Pathophysiology, Growth and Progression of Endometriosis

子宫内膜异位症的病理生理学、生长和进展

• 批准号: 16591671
• 负责人: KHAN Khaleque
• 金额: $ 2.18万
• 依托单位: Nagasaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16591671/
• 关键词: Endometriosis; Peritoneal fluid; Macrophages; Endotoxin; HGF; TLR4

We demonstrated regulation of the growth of endometriosis by innate immune system and ovarian steroid hormones. As a cell component of endometriosis and innate immune system, we found a significantly increased infiltration of CD68-positive macrophages (Mφ) in the eutopic endometrium, ectopic endometrium and peritoneal fluid (PF) of women with endometriosis than that of non-endometriosis (Fertil Steril 81(3):652-661,2004). Bacterial endotoxin or lipopolysaccharide (LPS) acts as an initial inflammatory mediator and interacts with toll-like recpetor 4 (TLR) on Mφ and other dendritic cells and produces different proinflammatiry cytokines. We reported that Mφ isolated from women with endometriosis produced increased concentrations of cytokines and growth factors including HGF in response to LPS. As a pleiotropic growth factor, HGF either alone or in combination with LPS was involved in the growth of endometriosis in an autocrine and paracrine fashion (Hum Reprod 20:49-60,2005).We also demon … More strated Mφ-mediated regulation of HGF by ovarian steroids in women with endometriosis. Estrogen (ER) and progesterone receptor (PR) were expressed in Mφ and endometrial cells at both protein and mRNA levels. Macrophages in response to estrogen produced higher concentrations of HGF and other cytokines and established that HGF may be involved in the growth of endometriosis either alone or together with estrogen (Hum Reprod 20(7):2004-2013,2005).We reported for the time that endotoxin concentration in the PF was significantly higher in women with endometriosis than that in non-endometriosis. TLR4 was detected in Mφ and endometrial cells. Single or combined treatment of Mφ with LPS or Hsp70 produced significantly increased levels of HGF, VEGF, IL-6 and TNFα in women with endometriosis. Pretreatment of cells with anti-TLR4 antibody significantly reduced the production of all these cytokines as well as growth of endometriosis. Our results suggested that endotoxin in PF may promote TLR4-mediated growth of endometriosis.It was very interesting to detect a significantly higher colony formation of Escherichia coli (E.coli) when we cultured menstrual blood of women with endometriosis than that in non-endmetriosis. This indicates that E.coli in menstrual blood could be a source of increased endotoxin in PF and consequently regulate TLR4-mediated growth of endometriosis. Less

我们证明了先天免疫系统和卵巢类固醇激素对子宫内膜异位症生长的调节。作为子宫内膜异位症和先天免疫系统的一种细胞成分，我们发现子宫内膜异位症患者在位内膜、异位内膜和腹腔液中CD68阳性巨噬细胞(M-φ)的表达显著高于非内异症患者(Fertil Steril 81(3)：652-661,2004)。细菌内毒素或脂多糖作为初始炎症介质，与M-φ等树突状细胞表面的Toll样受体4相互作用，产生不同的致炎细胞因子。我们报道了从子宫内膜异位症患者体内分离出的M-φ对脂多糖的反应产生了包括肝细胞生长因子在内的细胞因子和生长因子的浓度升高。作为一种多效性生长因子，肝细胞生长因子单独或联合脂多糖以自分泌和旁分泌的方式参与子宫内膜异位症的生长(Hum Reprod 20：49-60,2005)。我们也恶魔…子宫内膜异位症患者卵巢激素对肝细胞生长因子的调节更多地依赖M-φ。雌激素(ER)和孕激素受体(PR)在M-φ和子宫内膜细胞中均有表达。巨噬细胞对雌激素的反应产生更高浓度的HGF和其他细胞因子，并证实HGF可能单独或与雌激素一起参与子宫内膜异位症的生长(Hum Reprod 20(7)：2004-2013,2005)。我们首次报道了子宫内膜异位症患者PF中的内毒素浓度显著高于非内异症患者。TLR4在M-φ和子宫内膜细胞中表达。M-φ与脂多糖或热休克蛋白70单独或联合治疗可显著提高子宫内膜异位症患者血清中肝细胞生长因子、血管内皮生长因子、白介素6和肿瘤坏死因子α的水平。用抗TLR4抗体处理细胞后，上述细胞因子的产生以及子宫内膜异位症的生长均明显减少。我们的结果提示PF中的内毒素可能促进TLR4介导的子宫内膜异位症的生长。在我们培养的子宫内膜异位症患者的月经血中检测到明显高于非子宫内膜异位症患者的大肠埃希氏菌集落形成是非常有趣的。这表明月经血中的大肠杆菌可能是PF内毒素增加的一个来源，从而调节TLR4介导的子宫内膜异位症的生长。较少

项目成果

Detection of Escherichia coli in menstrual blood and endotoxin in peritoneal fluid : an implication in pelvic inflammation and toll-like rcccptor 4 (TLR41)-mediated growth of endometriosis

经血中大肠杆菌和腹膜液中内毒素的检测：盆腔炎症和 Toll 样 rcccptor 4 (TLR41) 介导的子宫内膜异位症生长的暗示

• 发表时间: 2005
• 期刊: Eur J Obstet Gynecol Reprod Biol 123
• 作者: Khan KN;Fujishita A;Kitajima M;Hiraki K;Masuzaki H;Sekine I;Matsuyama T;Ishimaru T
• 通讯作者: Ishimaru T

Regulation of hepatocyte growth factor by basal and stimulated macrophages in women with endometriosis

• DOI: 10.1093/humrep/deh525
• 发表时间: 2005-01-01
• 期刊: HUMAN REPRODUCTION
• 影响因子: 6.1
• 作者: Khan, KN;Masuzaki, H;Ishimaru, T
• 通讯作者: Ishimaru, T

Laparoscopic salpingotomy for tubal pregnancy : comparison of linear salpingotomy with and without suturing

腹腔镜输卵管妊娠输卵管切开术：缝合与不缝合线性输卵管切开术的比较

• 发表时间: 2004
• 期刊: Human Reproduction 19(5)
• 作者: Fujishita A;Masuzaki H;Khan KN;Kitajima M;Hiraki K;Ishimaru T
• 通讯作者: Ishimaru T

Estrogen and progesterone receptor expression in macrophages and regulation of hepatocyte growth factor by ovarian steroids in women with endometriosis

• DOI: 10.1093/humrep/deh897
• 发表时间: 2005-07-01
• 期刊: HUMAN REPRODUCTION
• 影响因子: 6.1
• 作者: Khan, KN;Masuzaki, H;Ishimaru, T
• 通讯作者: Ishimaru, T

Differential macrophage infiltration in early and advanced endometriosis and adjacent peritoneum

• DOI: 10.1016/j.fertnstert.2003.07.037
• 发表时间: 2004-03-01
• 期刊: FERTILITY AND STERILITY
• 影响因子: 6.7
• 作者: Khan, KN;Masuzaki, H;Ishimaru, T
• 通讯作者: Ishimaru, T