Kita Takeshi, Hata Yasuaki, Arita Ryoichi, Kawahara Shuhei, Miura Muneki, Nakao Shintaro, Mochizuki Yasutaka, Enaida Hiroshi, Goto Yoshinobu, Shimokawa Hiroaki, Hafezi-Moghadam Ali, Ishibashi Tatsuro
Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan.
Proc Natl Acad Sci U S A. 2008 Nov 11;105(45):17504-9. doi: 10.1073/pnas.0804054105. Epub 2008 Oct 24.
Cicatricial contraction of preretinal fibrous membrane is a cause of severe vision loss in proliferative vitreoretinal diseases such as proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR). TGF-beta is overexpressed in the vitreous of patients with proliferative vitreoretinal diseases and is also detectable in the contractile membranes. Therefore, TGF-beta is presumed to contribute to the cicatricial contraction of the membranes, however, the underlying mechanisms and TGF-beta's importance among various other factors remain to be elucidated. Vitreous samples from PDR or PVR patients caused significantly larger contraction of hyalocyte-containing collagen gels, compared with nonproliferative controls. The contractile effect was strongly correlated with the vitreal concentration of activated TGF-beta2 (r = 0.82, P < 0.0001). PDR or PVR vitreous promoted expression of alpha-smooth muscle actin (alpha-SMA) and phosphorylation of myosin light chain (MLC), a downstream mediator of Rho-kinase (ROCK), both of which were dramatically but incompletely suppressed by TGF-beta blockade. In contrast, fasudil, a potent and selective ROCK inhibitor, almost completely blocked the vitreous-induced MLC phosphorylation and collagen gel contraction. Fasudil disrupted alpha-SMA organization, but it did not affect its vitreal expression. In vivo, fasudil significantly inhibited the progression of experimental PVR in rabbit eyes without affecting the viability of retinal cells by electroretinographic and histological analyses. These results elucidate the critical role of TGF-beta in mediating cicatricial contraction in proliferative vitreoretinal diseases. ROCK, a key downstream mediator of TGF-beta and other factors might become a unique therapeutic target in the treatment of proliferative vitreoretinal diseases.
视网膜前纤维膜的瘢痕收缩是增殖性玻璃体视网膜疾病（如增殖性糖尿病视网膜病变（PDR）和增殖性玻璃体视网膜病变（PVR））导致严重视力丧失的原因之一。转化生长因子-β（TGF-β）在增殖性玻璃体视网膜疾病患者的玻璃体中过度表达，在收缩膜中也可检测到。因此，推测TGF-β促成了膜的瘢痕收缩，然而，其潜在机制以及TGF-β在各种其他因素中的重要性仍有待阐明。与非增殖性对照相比，PDR或PVR患者的玻璃体样本导致含玻璃体细胞的胶原凝胶收缩明显更大。收缩效应与活化的TGF-β2的玻璃体浓度密切相关（r = 0.82，P < 0.0001）。PDR或PVR玻璃体促进α-平滑肌肌动蛋白（α-SMA）的表达和肌球蛋白轻链（MLC）的磷酸化，MLC是Rho激酶（ROCK）的下游介质，两者都被TGF-β阻断剂显著但不完全抑制。相反，法舒地尔是一种有效且选择性的ROCK抑制剂，几乎完全阻断了玻璃体诱导的MLC磷酸化和胶原凝胶收缩。法舒地尔破坏了α-SMA的组织，但不影响其在玻璃体中的表达。在体内，通过视网膜电图和组织学分析，法舒地尔显著抑制了兔眼实验性PVR的进展，而不影响视网膜细胞的活力。这些结果阐明了TGF-β在介导增殖性玻璃体视网膜疾病瘢痕收缩中的关键作用。ROCK是TGF-β和其他因素的关键下游介质，可能成为治疗增殖性玻璃体视网膜疾病的独特治疗靶点。
