Apoptosis in proliferative vitreoretinal disorders: Possible involvement of TGF-beta-induced RPE cell apoptosis
Apoptosis in proliferative vitreoretinal disorders: Possible involvement of TGF-beta-induced RPE cell apoptosis
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DOI：
10.1006/exer.1997.0341
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发表时间：
1997-09-01
影响因子：
3.4
通讯作者：
Weller, M
中科院分区：
文献类型：
--
作者：
Esser, P;Heimann, K;Weller, M
靶向诱导细胞凋亡是控制增殖细胞无限生长的一种新的治疗方法。由于玻璃体视网膜界面细胞的大量增殖是增殖性玻璃体视网膜疾病的一个关键特征，我们试图鉴定增殖性玻璃体视网膜病变（PVR）、增殖性糖尿病视网膜病变（PDR）和黄斑皱褶患者视网膜前膜中的细胞凋亡。此外，我们评估了转化生长因子-β（TGF-β）诱导视网膜色素上皮（RPE）细胞凋亡的可能性，通过原位DNA末端标记和吖啶橙子染色鉴定所有玻璃体视网膜疾病患者视网膜前膜石蜡包埋组织切片上的凋亡细胞。标记的细胞核或浓缩的染色质分散在整个细胞膜上或成簇出现。大多数凋亡细胞RPE衍生的，通过细胞角蛋白免疫化学评估。未检测到凋亡的胶质细胞。在PVR中，增殖活性（经Ki-67免疫化学证实）与病史短和疾病进展快相关。在长期PVR或进展缓慢的牵拉性视网膜脱离中观察到更频繁的细胞核凋亡。通过生物测定，在所有对照玻璃体样本中检测到TGF-β，浓度低于20 ng ml（-1）。病理性玻璃体中TGF-β水平增加高达20倍。在所有患者组中均观察到显著异质性。PVR中TGF-β的活化程度明显高于PDR。通过电镜、原位DNA末端标记、彗星试验和组蛋白相关DNA片段的光度酶免疫分析，在培养的人RPE细胞中证实了TGF-β的促凋亡作用，凋亡似乎是增殖性玻璃体视网膜疾病中特定细胞群生长控制的关键调节机制。给予促凋亡生长因子如TGF-β可能提供一种新的方法来抑制玻璃体视网膜界面的细胞增殖。(C)出版社：Academic Press Limited。
The targeted induction of apoptosis is a novel therapeutic approach to control the unlimited growth of proliferating cells. Since massive proliferation of cells at the vitreoretinal interface is a key feature of proliferative vitreoretinal disorders, we sought to identify apoptosis in epiretinal membranes from patients with proliferative vitreoretinopathy (PVR), proliferative diabetic retinopathy (PDR) and macular pucker. Further, we evaluated the possible induction of apoptosis of retinal pigment epithelial (RPE) cells by transforming growth factor-beta (TGF-beta).Apoptotic cells were identified by in situ DNA end labeling and acridine orange staining on paraffin-embedded tissue sections from epiretinal membranes of patients with all vitreoretinal disorders examined. Labeled nuclei or condensed chromatin were scattered throughout the membranes or occurred in clusters. Most apoptotic cells were RPE-derived, as assessed by cytokeratin immunochemistry. No apoptotic glial cells were detected. In PVR, proliferative activity, as confirmed by Ki-67 immunochemistry, was associated with short history and rapid disease progression. Apoptotic nuclei were observed more frequently in long-standing PVR or slow progression towards traction retinal detachment. TGF-beta was detected in all control vitreous samples by bioassay at concentrations below 20 ng ml(-1). TGF-beta levels increased up to 20-fold in pathological vitreous. Marked heterogeneity was observed in all patient groups. The degree of TGF-beta activation was significantly higher in PVR than in PDR. Proapoptotic effects of TGF-beta were demonstrated in cultured human RPE cells by electron microscopy, in situ DNA end labeling, comet assay and a photometric enzyme immunoassay for histone-associated DNA fragments.Apoptosis appears to be a key regulatory mechanism of growth control of specific cell populations in proliferative vitreoretinal disorders. Administration of proapoptotic growth factors such as TGF-beta may provide a novel approach to inhibit cellular proliferation at the vitreoretinal interface. (C) 1997 Academic Press Limited.