Hyperoxia causes angiopoietin 2-mediated acute lung injury and necrotic cell death.
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.
Bhandari
Vineet
V
Division of Perinatal Medicine, Yale University School of Medicine, Department of Pediatrics, 333 Cedar Street, New Haven, Connecticut 06520-8064, USA.
Choo-Wing
Rayman
R
Lee
Chun G
CG
Zhu
Zhou
Z
Nedrelow
Jonathan H
JH
Chupp
Geoffrey L
GL
Zhang
Xucher
X
Matthay
Michael A
MA
Ware
Lorraine B
LB
Homer
Robert J
RJ
Lee
Patty J
PJ
Geick
Anke
A
de Fougerolles
Antonin R
AR
Elias
Jack A
JA
D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D016923:Cell Death; D018496:Hyperoxia / Q000503:physiopathology*; D051379:Mice; D011654:Pulmonary Edema / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering
D042702:Angiopoietin-2; D012333:RNA, Messenger; D034741:RNA, Small Interfering