2008-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/647836腹膜纖維化症候群(PFS)是指長期腹膜透析病患的腹膜所發生之合併症。過去 我們所探討的主要是注重在較嚴重的PFS 病理表現與可能治療方式。腹腔內出血 (hemoperitoneum)在PD 病患並不少見(約8.4%)，雖然未必有特殊不適，但是反覆發 生之後，對腹膜組織的長期影響，值得研究。此外，從基礎研究的有限探討指出: 腹 腔內出血的影響與PFS 的發生機轉有許多相近點，都會加重腹腔內炎症反應，刺激 各種生長因子表現、甚至誘發腹膜沾黏。但是相關細胞或動物模式以及詳細機轉、 甚至可能的輔助治療方向等，目前都尚未有人研究報告過。我們想驗證的假說是: 腹 腔內出血反應所誘發之腹膜變化，會有早發性的細胞自噬和細胞凋亡現象發生；利 用新建立的動物模式與影像檢查系統，我們擬找到生物標記用以研究藥物預防的生 體效果。 本計畫的第一年的研究主題是: 先建立腹腔內出血之動物模式，再配合 PET/CT 與核子醫學等影像技術，然後對照病理組織變化與影像偵測結果、血清及腹 腔液中之細胞激素，找出臨床上及後續(第二年細胞實驗)可用之生物標記。第二年假 說與研究主題是: 出血後所餘留在腹腔內之游離鐵可能會經由氧化壓力傷害，構成腹 膜組織早期變化，或加速PFS 生成。因此，擬延續前一年動物模式，加做氧化壓力 之病理研究； 同時開始細胞實驗，探討游離鐵對細胞自噬現象和細胞凋亡、PFS 或 腹膜纖維化的有關機轉。第三年假說與研究主題是: 既然出血與游離鐵會與細胞自噬 現象、細胞凋亡、及腹膜纖維化有關，使用抗氧化劑(N-acetylcysteine)或使用噬鐵結 合劑(deferroxamine)，在細胞模式與動物實驗同步觀察可能效果，並結合第一年動物 模式所探討之影像或生物標記， 了解指標適用性。臨床試驗部分(共包括前後三年): 擬收集長期PD 病患的腹腔引流液，檢留細胞樣本、組織液、血清做定期分析，比較 腹膜功能與老化標記。同時配合原來臨床常規每半年定期功能測試(PET)，事後分析 預後與各種標記。本計劃的結果可以提供PFS 發病早期的細胞與組織變化，及做為 臨床上藥物治療的重要藥理基礎。Peritoneal fibrosing syndrome (PFS) is a non-rare, but serious complication of peritoneal dialysis (PD). In the past, we had published several research articles of basic and animal studies on PFS. Without exception, these investigations focus mainly on long-term and advanced stage of PFS. As far as we know, researches on early pre-PFS stage is extremely limited. Hemoperitoneum is common in PD patients, with a reported incidence of around 8.4%. Most of the hemoperitoneum occurred in women, during menstruation cycle or asymptomatic. What will happen to human peritoneum and how about the relationship between these repeated episodes of hemoperitoneum and PFS remained undetermined. Our hypothesis is hemoperitoneum may predispose to the development of PFS, through accelerated apoptosis or autophagy of peritoneal mesothelial cells. Meanwhile, this deteriorated cell survival may be accompanied with stimulated local inflammation, cytokines production, and increased matrix production. This project includes cell culture study, animal (rat) model testing and human specimen analysis during a whole period of three years. In the first year, we will try to establish an appropriate rat model of hemoperitoneum. After detected by using PET/CT image program, these experimental rats were sacrificed for pathological study. Cytokines study from body fluid (peritoneal lavage, serum), histopathological specimen of rats and results of image analysis will be re-assembled for data-mining of biomarkers. In the 2nd year, we will test oxidative stress induced by blood, iron and iron-derived molecules on peritoneal mesothelial cells, with the main focus on cellular apoptosis and autophagy. Signal transduction pathways of these cellular changes also will be explored. In the 3rd year, we will test whether antioxidant (N-acetylcysteine), or iron-chelating agent (deferroxamine) can suppress cellular change or the accompanied matrix production. During this 3-year period, we scheduled to enroll over thirty patients on long-term PD to study human biomarkers in drained PD fluid, and correlate them with individual PET test characteristics. Through this 3-year, from in-vitro and in-vivo experiments to clinical survey, we will make it clear whether hemoperitoneum really benign. Or in contrast, we may prove this subclinical hemoperitoneum event may do harm to human peritoneum and contribute to some magnitude to the development of PPFS. If the latter is true, we also may have tested potential protective roles of antioxidant or iron-chelating agent used during hemoperitoneum. Our work is novel and has high clinical relevance in patient care of PD therapy.