Nature Medicine
- 12, 1286 - 1293 (2006)
Published online: 5 November 2006; | doi:10.1038/nm1494
Hyperoxia causes angiopoietin 2–mediated acute lung injury and necrotic cell deathVineet Bhandari1, Rayman Choo-Wing1, Chun G Lee2, Zhou Zhu2, Jonathan H Nedrelow1, Geoffrey L Chupp2, Xucher Zhang2, Michael A Matthay3, Lorraine B Ware4, Robert J Homer5, Patty J Lee2, Anke Geick6, Antonin R de Fougerolles6 & Jack A Elias21
Division of Perinatal Medicine, Yale University School of Medicine, Department of Pediatrics, 333 Cedar Street, New Haven, Connecticut 06520-8064, USA. 2
Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520-8057, USA. 3
Division of Pulmonary and Critical Care Medicine, University of California School of Medicine, 505 Parnassus Avenue, San Francisco, California 94143, USA. 4
Division of Allergy, Pulmonary & Critical Care Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, Tennessee 37232-2650, USA. 5
Department of Pathology, Yale University School of Medicine, 310 Cedar Street, New Haven, Connecticut 06520-8057, and Pathology and Laboratory Medicine Service, VA-CT Health Care System, 950 Campbell Avenue, West Haven, Connecticut 06516, USA. 6
Alnylam Pharmaceuticals, 300 Third Avenue, Cambridge, Massachusetts 02142, USA.
Correspondence should be addressed to Jack A Elias jack.elias@yale.edu 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.
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