子宮內膜異位症是生殖年齡婦女常見的疾病之一，其特徵是子宮內膜組織生長於子宮腔以外的地方。子宮內膜異位症形成最被接受的理論為植入論，即逆流經血所含子宮內膜組織附著於腹腔，植入後生長。血管新生是組織移植至異位處，能夠存活及生長的重要因素。子宮內膜異位症已被認為是一種雌激素依賴性的病症。由於子宮內膜異位症患者的腹腔內高量的白血球及細胞激素，子宮內膜異位症也被認為是’’發炎’的病症。然而雌激素和免疫細胞如何影響子宮內膜異位組織的血管新生及生長至今仍是不清楚。因此我們利用手術誘導異位子宮形成之小鼠模式，探討雌激素與免疫細胞在異位子宮血管新生及生長的角色。首先將小鼠部分子宮組織移植於腹腔壁，並切除其卵巢，然後自皮下埋入含雌激素或芝蔴油之膠囊。在子宮移植後1至7天，我將小鼠犧牲後取其異位及正位子宮，利用BrdU incorporation來觀察異位子宮組織的生長及血管新生的情形。實驗結果顯示，在雌激素的刺激下，正位子宮有增生現象，但是在異位子宮，子宮移植後1至2天，細胞出現死亡及生長停止，並且部份血管有瓦解的現象。在4至5天時，異位子宮血管內皮細胞出現BrdU-positive cells，即使沒有雌激素刺激下，也有明顯血管新生。在子宮移植後5至7天，雌激素刺激之異位子宮細胞之增生現象明顯高於未處理者；這些結果顯示在異位子宮建立之初期，異位子宮組織內出現新生之血管。

　　此外，我們也分析子宮移植後異位子宮組織內免疫細胞的種類及小鼠腹腔內發炎的情形。我發現不論有或沒有雌激素補充的小鼠，其異位子宮組織在移植2至4天後出現大量嗜中性球細胞與巨噬細胞，而且腹腔嗜中性球細胞的數量及細胞驅化素(MIP-1α, MIP-2)的含量也上升；腹腔內之巨噬細胞數量在子宮組織移植前後雖未改變，但組織移植後之腹腔巨噬細胞分泌細胞驅化素能力增加。自腹腔分離之嗜中性球細胞與巨噬細胞在培養時可分泌較高量VEGF，其分泌可受到IL-6，TNF-α及LPS的調控。此外，嗜中性球細胞與巨噬細胞也分泌IL-6、TNF-α、MIP-1α及MIP-2。綜合而言，子宮組織異位初期所出現之嗜中性球細胞與巨噬細胞可能促進血管新生，進而協助子宮組織在異位處生長。

　　我們進一步分析雌激素對於已存在異位子宮組織之影響。子宮自體移植於腹腔，三週後小鼠異位子宮組織已形成，然後再自小鼠皮下埋入含雌激素或芝蔴油之膠囊。之後，在不同的時段將小鼠犧牲後取異位及正位子宮組織，觀察其血管新生及內膜細胞增生的情形，組織內免疫細胞的變化。實驗結果發現，雌激素可刺激異位子宮及正位子宮組織內膜細胞的增生、血管新生及增加嗜中性球細胞及巨噬細胞的數量，而且子宮組織以及嗜中性球細胞和巨噬細胞可表現VEGF。

　　綜合言之，利用手術誘導異位子宮形成之小鼠模式，我們得知雌激素可刺激異位子宮組織之生長、血管新生及免疫細胞浸潤入組織內，而嗜中性球細胞及巨噬細胞可能是促使異位子宮組織建立初期血管新生的重要因子。

　　Endometriosis is characterized by the growth of endometrial tissues outside the uterine cavity. The implantation hypothesis is widely accepted as the etiology of endometriosis. To survive at ectopic site, the development of new blood supply is important. There are substantial evidences showing that the progression of endometriosis is estrogen-dependent and that abnormal inflammatory responses are associated with endometriosis. However, how estrogen and immune factors can contribute to endometriotic angiogenesis and growth is not clear. In this study, mouse model of surgically induced endometriosis was used to investigate the effect of estrogen on immune factors and angiogenesis during the development of endometriosis.

　　Uterine tissues were autotransplanted into peritoneum of ovariectomized mice supplemented with 17beta-estradiol or oil. At different days, cell proliferation and angiogenesis in ectopic and eutopic uterine tissues were examined. Our results showed that estrogen stimulated cell proliferation in eutopic tissues. However, no BrdU-positive cells were detected in ectopic tissues at 1 to 2 days after transplantation. Meanwhile, some disintegrated blood vessels were observed in ectopic tissues. Despite of the presence or absence of estrogen, BrdU-positive cells were detected in vascular endothelial cells of ectopic tissues at day 4 to day 5, indicating that angiogenesis occurred at these periods and that is not estrogen-associated event. Subsequently at day 5 to 7, cell proliferation in ectopic tissues of estrogen-treated mice was higher than control, suggesting that estrogen plays an important role in ectopic tissue growth after angiogenesis.

　　The types of infiltrated immune cells in ectopic tissues and in peritoneal cavity were also investigated. Profound infiltration of macrophage and neutrophil in ectopic tissues occurred in vehicle- or estrogen-treated mice at day 2 and day 4. The number of neutrophil and chemokine levels of MIP-1alpha and MIP-2 in peritoneal fluid also reached peak during this period. Although the number of macrophages in peritoneal cavity did not change, the basal secretions of chemokines from peritoneal macrophages after tissue transplantation were much higher than those from day 0. Peritoneal neutrophil and macrophage in culture secreted VEGF, which could be stimulated by TNF-α, IL-6 or LPS. Furthermore, peritoneal neutrophils and macrophages also secreted TNF-α, IL-6, MIP-1α and MIP-2. These results suggest that there may be a positive loop in recruiting leukocytes and promoting cytokine secretion in peritoneal cavity. Taken together, neutrophils and macrophages may promote neovascularization thereby helping the subsequent growth of ectopic endometrial implants at early stage of endometriosis.

　　The effect of estrogen on angiogenesis and immune response of pre-existed endometriotic tissue was also studied. Mice were ovariectomized and transplanted with uterine tissue. Three weeks later after the formation of endometriotic tissues, mice were divided into vehilce-treated and estrogen-treated groups. At different days mice were sacrificed and their eutopic and ectopic tissues were collected and analyzed. Without estrogen treatment, there were no obvious changes in cell proliferation, angiogenesis, and leukocytes infiltration. With estrogen treatment, the proliferation of endometrial cell and endothelial cell, the infiltration of neutrophils and macrophages, VEGF expression, and vascular permeability in eutopic and ectopic tissues were increased.

　　In conclusion, neutrophil and macrophage may promote endometriotic angiogenesis at early stage of endometriosis, and estrogen may further stimulate the growth and immune response of endometriotic tissues after establishing the blood supply.

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