Inhibition of platelet-derived growth factor signaling attenuates pulmonary fibrosis.
Inhibition of platelet-derived growth factor signaling attenuates pulmonary fibrosis.
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DOI：
10.1084/jem.20041393
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发表时间：
2005-03-21
期刊：
影响因子：
--
通讯作者：
Huber PE
中科院分区：
文献类型：
--
作者：
Abdollahi A;Li M;Ping G;Plathow C;Domhan S;Kiessling F;Lee LB;McMahon G;Gröne HJ;Lipson KE;Huber PE
肺纤维化是多种疾病的结果，没有令人满意的治疗选择。治疗诱导的纤维化也限制了化疗和放疗在许多癌症中的疗效。在这里，我们研究了血小板衍生生长因子（PDGF）受体酪氨酸激酶抑制剂（RTKIs）减轻辐射诱导的肺纤维化的潜力。照射C57 BL/6小鼠的胸部（20戈伊），并用三种不同的PDGF RTKI（SU 9518、SU 11657或伊马替尼）处理小鼠。发现辐照诱导严重的肺纤维化，导致小鼠存活率显著降低。PDGF RTKIs治疗显著减弱了肺纤维化的发展，与临床、组织学和计算机断层扫描结果具有良好的相关性。重要的是，RTKI还延长了受辐射小鼠的寿命。我们发现，辐射上调PDGF（A-D）亚型的表达，导致PDGF受体的磷酸化，这被RTKI强烈抑制。我们的研究结果表明PDGF信号在肺纤维化的发病机制中起着关键作用，并表明抑制纤维化而不是炎症对抗纤维化治疗至关重要。这项研究为治疗特发性或治疗相关形式的肺纤维化提供了一种潜在的新方法。
Pulmonary fibrosis is the consequence of a variety of diseases with no satisfying treatment option. Therapy-induced fibrosis also limits the efficacy of chemotherapy and radiotherapy in numerous cancers. Here, we studied the potential of platelet-derived growth factor (PDGF) receptor tyrosine kinase inhibitors (RTKIs) to attenuate radiation-induced pulmonary fibrosis. Thoraces of C57BL/6 mice were irradiated (20 Gy), and mice were treated with three distinct PDGF RTKIs (SU9518, SU11657, or Imatinib). Irradiation was found to induce severe lung fibrosis resulting in dramatically reduced mouse survival. Treatment with PDGF RTKIs markedly attenuated the development of pulmonary fibrosis in excellent correlation with clinical, histological, and computed tomography results. Importantly, RTKIs also prolonged the life span of irradiated mice. We found that radiation up-regulated expression of PDGF (A–D) isoforms leading to phosphorylation of PDGF receptor, which was strongly inhibited by RTKIs. Our findings suggest a pivotal role of PDGF signaling in the pathogenesis of pulmonary fibrosis and indicate that inhibition of fibrogenesis, rather than inflammation, is critical to antifibrotic treatment. This study points the way to a potential new approach for treating idiopathic or therapy-related forms of lung fibrosis.
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影响因子：
16
作者：
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