Epithelial cell death is an important contributor to oxidant-mediated acute lung injury.
BACKGROUND
Acute lung injury and the acute respiratory distress syndrome are characterized by increased lung oxidant stress and apoptotic cell death. The contribution of epithelial cell apoptosis to the development of lung injury is unknown.


OBJECTIVE
To determine whether oxidant-mediated activation of the intrinsic or extrinsic apoptotic pathway contributes to the development of acute lung injury.


METHODS
Exposure of tissue-specific or global knockout mice or cells lacking critical components of the apoptotic pathway to hyperoxia, a well-established mouse model of oxidant-induced lung injury, for measurement of cell death, lung injury, and survival.


RESULTS
We found that the overexpression of SOD2 prevents hyperoxia-induced BAX activation and cell death in primary alveolar epithelial cells and prolongs the survival of mice exposed to hyperoxia. The conditional loss of BAX and BAK in the lung epithelium prevented hyperoxia-induced cell death in alveolar epithelial cells, ameliorated hyperoxia-induced lung injury, and prolonged survival in mice. By contrast, Cyclophilin D-deficient mice were not protected from hyperoxia, indicating that opening of the mitochondrial permeability transition pore is dispensable for hyperoxia-induced lung injury. Mice globally deficient in the BH3-only proteins BIM, BID, PUMA, or NOXA, which are proximal upstream regulators of BAX and BAK, were not protected against hyperoxia-induced lung injury suggesting redundancy of these proteins in the activation of BAX or BAK.


CONCLUSIONS
Mitochondrial oxidant generation initiates BAX- or BAK-dependent alveolar epithelial cell death, which contributes to hyperoxia-induced lung injury.
Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, 240 East Huron Street, Chicago, IL 60611, USA.
G R Scott
GR
Budinger
Gökhan M
GM
Mutlu
Daniela
D
Urich
Saul
S
Soberanes
Leonard J
LJ
Buccellato
Keenan
K
Hawkins
Sergio E
SE
Chiarella
Kathryn A
KA
Radigan
James
J
Eisenbart
Hemant
H
Agrawal
Sara
S
Berkelhamer
Siegfried
S
Hekimi
Jianke
J
Zhang
Harris
H
Perlman
Paul T
PT
Schumacker
Manu
M
Jain
Navdeep S
NS
Chandel
D055371:Acute Lung Injury / Q000209:etiology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000502:physiology; D004195:Disease Models, Animal; D018496:Hyperoxia / Q000150:complications / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D011650:Pulmonary Alveoli / Q000737:chemistry / Q000166:cytology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000032:analysis; D020545:Respiratory Mucosa / Q000378:metabolism / Q000503:physiopathology*; D013482:Superoxide Dismutase / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000099156:Superoxide Dismutase 2
D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D000099156:Superoxide Dismutase 2; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; C000631446:PPIF protein, mouse