Development of a new strategy for the prevention of ocular tissue fibrosis by targeting integrin-Smad craootalks

检测了成纤维细胞中细胞外基质组分和纤维化细胞因子的表达，所述成纤维细胞来自骨桥蛋白（OPN）或腱生蛋白C（TNC），两者都是α 9整联蛋白的配体、敲除小鼠和野生型小鼠。缺乏OPN或TNC降低了I型胶原、TGF-β 1和α-平滑肌肌动蛋白的表达。然而，OPN信号直接参与Smad 3和p38的磷酸化，TNC的缺乏不影响Smad 3表达水平或磷酸化。检测TNC基因敲除对角膜切口瘢痕愈合和角膜新生血管形成的影响。TNC的缺乏抑制瘢痕形成和血管生成。研究OPN基因敲除对另一种与血管生成相关的创伤愈合模型的影响，即激光照射脉络膜和视网膜后血管生成和瘢痕组织形成。在腹腔注射α 9整联蛋白中和抗体之前，还检查了OPN中和抗体剂量的影响，缺乏OPN或通过全身施用OPN中和抗体诱导的OPN信号转导抑制炎性细胞因子的表达、脉络膜新生血管和瘢痕组织形成。控制OPN或TNC信号传导将是眼瘢痕形成或与血管生成相关的疾病的新治疗策略。

The expression of extracellular matrix components and fibrotic cytokines in fibroblasts, which were from either osteopontin (OPN) or tenascin C (TNC), both of which are ligands of a9 integrin, knock-out and wild-type mice, were examined. Lacking OPN or TNC decreased the expression of type I collagen, TGF-b1, and alpha-smooth muscle actin. However OPN signaling is directly involved in phosphorylation of Smad3 and p38, the lack of TNC did not affect Smad3 expression levels or phosphorylation. The effects of TNC knock-out on wound healing models, which were scar healing after corneal incision and corneal angiogenesis, were examined. The lack of TNC inhibited both scarring and angiogenesis. The effects of OPN knock-out on another wound healing models associated with angiogenesis, which were angiogenesis and scar tissue formation after laser irradiation on choroid and retina, were examined. The effects of dose of OPN neutralizing antibody were also examined before intraperitoneal administration of a9 integrin neutralizing antibody .Lacking OPN or blocking its signaling induced by systemic administration of an OPN neutralizing antibody suppressed the expression of inflammatory cytokines, choroidal neovascularization and scar tissue formation. Controlling OPN or TNC signaling would be a new treatment strategy for ocular scarring or diseases associated with angiogenesis.