Transforming growth factor beta-1 released from platelets contributes to hypercoagulability in veno-occlusive disease following hematopoetic stem cell transplantation
Transforming growth factor beta-1 released from platelets contributes to hypercoagulability in veno-occlusive disease following hematopoetic stem cell transplantation
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DOI：
10.1016/j.thromres.2004.12.010
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发表时间：
2005-01-01
影响因子：
7.5
通讯作者：
Pihusch, R
中科院分区：
文献类型：
--
作者：
Pihusch, V;Pihusch, M;Pihusch, R
背景：肝静脉闭塞性疾病（VOD）是异基因造血干细胞移植（HSCT）后最严重的并发症之一。血小板减少症伴血小板输注无效表明这些患者的血小板消耗增加。血小板和内皮细胞之间的相互作用可能导致窦内皮细胞的高凝状态，作为 VOD 发病机制的核心机制。研究设计：体外研究了活化血小板对培养的人内皮细胞的影响。我们重点关注内皮细胞释放的纤溶酶原激活剂抑制剂 1 (PAI-1)，早期发现 VOD 患者血浆中的纤溶酶原激活剂抑制剂 1 (PAI-1) 显着升高。从人脐带 (HUVEC) 中分离出的内皮细胞与活化的血小板一起孵育。通过 ELISA 技术测定在存在或不存在特异性抗体的情况下 PAI-1 的释放。通过流式细胞术分析观察内皮细胞上的组织因子 (TF) 表达。结果：与未处理的培养物相比，与活化血小板一起孵育的 HUVEC 释放显着更多的 PAI-1。 HUVEC 与活化血小板一起孵育后，内皮 PAI-1 分泌被针对人转化生长因子 β-1 (TGF β-1) 的 IgG 单克隆抗体完全抑制。相反，在通过针对活化血小板表面表达的 CD154 (CD40L) 的 IgG 单克隆抗体抑制 HUVEC 与血小板相互作用后，PAI-1 的产生并未受到抑制。 TGFβ-1刺激后观察到内皮细胞表面PAI-1释放增加和组织因子(TF)表达增加。结论：活化血小板释放的TGFβ-1通过增加内皮细胞PAI-1产生和TF表达，导致肝VOD患者肝窦内皮的止血失衡。作为一种有效的促纤维化细胞因子，TGF beta-1 可能进一步参与 VOD 中发生的静脉硬化和肝窦纤维化。 (c) 2004 Elsevier Ltd. 保留所有权利。
Background: Hepatic veno-occlusive disease (VOD) is one of the most disastrous complications after allogeneic hematopoetic stem cell transplantation (HSCT). Thrombocytopenia with refractoriness to platelet transfusions suggests an increased platelet consumption in these patients. Interactions between platelets and endothelial cells might contribute to the hypercoagulable state at the sinusoidal endothelium as a central mechanism in the pathogenesis of VOD.Study design: The influence of activated platelets on cultured human endothelial cells was investigated in vitro. We focused on the release of plasminogen activator inhibitor-1 (PAI-1) from endothelial cells which has earlier been found to be significantly elevated in plasma of VOD patients. Endothelial cells isolated from human umbilical cords (HUVEC) were incubated with activated platelets. The release of PAI-1 in the presence or absence of specific antibodies was determined by ELISA technique. Tissue factor (TF) expression on endothelial cells was observed by flowcytometric analysis.Results: HUVEC incubated with activated platelets were found to release significantly more PAI-1 compared to untreated cultures. The endothelial PAI-1-secretion after incubation of HUVEC with activated platelets was completely inhibited by an IgG monoclonal antibody against human transforming growth factor beta-1 (TGF beta-1). In contrast, PAI-1 production was not suppressed after inhibition of HUVEC-platelet-interaction by an IgG monoclonal antibody against CD154 (CD40L) expressed on the surface of activated platelets. An increased release of PAI-1 and an increased expression of tissue factor (TF) on the endothelial cell surface were observed after stimulation with TGF beta-1.Conclusion: TGF beta-1 released from activated platelets contributes to the hemostatic imbalance at the sinusoidal endothelium in patients with hepatic VOD by increase of endothelial cell PAI-1 production and TF expression. As a potent profibrotic cytokine, TGF beta-1 might further be involved in phlebosclerosis and sinusoidal fibrosis occurring in VOD. (c) 2004 Elsevier Ltd. All rights reserved.