Regulation of collagen turnover in human skin fibroblasts exposed to a gadolinium-based contrast agent.
Regulation of collagen turnover in human skin fibroblasts exposed to a gadolinium-based contrast agent.
复制标题
DOI：
10.1097/rli.0b013e3181a4d7e9
复制
发表时间：
2009-08
影响因子：
6.7
通讯作者：
Varani J
中科院分区：
文献类型：
--
作者：
Bhagavathula N;DaSilva M;Aslam MN;Dame MK;Warner RL;Xu Y;Fisher GJ;Johnson KJ;Swartz R;Varani J
肾源性系统性纤维化（NSF）是一种与肾衰竭患者在磁共振成像期间暴露于钆基造影剂（GBCA）相关的临床综合征。最近，我们证明GBCA暴露导致人皮肤成纤维细胞中基质金属蛋白酶-1（MMP-1）和金属蛋白酶组织抑制剂-1（TIMP-1）水平升高。本工作的目标是评估改变MMP-1 / TIMP-1表达和胶原蛋白产生/沉积之间的关系，以及导致GBCA刺激改变MMP-1和TIMP-1产生的细胞内信号事件。用一种目前使用的GBCA（Omniscan）处理人真皮成纤维细胞。增殖被定量为MMP-1、TIMP-1、I型前胶原和I型胶原的水平。同时评估信号传导事件，并使用信号传导抑制剂。暴露于Omniscan的成纤维细胞MMP-1和TIMP-1水平均增加。Omniscan治疗干扰胶原蛋白周转，导致I型胶原沉积增加，而I型前胶原蛋白的产生没有增加。丝裂原活化蛋白激酶信号抑制剂U 0126和磷脂酰肌醇-3激酶抑制剂LY 294002可降低MMP-1水平。U 0126也降低TIMP-1水平，但LY 294002增加TIMP-1。这些数据为欧智康治疗皮肤中胶原蛋白沉积的复杂调节提供了证据。他们认为Omniscan暴露的主要影响是调节胶原蛋白分解的酶/抑制剂系统，而不是胶原蛋白本身的产生。
Nephrogenic systemic fibrosis (NSF) is a clinical syndrome linked with exposure in renal failure patients to gadolinium-based contrast agents (GBCAs) during magnetic resonance imaging. Recently, we demonstrated that GBCA exposure led to increased matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinases-1 (TIMP-1) levels in human skin fibroblasts. The goals of the present work were to assess the relationship between altered MMP-1 / TIMP-1 expression and collagen production / deposition, and the intracellular signaling events that lead from GBCA stimulation to altered MMP-1 and TIMP-1 production. Human dermal fibroblasts were treated with one of the currently used GBCAs (Omniscan). Proliferation was quantified as were levels of MMP-1, TIMP-1, procollagen type I and collagen type I. Signaling events were concomitantly assessed, and signaling inhibitors were used. Fibroblasts exposed to Omniscan had increases in both MMP-1 and TIMP-1 levels. Omniscan treatment interfered with collagen turnover, leading to increased type I collagen deposition without an increase in type I procollagen production. U0126, an inhibitor of mitogen-activated protein kinase signaling, and LY294002, a phosphatidylinositol-3 kinase inhibitor, reduced MMP-1 levels. U0126 also reduced TIMP-1 levels, but LY294002 increased TIMP-1. These data provide evidence for complex regulation of collagen deposition in Omniscan-treated skin. They suggest that the major effect of Omniscan exposure is on an enzyme / inhibitor system that regulates collagen breakdown rather than on collagen production, per se.