P38 MAP kinase: Essential role in hypoxia-mediated human pulmonary artery fibroblast proliferation
P38 MAP kinase: Essential role in hypoxia-mediated human pulmonary artery fibroblast proliferation
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DOI：
10.1016/j.pupt.2006.08.007
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发表时间：
2007-01-01
影响因子：
3.2
通讯作者：
Welsh, David J.
中科院分区：
文献类型：
--
作者：
Mortimer, Heather J.;Peacock, Andrew J.;Welsh, David J.
肺动脉高压（PAH）是一种导致血管壁增厚的疾病。由于成纤维细胞增殖和细胞外基质沉积增加，在外膜中观察到一些最显著的变化。本实验室先前使用动物模型的工作表明，肺动脉而不是全身动脉成纤维细胞对低氧暴露增殖，并且这种反应依赖于p38丝裂原活化蛋白激酶（p38 MAPK）的激活。在这项研究中，我们希望确定是否人肺动脉成纤维细胞（HPAFs）在急性低氧暴露条件下（35毫米汞柱，24小时）的行为相似。通过[H-3]胸苷摄取和使用Western印迹技术进行的蛋白质测定来评估成纤维细胞增殖。HPAFs对急性低氧暴露有增殖反应，而人体动脉成纤维细胞则无此反应。这种低氧介导的增殖是p38 MAPK依赖性的，并且可以使用特异性p38 MAPK抑制剂来阻断。缺氧诱导因子-1（HIF-1）的表达在缺氧的肺细胞中增加，但在全身细胞中没有，并且可以用p38抑制剂部分消除。这项工作在人证实了我们以前的研究结果，在动物之间存在显着差异的肺循环和体循环之间的反应缺氧暴露。本研究强调了p38 MAPK和HIF-1在缺氧介导的肺动脉外膜成纤维细胞增殖中的重要性。爱思唯尔有限公司出版
Pulmonary arterial hypertension (PAH) is a disease that results in thickening of the vascular wall. Some of the most prominent changes are seen in the adventitia as a result of fibroblast proliferation and increased extracellular matrix deposition. Previous work from this laboratory using animal models has shown that pulmonary but not systemic artery fibroblasts proliferate to hypoxic exposure and that this response is dependent on activation of p38 mitogen-activated protein kinase (p38MAPK). In this study, we wished to determine whether human pulmonary artery fibroblasts (HPAFs) behaved similarly under conditions of acute hypoxic exposure (35 mmHg for 24 h). Fibroblast proliferation was assessed by [H-3]thymidine uptake and protein assays performed using Western blotting techniques. HPAFs proliferated in response to acute hypoxic exposure, human systemic artery fibroblasts did not. This hypoxia-mediated proliferation was p38 MAPK dependent and could be blocked using a specific p38 MAPK inhibitor. Hypoxia-inducible factor-1 (HIF-1) expression was increased in hypoxic pulmonary but not systemic cells and could be partially abrogated with the p38 inhibitor. This work in man confirmed our previous findings in animals that significant differences exist between the pulmonary and systemic circulations in response to hypoxic exposure. This study highlights the importance of p38 MAPK and HIF-1 in hypoxia-mediated proliferation of pulmonary artery adventitial fibroblasts. Published by Elsevier Ltd.