Polyglycolic acid-induced inflammation: Role of hydrolysis and resulting complement activation
Polyglycolic acid-induced inflammation: Role of hydrolysis and resulting complement activation
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DOI：
10.1089/ten.2006.12.301
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发表时间：
2006-02-01
影响因子：
--
通讯作者：
Stahl, GL
中科院分区：
文献类型：
--
作者：
Ceonzo, K;Gaynor, A;Stahl, GL
组织和器官的替代迅速超过了现有的供应。组织生物工程有望提供更多的组织可用性。目前使用的支架多种多样，而聚乙醇酸（PGA）目前用于可吸收缝合线和骨科针，为组织发育提供了良好的支持。不幸的是，PGA在植入后会引起局部炎症反应。因此，我们在体外和体内研究了炎症的分子机制。降解PGA诱导小鼠急性腹膜炎，以腹腔注射中性粒细胞（PMN）浸润为特征。使用PGA的代谢物乙醇酸也观察到类似的结果。通过经典补体途径溶血试验、C3a和C5a的产生以及C3和免疫球蛋白的沉积可以确定，溶解的PGA或糖苷，而不是天然的PGA，激活了人血清中的经典补体途径。为了研究这些体外观察是否转化为体内发现，我们使用了基因工程小鼠。与基因对照组（WT）相比，在C1q、因子D、C1q和因子D或C2和因子B缺乏的小鼠中，腹腔注射乙醇内酯或溶解的PGA可显著减少PMN浸润。缺乏C6的小鼠也表现出急性腹膜炎。然而，用抗C5的单克隆抗体治疗WT或C6缺陷小鼠可防止炎症反应。这些数据表明PGA水解成乙醇酸激活了经典的补体途径。此外，补体通过替代途径扩增，C5a的产生可诱导炎症。抑制C5a可能提供一种潜在的治疗方法，以限制植入后pga衍生材料相关的炎症。
Tissue and organ replacement have quickly outpaced available supply. Tissue bioengineering holds the promise for additional tissue availability. Various scaffolds are currently used, whereas polyglycolic acid ( PGA), which is currently used in absorbable sutures and orthopedic pins, provides an excellent support for tissue development. Unfortunately, PGA can induce a local inflammatory response following implantation. Therefore, we investigated the molecular mechanism of inflammation in vitro and in vivo. Degraded PGA induced an acute peritonitis, characterized by neutrophil (PMN) infiltration following intraperitoneal injection in mice. Similar observations were observed using the metabolite of PGA, glycolide. Dissolved PGA or glycolide, but not native PGA, activated the classical complement pathway in human sera, as determined by classical complement pathway hemolytic assays, C3a and C5a production, and C3 and immunoglobulin deposition. To investigate whether these in vitro observations translated to in vivo findings, we used genetically engineered mice. Intraperitoneal administration of glycolide or dissolved PGA in mice deficient in C1q, factor D, C1q and factor D, or C2 and factor B demonstrated significantly reduced PMN infiltration compared to congenic controls (WT). Mice deficient in C6 also demonstrated acute peritonitis. However, treatment of WT or C6 deficient mice with a monoclonal antibody against C5 prevented the inflammatory response. These data suggest that the hydrolysis of PGA to glycolide activates the classical complement pathway. Furthermore, complement is amplified via the alternative pathway and inflammation is induced by C5a generation. Inhibition of C5a may provide a potential therapeutic approach to limit the inflammation associated with PGA-derived materials following implantation.