Bcl-2-related protein A1 is an endogenous and cytokine-stimulated mediator of cytoprotection in hyperoxic acute lung injury
Bcl-2-related protein A1 is an endogenous and cytokine-stimulated mediator of cytoprotection in hyperoxic acute lung injury
复制标题
DOI：
10.1172/jci200523004
复制
发表时间：
2005-04-01
影响因子：
15.9
通讯作者：
Elias, JA
中科院分区：
文献类型：
--
作者：
He, CH;Waxman, AB;Elias, JA
高氧急性肺损伤（HALI）的特征在于具有细胞凋亡和坏死特征的细胞死亡反应，其可被IL-11和其他干预措施抑制。我们假设Bfl-1/A1是一种抗凋亡Bcl-2蛋白，是HALI的关键调节因子，也是IL-11诱导的细胞保护作用的介质。为了验证这一点，我们表征了A1基因座正常和缺失的WT和IL-11 Tg（+）小鼠的A1表达和氧敏感性。在WT小鼠中，100%O-2导致TUNEL+细胞死亡，诱导和激活内在和神经死亡途径，以及肺泡蛋白渗漏。Bcl-2和Bcl-xl也被诱导为明显的保护性反应。A1在高氧中被诱导，而在A1-null小鼠中，高氧的毒性作用被夸大，Bcl-2和Bcl-xl未被诱导，并且观察到过早死亡。相反，IL-11刺激A1，减少高氧的毒性作用，刺激Bcl-2和Bcl-xl，并提高小鼠在100%O-2中的存活率。在A1基因敲除小鼠中，IL-11诱导的保护作用、生存优势以及Bcl-2和Bc 1-x1诱导作用均显著降低。VEGF还通过A1依赖性机制提供保护。在体外高氧刺激A1，A1过表达抑制氧化诱导的上皮细胞凋亡和坏死。Al是氧化剂诱导的肺损伤、细胞凋亡、坏死以及Bcl-2和Bcl-xl基因表达的重要调节剂，并且是IL-11和VEGF诱导的细胞保护的关键介质。
Hyperoxic acute lung injury (HALI) is characterized by a cell death response with features of apoptosis and necrosis that is inhibited by IL-11 and other interventions. We hypothesized that Bfl-1/A1, an antiapoptotic Bcl-2 protein, is a critical regulator of HALI and a mediator of IL-11-induced cytoprotection. To test this, we characterized the expression of A1 and the oxygen susceptibility of WT and IL-11 Tg(+) mice with normal and null A1 loci. In WT mice, 100% O-2 caused TUNEL+ cell death, induction and activation of intrinsic and mitochondrial-death pathways, and alveolar protein leak. Bcl-2 and Bcl-xl were also induced as an apparent protective response. A1 was induced in hyperoxia, and in A1-null mice, the toxic effects of hyperoxia were exaggerated, Bcl-2 and Bcl-xl were not induced, and premature death was seen. In contrast, IL-11 stimulated A1, diminished the toxic effects of hyperoxia, stimulated Bcl-2 and Bcl-xl, and enhanced murine survival in 100% O-2. In A1-null mice, IL-11-induced protection, survival advantage, and Bcl-2 and Bc1-x1 induction were significantly decreased. VEGF also conferred protection via an A1 -dependent mechanism. In vitro hyperoxia also stimulated A1, and A1 overexpression inhibited oxidant-induced epithelial cell apoptosis and necrosis. Al is an important regulator of oxidant-induced lung injury, apoptosis, necrosis, and Bcl-2 and Bcl-xl gene expression and a critical mediator of IL-11- and VEGF-induced cytoprotection.