Oxidative stress and apoptosis interact and cause emphysema due to vascular endothelial growth factor receptor blockade
Oxidative stress and apoptosis interact and cause emphysema due to vascular endothelial growth factor receptor blockade
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DOI：
10.1165/rcmb.2002-0228oc
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发表时间：
2003-07-01
影响因子：
6.4
通讯作者：
Flores, SC
中科院分区：
文献类型：
--
作者：
Tuder, RM;Zhen, L;Flores, SC
我们以前已经证明，血管内皮生长因子（VEGF）受体阻断诱导的肺内皮细胞存活失败导致肺泡间隔细胞凋亡和肺气肿。由于细胞凋亡和氧化应激可能是病理生物学联系，我们假设，氧化应激在肺泡隔细胞凋亡和VEGF受体阻断诱导的肺气肿中起着重要作用。与对照组相比，VEGF受体阻断剂SU5416处理的大鼠肺泡扩大，肺泡间隔细胞凋亡，氧化应激标志物的表达增加，所有这些都被超氧化物歧化酶模拟物M40419阻止。与SU5416处理的肺相比，SU5416+M40419处理的肺中肺结构的保留与间隔细胞增殖增加以及促存活和抗凋亡Akt的磷酸化增强相关。与氧化应激和细胞凋亡之间的正反馈相互作用一致，我们发现细胞凋亡在氧化应激领域占主导地位，并且广谱半胱天冬酶抑制剂的细胞凋亡阻断显著降低了SU5416治疗诱导的氧化应激标志物的表达。氧化应激和细胞凋亡可能是人类和实验性肺气肿的重要共同介质，在VEGF受体阻断诱导的肺气肿中引起肺细胞破坏。
We have previously demonstrated that a failure of pulmonary endothelial cell survival induced by vascular endothelial growth factor (VEGF) receptor blockade results in lung alveolar septal cell apoptosis and emphysema. Because apoptosis and oxidative stress may be pathobiologically linked, we hypothesized that oxidative stress has a central role in alveolar septal cell apoptosis and emphysema induced by VEGF receptor blockade. When compared with control animals, rats treated with the VEGF receptor blocker SU5416 showed increased alveolar enlargement, alveolar septal cell apoptosis, and expression of markers of oxidative stress, all of which were prevented by the superoxide dismutase mimetic M40419. The preservation of lung structure in SU5416+M40419-treated lungs was associated with increased septal cell proliferation, and enhanced phosphorylation of the prosurvival and antiapoptotic Akt, when compared with SU5416-treated lungs. Consistent with a positive feedback interaction between oxidative stress and apoptosis, we found that apoptosis predominated in areas of oxidative stress, and that apoptosis blockade by a broad spectrum caspase inhibitor markedly reduced the expression of markers of oxidative stress induced by SU5416 treatment. Oxidative stress and apoptosis, which cause lung cellular destruction in emphysema induced by VEGF receptor blockade, may be important mediators common to human and experimental emphysema.