SPARC deficiency results in improved surgical survival in a novel mouse model of glaucoma filtration surgery.
SPARC deficiency results in improved surgical survival in a novel mouse model of glaucoma filtration surgery.
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DOI：
10.1371/journal.pone.0009415
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发表时间：
2010-02-25
期刊：
影响因子：
3.7
通讯作者：
Wong TT
中科院分区：
文献类型：
--
作者：
Seet LF;Su R;Barathi VA;Lee WS;Poh R;Heng YM;Manser E;Vithana EN;Aung T;Weaver M;Sage EH;Wong TT
青光眼是一种经常与眼内压升高相关的疾病，可以通过滤过手术缓解。然而，术后结膜下疤痕反应阻碍了过滤效率，是实现长期手术成功的主要障碍。目前应用抗增殖药物来调节疤痕反应并不理想，因为这些通常会引起危及视力的并发症。 SPARC（分泌蛋白，酸性且富含半胱氨酸）是一种基质细胞蛋白，参与细胞外基质 (ECM) 的产生和组织。在这项研究中，我们在 SPARC 无效小鼠的实验性青光眼滤过模型中研究了手术后伤口的存活率。 SPARC 的缺失导致手术伤口存活率显着 (87.5%)，而野生型 (WT) 对应物的存活率为 0%。较大的 SPARC-null 伤口意味着与 WT 伤口相比，通过结膜下间隙的房水过滤更有效。手术存活率和滤过效率的显着增加与 SPARC-null 伤口中胶原 ECM 较少、胶原纤维直径较小以及组织松散的结膜下基质有关。相比之下，WT 伤口表现出密集的胶原 ECM，没有过滤能力的证据。免疫定位测定证实了 ECM 蛋白在 WT 中积累，但在 SPARC-null 伤口中没有积累。体内观察结果通过体外 WT 和 SPARC-null 结膜成纤维细胞的补充数据得到证实。这些发现表明，SPARC 的消耗会导致术后 ECM 重塑发生固有变化，有利于伤口维护。本报告中提供的证据强烈支持以 SPARC 为目标来提高青光眼滤过手术的成功率。
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.
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