue; four of these were identified during caesarian section, confirming one prior report of endometriosis in pregnant animals. Twenty-eight (65%) were diagnosed at or shortly preceding necropsy. When diagnosed by a palpable abdominal mass, there was a significantly greater likelihood the animal died or was killed as a result of complications of endometriosis. When diagnosis was at necropsy, there was a significantly greater likelihood that the animal died from causes unrelated to endometriosis. Early identification with surgical removal appears to provide a benefit for both survival and delivering offspring after diagnosis. In twenty-one baboons (49%), endometriosis affected multiple sites within the peritoneal cavity. In the remaining baboons, lesions were more localized. Ovarian involvement was seen in sixteen (37%) of these baboons. This paper is the first to describe significant ovarian involvement in baboons, previously considered a limitation of the usefulness of this species as an animal model. We also describe the first reported endometriosis seeding of an abdominal surgery scar in a baboon. Many of these baboons were middle aged, had few or no offspring, or had evidence of a long duration of uninterrupted menstrual cycles, consistent with risk factors for women. Endometriosis was an incidental finding in 17 (40%) of these baboons, consistent with previous reports of minimal endometriosis as a common asymptomatic finding in baboons and in women. Overall, endometriosis in baboons presents a spontaneously occurring animal model that shares important features with the disease in women and the rhesus macaque.     

Pharmacologic properties of CDB(VA)-2914

CDB(VA)-2914 (17alpha-acetoxy-11beta-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione) is a synthetic steroid that demonstrates potent progesterone antagonist activity in vitro and in vivo. Its binding and antagonist potency with respect to the glucocorticoid receptor is significantly reduced compared to that of mifepristone, indicating that CDB(VA)-2914 belongs to a new class of dissociated progesterone receptor modulators that have reduced antiglucorticoid activity. The pharmacological effects of CDB(VA)-2914 have been examined in a variety of animal models, the results of which are reviewed in this paper. CDB(VA)-2914 inhibits ovulation in rats in a dose-dependent manner upon single-dose oral administration and exhibits antifertility activity during continuous low-dose administration. CDB(VA)-2914 is also effective in animal models of postcoital contraception. This paper also presents the results of metabolism studies undertaken to link the results of the animal models to potential human applications. Because of its unique pharmacological profile, CDB(VA)-2914 is a promising candidate for use in contraception as well as treatment of uterine fibroids and endometriosis.     

血清蛋白质指纹图谱模型在子宫内膜异位症诊断中的应用

用表面加强激光解析电离飞行时间质谱(SELDI-TOF-MS)和蛋白质芯片检测子宫内膜异位症(endometriosis,EM)患者血清蛋白质指纹图谱,探讨诊断模型在EM诊断中的临床应用价值。用SELDI-TOF-MS技术和H4蛋白质芯片检测16例EM和16例正常女性的血清蛋白质指纹图谱,并建立诊断模型。然后,对16名健康人和16例EM患者样本进行盲法测试验证该模型。筛选出4个有明显表达差异的蛋白质,其质荷比(m/z)分别为8141、6096、5894、3269。建立的诊断模型对EM检测的灵敏度为87.5%(14/16),特异性为93.75%(15/16),总准确率为90.625%(29/32)。SELDI-TOF-MS对小样本的EM诊断具有较高的敏感性和特异性,在EM的诊断及标志物筛选等方面具有较好的诊断价值。     

Association between interleukin-10 promoter polymorphisms and endometriosis: A meta-analysis

To investigate the influence of the interleukin-10 gene promoter polymorphisms on the susceptibility of endometriosis, we examined the association by performing a meta-analysis. The PubMed, Embase, HuGE Navigator and CNKI were searched to identify eligible studies. We then conducted a meta-analysis to examine the association between interleukin-10 gene promoter polymorphisms and endometriosis. Eight case–control studies which examined the association between the IL-10 gene promoter polymorphisms and the susceptibility to endometriosis were finally included in the meta-analysis. Meta-analysis of the IL-10 − 592 A/C polymorphisms showed a significant increased risk of endometriosis in the overall and Asian population in all genetic models and allele contrast. However, meta-analysis of the IL-10 − 1082 A/G and IL-10 − 819 T/C polymorphisms showed no association with endometriosis in all genetic models and allele contrast in the overall and Asian population samples. In addition, there was not a significant association between the IL-10 − 592 A/C gene promoter polymorphisms with the severity of endometriosis.     

Synthesis and biological evaluation of water-soluble progesterone-conjugated probes for magnetic resonance imaging of hormone related cancers

Progesterone receptor (PR) is strongly associated with disease prognosis and therapeutic efficacy in hormone-related diseases such as endometriosis and breast, ovarian, and uterine cancers. Receptor status is currently determined by immunohistochemistry assays. However, noninvasive PR imaging agents could improve disease detection and help elucidate pathological molecular pathways, leading to new therapies and animal disease models. A series of water-soluble PR-targeted magnetic resonance imaging (MRI) probes were synthesized using Cu(I)-catalyzed click chemistry and evaluated in vitro and in vivo. These agents demonstrated activation of PR in vitro and preferential accumulation in PR(+) compared to PR(-) human breast cancer cells with low toxicity. In xenograft tumor models, the agents demonstrated enhanced signal intensity in PR(+) tumors compared to PR(-) tumors. The results suggest that these agents may be promising MRI probes for PR(+) diseases.