Recombinant GPI-anchored TIMP-1 stimulates growth and migration of peritoneal mesothelial cells.
Recombinant GPI-anchored TIMP-1 stimulates growth and migration of peritoneal mesothelial cells.
复制标题
DOI：
10.1371/journal.pone.0033963
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Nelson PJ
中科院分区：
文献类型：
--
作者：
Djafarzadeh R;Sauter M;Notohamiprodjo S;Noessner E;Goyal P;Siess W;Wörnle M;Ribeiro A;Himmelein S;Sitter T;Nelson PJ
间皮细胞在术后腹腔粘连以及与长期腹膜透析相关的腹膜恶化的发病机制中至关重要。间皮剥脱是这些过程中病理生理学上重要的发现。基质金属蛋白酶 (MMP) 生物学是间皮稳态和伤口修复的基础。金属蛋白酶的内源性组织抑制剂 (TIMP) 可调节 MMP 活性。通过添加糖基磷脂酰肌醇 (GPI) 锚来修饰人 TIMP-1，生成了一种重组蛋白，可有效地将 TIMP-1 聚焦在细胞表面。用 TIMP-1-GPI 处理原代间皮细胞可促进其动员和迁移，从而显着提高伤口实验闭合率。用TIMP-1-GPI处理的间皮细胞表现出剂量依赖性的细胞增殖增加，MMP-2、MMP-9、TNF-α和尿激酶型纤溶酶原激活剂（uPA）的分泌减少，但组织纤溶酶原激活剂（t-PA）增加。治疗导致潜在 TGF-β1 的表达和加工减少。 TIMP-1-GPI 刺激体外伤口快速有效闭合。该药物可增强间皮细胞的增殖和迁移，并具有纳克级的生物活性。 TIMP-1-GPI的应用可能代表一种限制或修复受损间皮的新方法。
Mesothelial cells are critical in the pathogenesis of post-surgical intraabdominal adhesions as well as in the deterioration of the peritoneal membrane associated with long-term peritoneal dialysis. Mesothelial denudation is a pathophysiolocigally important finding in these processes. Matrix metalloproteinase (MMP) biology underlies aspects of mesothelial homeostasis as well as wound repair. The endogenous tissue inhibitors of metalloproteinases (TIMPs) moderate MMP activity. By modifying human TIMP-1 through the addition of a glycosylphosphatidylinositol (GPI) anchor, a recombinant protein was generated that efficiently focuses TIMP-1 on the cell surface. Treatment of primary mesothelial cells with TIMP-1-GPI facilitates their mobilization and migration leading to a dramatic increase in the rate of wound experimental closure. Mesothelial cells treated with TIMP-1-GPI showed a dose dependent increase in cell proliferation, reduced secretion of MMP-2, MMP-9, TNF-α and urokinase-type plasminogen activator (uPA), but increased tissue plasminogen activator (t-PA). Treatment resulted in reduced expression and processing of latent TGF-β1. TIMP-1-GPI stimulated rapid and efficient in vitro wound closure. The agent enhanced mesothelial cell proliferation and migration and was bioactive in the nanogram range. The application of TIMP-1-GPI may represent a new approach for limiting or repairing damaged mesothelium.
登录
查看更多内容
影响因子：
3.7
作者：
Klier, CM;Nelson, EL;Nelson, PJ
通讯作者：
Nelson, PJ
影响因子：
19.6
作者：
Li, FK;Davenport, A;Topley, N
通讯作者：
Topley, N
影响因子：
2.5
作者：
Haslinger, B;Mandl-Weber, S;Sitter, T
通讯作者：
Sitter, T
影响因子：
15.9
作者：
MARSHALL, BC;SANTANA, A;WELGUS, HG
通讯作者：
WELGUS, HG
影响因子：
8.8
作者：
Edwards, J G;McLaren, J;Jones, J L;Waller, D A;O'Byrne, K J
通讯作者：
O'Byrne, K J