Inhibition of VEGF receptors causes lung cell apoptosis and emphysema
Inhibition of VEGF receptors causes lung cell apoptosis and emphysema
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DOI：
10.1172/jci10259
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发表时间：
2000-12-01
影响因子：
15.9
通讯作者：
Voelkel, NF
中科院分区：
文献类型：
--
作者：
Kasahara, Y;Tuder, RM;Voelkel, NF
肺气肿是一个重要的全球性健康问题，其特征在于肺泡结构的丧失。由于VEGF是内皮细胞存活所需的营养因子，并且在肺中大量表达，因此我们假设长期阻断VEGF受体可诱导肺泡细胞凋亡和肺气肿。用VEGF受体阻断剂SU 5416对大鼠进行慢性治疗导致空气空间扩大，表明肺气肿。VEGF受体抑制剂SU 5416诱导肺泡隔细胞凋亡，但不抑制肺细胞增殖。通过血管造影观察，SU 5416处理的大鼠肺显示肺动脉树修剪，尽管我们没有观察到炎性细胞或纤维化的肺浸润。SU 5416治疗导致VEGF受体2（VEGFR-2）、磷酸化VEGFR-2和与VEGFR-2复合的Akt-1的肺表达降低。用半胱天冬酶抑制剂Z-Asp-CH 2-DCB处理防止了SU 5416诱导的隔细胞凋亡和肺气肿的发展。这些发现表明，VEGF受体信号是维持肺泡结构所必需的，并且进一步地，肺泡间隔细胞凋亡有助于肺气肿的发病机制。
Pulmonary emphysema, a significant global health problem, is characterized by a loss of alveolar structures. Because VEGF is a trophic factor required for the survival of endothelial cells and is abundantly expressed in the lung, we hypothesized that chronic blockade of VEGF receptors could induce alveolar cell apoptosis and emphysema. Chronic treatment of rats with the VEGF receptor blocker SU5416 led to enlargement of the air spaces, indicative of emphysema. The VEGF receptor inhibitor SU5416 induced alveolar septal cell apoptosis but did not inhibit lung cell proliferation. Viewed by angiography, SU5416-treated rat lungs showed a pruning of the pulmonary arterial tree, although we observed no lung infiltration by inflammatory cells or fibrosis. SU5416 treatment led to a decrease in lung expression of VEGF receptor 2 (VEGFR-2), phosphorylated VEGFR-2, and Akt-1 in the complex with VEGFR-2. Treatment with the caspase inhibitor Z-Asp-CH2-DCB prevented SU5416-induced septal cell apoptosis and emphysema development. These findings suggest that VEGF receptor signaling is required for maintenance of the alveolar structures and, further, that alveolar septal cell apoptosis contributes to the pathogenesis of emphysema.