Trauma-hemorrhagic shock-induced pulmonary epithelial and endothelial cell injury utilizes different programmed cell death signaling pathways
Trauma-hemorrhagic shock-induced pulmonary epithelial and endothelial cell injury utilizes different programmed cell death signaling pathways
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DOI：
10.1152/ajplung.00491.2007
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发表时间：
2009-03-01
影响因子：
4.9
通讯作者：
Feinman, Rena
中科院分区：
文献类型：
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作者：
Barlos, Dimtrios;Deitch, Edwin A.;Feinman, Rena
Barlos D、Deitch EA、Watkins AC、Caputo FJ、Lu Q、Abungu B、科罗拉多I、Xu DZ、Feinman R.创伤出血性休克诱导的肺上皮和内皮细胞损伤利用不同的程序性细胞死亡信号通路。美国生理学杂志肺细胞分子生理学296：L404-L417，2009年。首次发表于2008年12月31日; doi：10.1152/ajplung.00491.2007。创伤-失血性休克（T/HS）后的肠缺血导致肠屏障功能障碍和肠系膜淋巴中生物活性和组织损伤因子的产生/释放，这反过来又导致急性肺损伤和全身炎症状态。由于T/HS诱导的肺损伤与肺内皮细胞和上皮细胞程序性细胞死亡（PCD）相关，并被肠系膜淋巴管结扎废除，我们试图研究所涉及的细胞途径。与创伤-假休克（T/SS）大鼠相比，PCD大鼠肺上皮细胞caspase-3和M30表达显著增加，而内皮细胞凋亡诱导因子（AIF）表达增加，而caspase-3表达不增加。这种AIF介导的肺内皮PCD反应在原位股静脉测定中得到验证，其中发现内皮细胞表达AIF但不表达半胱天冬酶-3。为了补充这些研究，使用人脐静脉内皮细胞（HUVEC）、人肺微血管内皮细胞（HLMEC）和人肺泡II型上皮细胞（A549）系作为体外模型。T/HS淋巴液可诱导HUVEC和HLMEC中AIF核转位，而caspase抑制对这些细胞无保护作用。为了证明原理，HUVEC中的AIF沉默逆转了T/HS对细胞活力和DNA片段化的细胞毒性作用。在A549细胞中，T/HS淋巴激活caspase-3介导的凋亡，这被N-苄氧羰基-Val-Ala-Asp（zVAD）部分消除。此外，T/HS淋巴液未引起AIF在A549细胞中的核转位。总的来说，T/HS诱导的肺内皮细胞PCD通过AIF依赖性半胱天冬酶非依赖性途径发生，而上皮细胞通过半胱天冬酶依赖性途径发生凋亡。
Barlos D, Deitch EA, Watkins AC, Caputo FJ, Lu Q, Abungu B, Colorado I, Xu DZ, Feinman R. Trauma-hemorrhagic shockinduced pulmonary epithelial and endothelial cell injury utilizes different programmed cell death signaling pathways. Am J Physiol Lung Cell Mol Physiol 296: L404-L417, 2009. First published December 31, 2008; doi: 10.1152/ajplung.00491.2007.-Intestinal ischemia after trauma-hemorrhagic shock (T/HS) results in gut barrier dysfunction and the production/release of biologically active and tissue injurious factors in the mesenteric lymph, which, in turn, causes acute lung injury and a systemic inflammatory state. Since T/HS-induced lung injury is associated with pulmonary endothelial and epithelial cell programmed cell death (PCD) and was abrogated by mesenteric lymph duct ligation, we sought to investigate the cellular pathways involved. Compared with trauma-sham shock (T/SS) rats, a significant increase in caspase-3 and M30 expression was detected in the pulmonary epithelial cells undergoing PCD, whereas apoptosis-inducing factor (AIF), but not caspase-3, was detected in endothelial cells undergoing PCD. This AIF-mediated pulmonary endothelial PCD response was validated in an in situ femoral vein assay where endothelial cells were found to express AIF but not caspase-3. To complement these studies, human umbilical vein endothelial cell (HUVEC), human lung microvascular endothelial cell (HLMEC), and human alveolar type II epithelial cell (A549) lines were used as in vitro models. T/HS lymph induced the nuclear translocation of AIF in HUVEC and HLMEC, and caspase inhibition in these cells did not afford any cytoprotection. For proof of principle, AIF silencing in HUVEC reversed the cytotoxic effects of T/HS on cell viability and DNA fragmentation. In A549 cells, T/HS lymph activated caspase-3-mediated apoptosis, which was partially abrogated by N-benzyloxycarbonyl-Val-Ala-Asp (zVAD). Additionally, T/HS lymph did not cause the nuclear translocation of AIF in A549 cells. Collectively, T/HS-induced pulmonary endothelial PCD occurs via an AIF-dependent caspase-independent pathway, whereas epithelial cells undergo apoptosis by a caspase-dependent pathway.