Kidney ischemia-reperfusion injury induces caspase-dependent pulmonary apoptosis
Kidney ischemia-reperfusion injury induces caspase-dependent pulmonary apoptosis
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DOI：
10.1152/ajprenal.90666.2008
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发表时间：
2009-07-01
影响因子：
4.2
通讯作者：
Rabb, Hamid
中科院分区：
文献类型：
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作者：
Hassoun, Heitham T.;Lie, Mihaela L.;Rabb, Hamid
Hassoun HT，Lie ML，Grigoryev DN，Liu M，Tuder RM，Rabb H。肾缺血再灌注损伤诱导半胱天冬酶依赖性肺细胞凋亡。 Am J Physiol Renal Physiol 297：F125-F137，2009。首次发表于 2009 年 4 月 29 日； doi:10.1152/ajprenal.90666.2008.-急性肾损伤 (AKI) 的远端器官影响是发病率和死亡率的主要原因。虽然人们对潜在机制知之甚少，但有限的数据表明炎症和细胞凋亡的作用。利用缺血性 AKI 诱导的肺功能障碍小鼠模型中的肺候选基因发现方法，我们发现了 66 个凋亡相关基因在缺血后 6 和/或 36 小时的显着肺激活，其中 6 个基因代表肿瘤坏死因子受体 (TNFR) 超家族，另外 23 个基因与 TNFR 通路相关。鉴于肺细胞凋亡是急性肺损伤 (ALI) 的重要致病机制，我们假设 AKI 会导致肺部促凋亡途径，从而促进肺损伤和炎症。与 1) 末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记和 2) 活性 caspase-3 (aC3) 活性、免疫印迹和免疫组织化学 (IHC) 的功能相关性确定了 24 小时肾 IRI 诱导的肺细胞凋亡，并且与 CD34 的共定位研究确定了主要是内皮细胞凋亡。在假手术或肾脏 IRI 之前 1 小时和之后 8 小时，用半胱天冬酶抑制剂 Z-VAD-FMK（0.25 mg ip）或媒介物处理小鼠，并在 36 小时测量支气管肺泡灌洗液蛋白作为肺渗漏的替代物。 Caspase 抑制可减少肾 IRI 后肺微血管的变化。在 AKI 期间野生型对照小鼠中观察到的肺细胞凋亡在 TNFR-/- 小鼠中不存在。使用最初的基因组方法进行发现，然后采用机械方法进行疾病靶向，我们证明肺内皮细胞凋亡是实验性 AKI 期间远端器官功能障碍的直接介质。
Hassoun HT, Lie ML, Grigoryev DN, Liu M, Tuder RM, Rabb H. Kidney ischemia-reperfusion injury induces caspase-dependent pulmonary apoptosis. Am J Physiol Renal Physiol 297: F125-F137, 2009. First published April 29, 2009; doi:10.1152/ajprenal.90666.2008.-Distant organ effects of acute kidney injury (AKI) are a leading cause of morbidity and mortality. While little is known about the underlying mechanisms, limited data suggest a role for inflammation and apoptosis. Utilizing a lung candidate gene discovery approach in a mouse model of ischemic AKI-induced lung dysfunction, we identified prominent lung activation of 66 apoptosis-related genes at 6 and/or 36 h following ischemia, of which 6 genes represent the tumor necrosis factor receptor ( TNFR) superfamily, and another 23 genes are associated with the TNFR pathway. Given that pulmonary apoptosis is an important pathogenic mechanism of acute lung injury (ALI), we hypothesized that AKI leads to pulmonary proapoptotic pathways that facilitate lung injury and inflammation. Functional correlation with 1) terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling and 2) active caspase-3 (aC3) activity, immunoblotting, and immunohistochemistry (IHC) identified kidney IRI-induced pulmonary apoptosis at 24 h, and colocalization studies with CD34 identified predominantly endothelial apoptosis. Mice were treated with the caspase inhibitor Z-VAD-FMK (0.25 mg ip) or vehicle 1 h before and 8 h after sham or kidney IRI, and bronchoalveolar lavage fluid protein was measured at 36 h as a surrogate for lung leak. Caspase inhibition reduced lung microvascular changes after kidney IRI. The pulmonary apoptosis seen in wild-type control mice during AKI was absent in TNFR-/- mice. Using an initial genomic approach to discovery followed by a mechanistic approach to disease targeting, we demonstrate that pulmonary endothelial apoptosis is a direct mediator of the distant organ dysfunction during experimental AKI.