Reactive oxygen species and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase mediate hyperoxia-induced cell death in lung epithelium.
Reactive oxygen species and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase mediate hyperoxia-induced cell death in lung epithelium.
复制标题
活性氧和细胞外信号调节激酶 1/2 丝裂原激活蛋白激酶介导肺上皮细胞高氧诱导的细胞死亡。
DOI：
10.1165/rcmb.2002-0156oc
复制
发表时间：
2003
影响因子：
6.4
通讯作者：
Lee,PattyJ
中科院分区：
文献类型：
--
作者：
Zhang,Xuchen;Shan,Peiying;Sasidhar,Madhu;Chupp,GeoffreyL;Flavell,RichardA;Choi,AugustineMK;Lee,PattyJ
高氧治疗（高氧）通常是治疗呼吸衰竭患者所必需的。然而，高氧可能通过增加肺上皮细胞死亡而加剧急性肺损伤的发生。因此，阻断肺上皮细胞死亡是重要的保护和治疗策略。在本研究中，通过dna阶梯、末端脱氧核苷酸转移酶dUTP缺口末端标记和Annexin v -异硫氰酸荧光素流式细胞术检测，高氧（95% O2）导致小鼠肺上皮细胞死亡。通过烟酰胺腺嘌呤二核苷酸磷酸还原（NADPH）氧化酶活性和流式细胞术分析，我们发现高氧增加了超氧化物的产生，并通过Western blot分析增加了磷酸化细胞外信号调节激酶（ERK）1/2。这些过程被活性氧抑制剂二苯碘（DPI）和丝裂原活化蛋白（MAP）或ERK激酶(MEK)/ERK1/2途径的抑制剂PD98059所抑制。高氧状态下ERK1/2的激活也受到DPI的抑制。高氧诱导的细胞死亡与细胞色素释放、随后的caspase 9和3激活以及聚（adp -核糖基）聚合酶裂解有关，这些都可以被DPI和PD98059抑制。然而，广泛的caspase抑制剂z-VAD-FMK保护细胞免于死亡，而不影响超氧化物的产生和ERK1/2的激活。综上所述，我们的数据表明，高氧通过激活NADPH氧化酶产生活性氧（ROS）， ROS通过ERK1/2 MAPK激活介导肺上皮细胞死亡，并在肺上皮细胞中发挥caspase激活的上游作用。
Therapy with high oxygen concentrations (hyperoxia) is often necessary to treat patients with respiratory failure. However, hyperoxia may exacerbate the development of acute lung injury, perhaps by increasing lung epithelial cell death. Therefore, interrupting lung epithelial cell death is an important protective and therapeutic strategy. In the present study, hyperoxia (95% O2) results in murine lung epithelium cell death by DNA-laddering, terminal deoxynucleotidyltransferase dUTP nick end labeling, and Annexin V–fluorescein isothiocyanate flow cytometry assay. We show that hyperoxia increases superoxide production, as assessed by nicotinamide adenine dinucleotide phosphate reduced (NADPH) oxidase activity and flow cytometric assay, and increases phospho–extracellular signal-regulated kinase (ERK)1/2 by Western blot analysis. These processes are inhibited by a reactive oxygen species inhibitor, diphenylene iodonium (DPI), and by an inhibitor of the mitogen-activated protein (MAP) or ERK kinase (MEK)/ERK1/2 pathway, PD98059. ERK1/2 activation in hyperoxia is also inhibited by DPI. Hyperoxia-induced cell death is associated with cytochromecrelease, subsequent caspase 9 and 3 activation, and poly (ADP-ribosyl) polymerase cleavage, which can all be suppressed by DPI and PD98059. However, the broad caspase inhibitor z-VAD-FMK protects cells from death without affecting superoxide generation and ERK1/2 activation. Taken together, our data suggest that hyperoxia, by virtue of activating NADPH oxidase, generates reactive oxygen species (ROS), which mediates cell death of lung epithelium via ERK1/2 MAPK activation, and functions upstream of caspase activation in lung epithelial cells.
登录
查看更多内容
DOI：
10.1152/ajplung.1999.277.3.l589
发表时间：
1999-09-01
影响因子：
4.9
作者：
Petrache, I;Choi, ME;Choi, AMK
通讯作者：
Choi, AMK
糖皮质激素地塞米松和钙 ATP 酶抑制剂毒胡萝卜素诱导细胞凋亡涉及 Bc1-2 调节的 caspase 激活
影响因子：
4.1
作者：
Karen S McColl;Huiling He;H. Zhong;C. Whitacre;N. Berger;C. Distelhorst
通讯作者：
C. Distelhorst
DOI：
10.1016/s0021-9258(18)82362-6
发表时间：
1993-07
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
R. Davis
通讯作者：
R. Davis
影响因子：
7.3
作者：
Mocanu, MM;Baxter, GF;Yellon, DM
通讯作者：
Yellon, DM
溶血磷脂酰胆碱通过内皮 NADH/NADPH 氧化酶增强超氧阴离子的产生。
影响因子：
4.4
作者：
S. Takeshita;N. Inoue;D. Gao;Y. Rikitake;S. Kawashima;R. Tawa;H. Sakurai;M. Yokoyama
通讯作者：
M. Yokoyama