Ocular Wound Healing and Therapeutics Group, Singapore Eye Research Institute, Singapore, Singapore.
PLoS One. 2010 Feb 25;5(2):e9415. doi: 10.1371/journal.pone.0009415.
Glaucoma is a disease frequently associated with elevated intraocular pressure that can be alleviated by filtration surgery. However, the post-operative subconjunctival scarring response which blocks filtration efficiency is a major hurdle to the achievement of long-term surgical success. Current application of anti-proliferatives to modulate the scarring response is not ideal as these often give rise to sight-threatening complications. SPARC (secreted protein, acidic and rich in cysteine) is a matricellular protein involved in extracellular matrix (ECM) production and organization. In this study, we investigated post-operative surgical wound survival in an experimental glaucoma filtration model in SPARC-null mice. Loss of SPARC resulted in a marked (87.5%) surgical wound survival rate compared to 0% in wild-type (WT) counterparts. The larger SPARC-null wounds implied that aqueous filtration through the subconjunctival space was more efficient in comparison to WT wounds. The pronounced increase in both surgical survival and filtration efficiency was associated with a less collagenous ECM, smaller collagen fibril diameter, and a loosely-organized subconjunctival matrix in the SPARC-null wounds. In contrast, WT wounds exhibited a densely packed collagenous ECM with no evidence of filtration capacity. Immunolocalization assays confirmed the accumulation of ECM proteins in the WT but not in the SPARC-null wounds. The observations in vivo were corroborated by complementary data performed on WT and SPARC-null conjunctival fibroblasts in vitro. These findings indicate that depletion of SPARC bestows an inherent change in post-operative ECM remodeling to favor wound maintenance. The evidence presented in this report is strongly supportive for the targeting of SPARC to increase the success of glaucoma filtration surgery.
青光眼是一种常伴有眼内压升高的疾病，可以通过过滤手术来缓解。然而，术后结膜下瘢痕形成反应会阻碍滤过效率，这是实现长期手术成功的主要障碍。目前应用抗增殖剂来调节瘢痕形成反应并不理想，因为这些药物常常会引起威胁视力的并发症。SPARC（富含半胱氨酸的酸性分泌蛋白）是一种参与细胞外基质（ECM）产生和组织的基质细胞蛋白。在这项研究中，我们在 SPARC 基因缺失小鼠的实验性青光眼滤过模型中研究了术后手术伤口的存活情况。与野生型（WT）相比，SPARC 基因缺失导致手术伤口的存活率明显提高（87.5%）。SPARC 基因缺失的伤口较大，这意味着与 WT 伤口相比，房水通过结膜下空间的滤过效率更高。手术存活率和滤过效率的显著增加与 ECM 中胶原含量减少、胶原纤维直径较小以及 SPARC 基因缺失伤口下的结膜下基质组织松散有关。相比之下，WT 伤口表现出密集排列的胶原 ECM，没有滤过能力的迹象。免疫定位检测证实了 ECM 蛋白在 WT 伤口中的积累，但在 SPARC 基因缺失伤口中则没有。体内观察结果与体外 WT 和 SPARC 基因缺失结膜成纤维细胞的补充数据相吻合。这些发现表明，SPARC 的耗竭赋予了术后 ECM 重塑以维持伤口的固有变化。本报告提供的证据强烈支持将 SPARC 作为靶点，以提高青光眼滤过手术的成功率。
