Li Xiaofei, de Boer Onno J, Ploegmaker Hanneke, Teeling Peter, Daemen Mat Jap, de Winter Robbert J, van der Wal Allard C
Department of Pathology, Academic Medical Center, University of Amsterdam, 1012WX Amsterdam, The Netherlands.
Department of Cardiology, Academic Medical Center, University of Amsterdam, 1012WX Amsterdam, The Netherlands.
Cardiovasc Pathol. 2016 Jan-Feb;25(1):40-6. doi: 10.1016/j.carpath.2015.09.007. Epub 2015 Oct 18.
Remodeling of extracellular matrix is a key process during wound healing, which is strictly regulated by matrix metalloproteinases (MMPs) and their tissue inhibitors [tissue inhibitors of metalloproteinases (TIMPs)]. In this study, we evaluated intrathrombotic MMPs and TIMPs and their cellular origin during thrombus evolution after disruption of coronary atherosclerotic plaque.
Thrombectomy materials (N=120) obtained from patients with acute myocardial infarction were histologically classified in three groups based on thrombus age: fresh (<1day), lytic (1-5days), or organized (>5days) thrombi; materials showing a heterogeneous composition were classified according to oldest part. Presence and cellular origin of MMPs (MMP-1, MMP-2, MMP-8, MMP-9, and MMP-14) and TIMPs (TIMP-1, TIMP-2, and TIMP-3) was evaluated with immunostains (double) and with polymerase chain reaction.
MMPs and TIMPs were present in all the thrombectomy samples. A distinct temporal change in extent and cellular origin of MMPs and TIMPs during thrombus evolution was observed. In the early (fresh and lytic) stages of thrombus, high numbers of neutrophilic granulocytes occupy the thrombus mass and produce large amounts of MMPs and TIMPs. However, with progression of thrombus evolution (organizing stage) and diminishment of neutrophil granulocytes, there is disappearance of MMP-8 and MMP-9, steep decline of MMP-1 and TIMP-2, and progressive decrease of TIMP-3. In contrast, intrathrombotic MMP-2 and MMP-14 are present at a constant high level during the entire process of thrombus evolution. These temporal changes indicate a complex time-dependent function of MMPs, which are largely granulocyte derived, in the healing process of thrombus after plaque disruption.
细胞外基质重塑是伤口愈合过程中的关键环节，这一过程受到基质金属蛋白酶（MMPs）及其组织抑制剂[金属蛋白酶组织抑制剂（TIMPs）]的严格调控。在本研究中，我们评估了冠状动脉粥样硬化斑块破裂后血栓形成过程中血栓内MMPs和TIMPs及其细胞来源。
从急性心肌梗死患者获取的血栓切除术材料（N = 120），根据血栓形成时间在组织学上分为三组：新鲜血栓（<1天）、溶解期血栓（1 - 5天）或机化血栓（>5天）；成分不均一的材料根据最陈旧部分进行分类。采用免疫染色（双重染色）和聚合酶链反应评估MMPs（MMP - 1、MMP - 2、MMP - 8、MMP - 9和MMP - 14）和TIMPs（TIMP - 1、TIMP - 2和TIMP - 3）的存在情况及其细胞来源。
在所有血栓切除术样本中均检测到MMPs和TIMPs。在血栓形成过程中，观察到MMPs和TIMPs的含量及细胞来源存在明显的时间变化。在血栓形成的早期（新鲜血栓和溶解期血栓阶段），大量中性粒细胞占据血栓块并产生大量MMPs和TIMPs。然而，随着血栓形成的进展（机化阶段）以及中性粒细胞数量的减少，MMP - 8和MMP - 9消失，MMP - 1和TIMP - 2急剧下降，TIMP - 3逐渐减少。相比之下，在血栓形成的整个过程中，血栓内的MMP - 2和MMP - 14始终保持较高水平。这些时间变化表明，在斑块破裂后血栓愈合过程中，MMPs发挥着复杂的时间依赖性作用，且MMPs主要来源于粒细胞。
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