Dual oxidase 2 in lung epithelia is essential for hyperoxia-induced acute lung injury in mice.
OBJECTIVE
Acute lung injury (ALI) induced by excessive hyperoxia has been employed as a model of oxidative stress imitating acute respiratory distress syndrome. Under hyperoxic conditions, overloading quantities of reactive oxygen species (ROS) are generated in both lung epithelial and endothelial cells, leading to ALI. Some NADPH oxidase (NOX) family enzymes are responsible for hyperoxia-induced ROS generation in lung epithelial and endothelial cells. However, the molecular mechanisms of ROS production in type II alveolar epithelial cells (AECs) and ALI induced by hyperoxia are poorly understood.


RESULTS
In this study, we show that dual oxidase 2 (DUOX2) is a key NOX enzyme that affects hyperoxia-induced ROS production, particularly in type II AECs, leading to lung injury. In DUOX2 mutant mice (DUOX2(thyd/thyd)) or mice in which DUOX2 expression is knocked down in the lungs, hyperoxia-induced ALI was significantly lower than in wild-type (WT) mice. DUOX2 was mainly expressed in type II AECs, but not endothelial cells, and hyperoxia-induced ROS production was markedly reduced in primary type II AECs isolated from DUOX2(thyd/thyd) mice. Furthermore, DUOX2-generated ROS are responsible for caspase-mediated cell death, inducing ERK and JNK phophorylation in type II AECs.


METHODS
To date, no role for DUOX2 has been defined in hyperoxia-mediated ALI despite it being a NOX homologue and major ROS source in lung epithelium.


CONCLUSIONS
Here, we present the novel finding that DUOX2-generated ROS induce AEC death, leading to hyperoxia-induced lung injury.
1 Research Center for Natural Human Defense System, Yonsei University College of Medicine , Seoul, South Korea .
Min-Ji
MJ
Kim
Jae-Chan
JC
Ryu
Younghee
Y
Kwon
Suhee
S
Lee
Yun Soo
YS
Bae
Joo-Heon
JH
Yoon
Ji-Hwan
JH
Ryu
D055371:Acute Lung Injury / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D000074623:Dual Oxidases; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D018496:Hyperoxia / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D010766:Phosphorylation / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism
D017382:Reactive Oxygen Species; D000074623:Dual Oxidases; D019255:NADPH Oxidases; C519130:Duox1 protein, mouse; D020169:Caspases