子宮內膜的腺體上皮細胞和基質細胞在子宮腔以外的任一器官或組織附著與生長稱之為子宮內膜異位症。臨床的症狀通常伴隨著慢性的長期腹痛和不孕，是一種在生育年齡婦女很常見的婦科疾病。雖然已經有很多的學說來說明子宮內膜異位症可能生成的原因，然而主要的成因和致病機轉仍未被清楚地被解釋。根據先前的研究指出，慢性的腹腔發炎是造成子宮內膜異位症的一個重要的致病因子。在病患的腹腔液中有較高濃度和發炎相關的細胞激素，其中包含介白素-1、介白素-6、介白素-8和甲型腫瘤壞死因子，這些細胞激素被認為可以促進異位的子宮內膜細胞的增生和存活等因素，進而導致子宮內膜異位症的生成，並且可以進一步的刺激巨噬細胞分泌更多的細胞激素，形成一個惡性循環。另一方面，當異位的子宮內膜組織經由輸卵管進入腹腔中時，首先會遭遇到嚴峻的缺氧環境，使得異位的組織缺乏氧氣和養分的供應。缺氧不論在病理和生理功能中皆被視為是個重要的因子來調控基因的表現；我們過去的研究指出在異位的細胞中，缺氧調控因子-1α (hypoxia inducible factor-1α, HIF-1α) 會被正向的調控。因此，我們假設異位的基質細胞中介白素-6和介白素-8的過度表現是由於缺氧所導致的，要證實這項假設，我們以缺氧處理原位的基質細胞來觀察對介白素-6和介白素-8的影響。結果顯示，無論是異位的組織或是分離後的異位基質細胞中，相較於原位的組織，介白素-6和介白素-8皆有明顯增加的情形。而將原位基質細胞處以缺氧的環境中會增加介白素-6和介白素-8的表現量。我們更進一步發現：缺氧不僅是透過增加介白素-6和介白素-8傳訊者 核醣核酸的轉錄作用，同時也會透過維持傳訊者核醣核酸的穩定性。除此之外，也利用人類臍帶靜脈內皮管柱形成實驗 (Tube formation assay) 發現，介白素-8會促進血管新生進而導致子宮內膜異位症的生成。綜合以上結果顯示：將原位基質細胞處以缺氧用來模擬子宮內膜組織逆流至腹腔中時所面臨的缺氧環境，的確會促進介白素-6和介白素-8的表現量上升，說明了缺氧是調控基質細胞中介白素-6和介白素-8上升的重要因子，在子宮內膜異位症生成中中扮演一個重要的角色，並且為研究子宮內膜異位症的病原學開啟了另一扇門。

Endometriosis is one of the most common gynecological diseases in women during reproductive age. It is characterized by the persistence and growth of vascularized endometrial tissue at ectopic sites, and is associated with pelvic pain and infertility. Although several hypotheses have been proposed, the etiology of endometriosis is still enigmatic. One of the most important pathological roles of endometriosis is chronic pelvic inflammation. Several inflammatory cytokines including interleukin-1 (IL-1), IL-6, IL-8 and tumor necrosis factor-α, are elevated in peritoneal fluid, which contributes to the formation of endometriosis through influencing the establishment and proliferation of ectopic endometrial implants and further cytokine secretion by macrophages. Endometrial stromal cells suffer from hypoxic stress after retrograding to pelvic capacity. Hypoxia is known to be a common pathophysiological feature that regulates gene expression and affects disease processes. Our previous studies demonstrated that hypoxia inducible factor-1α (HIF-1α) is upregulated in endometriotic stromal cells. Therefore, we hypothesized that overexpression of IL-6 and IL-8 in ectopic stromal cells might be induced by hypoxia. Our results demonstrated that IL-6 and IL-8 were overexpressed in ectopic endometriotic implants than that in eutopic stromal cells. Endometrial stromal cells treated with hypoxia significantly induced the expression of IL-6 and IL-8. We further demonstrated that hypoxia-regulated IL-6 and IL-8 expressions were not only mediated by transcriptional upregulation but also increased IL-6 and IL-8 mRNA stability. In addition, hypoxia-increased IL-8 expression promoted angiogenesis by tube formation assay. Taken together, treating eutopic stromal cells with hypoxia to mimic endometrial stromal cells suffering from hypoxic environment can induce IL-6 and IL-8 expressions. These data indicate the critical role of hypoxia-induced IL-6 and IL-8 expressions in the development of endometriosis that may shed lights on investigating novel molecular mechanisms of the etiology of endometriosis.

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