裂孔性視網膜剝離是目前造成失明的重要原因之一，一旦發生裂孔性視網膜剝離通常需要手術治療。然而，增殖性玻璃體視網膜病變常是造成手術失敗的主要原因。增殖性玻璃體視網膜病變發生時，視力癒後及手術成功率往往會明顯下降。但目前卻無一有效的治療或預防方法。雖然增殖性玻璃體視網膜病變的成因尚不清楚，一般認為視網膜色素上皮細胞在增殖性玻璃體視網膜病變發生時扮演了重要的角色。視網膜色素上皮細胞在發生視網膜剝離時，會爬行到玻璃體的位置，在玻璃體內存活、增生，並分泌出許多細胞外的基質蛋白，這些基質蛋白會讓增生的細胞可以貼附到視網膜上和視網膜形成連結，進而收縮造成視網膜再次剝離導致手術治療的失敗。Doxycycline是Tetracycline家族中一個強效的抗生素，目前亦普遍的在臨床上被使用。除了抗生素的效果外，在先前的研究當中也發現，doxycycline會抑制數種癌細胞的爬行、貼附、增生以及收縮。目前沒有doxycycline運用在治療PVR的相關研究，因此本研究計畫將探討doxycycline對於增殖性玻璃體視網膜病變的預防及治療效果。在研究中我們發現，doxycycline可以有效抑制人類視網膜色素上皮細胞株（ARPE-19）的增生、爬行及收縮。此外，我們發現doxycycline可以抑制ARPE-19細胞中NF-κB 及matrix metalloproteinases的活性，這可能是doxycycline抑制ARPE-19細胞增生、爬行及收縮的機制。在動物實驗中，我們成功的利用dispase及ARPE-19 cells建立了兩個PVR的小鼠動物模型。在口服doxycycline及腹腔施打doxycycline的治療途徑中，doxycycline並無法有效的降低PVR的疾病嚴重度。然而利用玻璃體內注射doxycycline的方式，則可以有效地降低了PVR疾病的嚴重度，且此結果可以在兩個不同的PVR動物模型中被重現。在人體試驗的部分，初步結果尚無法展現在doxycycline組和控制組的差異，主要係因目前收案人數有限，截至目前為止尚無不良藥物反應的發生，後續我們持續收案，以達到目標收案人數。未來，我們將進一步探討藥物作用的機轉，期能對PVR的發生機制有更深入的認識及了解。

Rhagmatogenous retinal detachment is a major cause of blindness nowadays, and surgical intervention is usually indicated. However, proliferative vitreoretinopathy (PVR) is the most common reason for the failure of this operation. Visual outcomes and the success of surgery are worse for retinal detachment that is complicated by PVR when compared to those of retinal detachment cases without PVR. Effective therapies are not available for PVR treatment and prevention. Although the pathophysiology of PVR is not clear, it is believed that retinal pigment epithelial cells play an important role. During the progression of retinal detachment, retinal pigment epithelial cells can migrate to the vitreous to survive, proliferate, form extracellular matrix proteins, and assemble into a membrane. Then the membrane can attach to the retina and subsequently contract, which can cause a new retinal detachment or failure of a surgically corrected detachment. Doxycycline is one of the potent and well-tolerated antibiotics in the tetracycline family that has been frequently used clinically. In previous studies, doxycycline is reported to inhibit the migration, adhesion, proliferation, and contraction of several cancer cell lines. It has not been tested as a treatment for PVR, so this project was designated to assess the effect of doxycycline in PVR treatment and prevention. In this study, doxycycline arrested the proliferation, migration, and contraction of human retinal pigment epithelial (ARPE-19) cell line with reduction in the total activity of matrix metalloproteinases and NF-κB activation. In vivo, we successfully set up two mouse PVR models by using dispase and ARPE-19 cells. Although oral doxycycline treatment and intraperitoneal injection of doxycycline failed to reduce PVR severity, we found that intravitreal injection of doxycycline effectively reduced the severity of PVR in two mouse models. In our clinical trial, there was no obvious difference between doxycycline and control groups due to limited case numbers. There were no severe adverse events noted till now, so the trial will keep going to include more participants. In future, we will try to uncover the action mechanism of doxycycline and lead to a better understanding of pathogenesis in PVR for the future development of effective PVR therapies.

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