Hyperoxia causes angiopoietin 2-mediated acute lung injury and necrotic cell death

被引:274
作者
Bhandari, Vineet
Choo-Wing, Rayman
Lee, Chun G.
Zhu, Zhou
Nedrelow, Jonathan H.
Chupp, Geoffrey L.
Zhang, Xucher
Matthay, Michael A.
Ware, Lorraine B.
Homer, Robert J.
Lee, Patty J.
Geick, Anke
de Fougerolles, Antonin R.
Elias, Jack A.
机构
[1] Yale Univ, Sch Med, Pulm & Crit Care Med Sect, New Haven, CT 06520 USA
[2] Yale Univ, Sch Med, Div Perinatal Med, Dept Pediat, New Haven, CT 06520 USA
[3] Univ Calif San Francisco, Sch Med, Div Pulm & Crit Care Med, San Francisco, CA 94143 USA
[4] Vanderbilt Univ, Med Ctr, Div Allergy Pulm & Crit Care Med, Nashville, TN 37232 USA
[5] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA
[6] VACT Hlth Care Syst, Pathol & Lab Med Serv, West Haven, CT 06516 USA
[7] Alnylam Pharmaceut, Cambridge, MA 02142 USA
关键词
D O I
10.1038/nm1494
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The angiogenic growth factor angiopoietin 2 (Ang2) destabilizes blood vessels, enhances vascular leak and induces vascular regression and endothelial cell apoptosis. We considered that Ang2 might be important in hyperoxic acute lung injury (ALI). Here we have characterized the responses in lungs induced by hyperoxia in wild-type and Ang2(-/-) mice or those given either recombinant Ang2 or short interfering RNA (siRNA) targeted to Ang2. During hyperoxia Ang2 expression is induced in lung epithelial cells, while hyperoxia-induced oxidant injury, cell death, inflammation, permeability alterations and mortality are ameliorated in Ang2(-/-) and siRNA-treated mice. Hyperoxia induces and activates the extrinsic and mitochondrial cell death pathways and activates initiator and effector caspases through Ang2-dependent pathways in vivo. Ang2 increases inflammation and cell death during hyperoxia in vivo and stimulates epithelial necrosis in hyperoxia in vitro. Ang2 in plasma and alveolar edema fluid is increased in adults with ALI and pulmonary edema. Tracheal Ang2 is also increased in neonates that develop bronchopulmonary dysplasia. Ang2 is thus a mediator of epithelial necrosis with an important role in hyperoxic ALI and pulmonary edema.
引用
收藏
页码:1286 / 1293
页数:8
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