Upregulation of xanthine oxidase by lipopolysaccharide, interleukin-1, and hypoxia. Role in acute lung injury.
LPS and selected cytokines upregulate xanthine dehydrogenase/xanthine oxidase (XDH/XO) in cellular systems. However, the effect of these factors on in vivo XDH/XO expression, and their contribution to lung injury, are poorly understood. Rats were exposed to normoxia or hypoxia for 24 h after treatment with LPS (1 mg/kg) and IL-1beta (100 microg/kg) or sterile saline. Lungs were then harvested for measurement of XDH/XO enzymatic activity and gene expression, and pulmonary edema was assessed by measurement of the wet/dry lung weight ratio (W/D). Although treatment with LPS + IL-1beta or hypoxia independently produced a 2-fold elevation (p < 0. 05 versus exposure to normoxia and treatment with saline) in lung XDH/XO activity and mRNA, the combination of LPS + IL-1beta and hypoxia caused a 4- and 3.5-fold increase in these values, respectively. XDH/XO protein expression was increased 2-fold by hypoxia alone and 1.3-fold by treatment with LPS + IL-1beta alone or combination treatment. Compared with normoxic lungs, W/D was significantly increased by exposure to hypoxia, LPS + IL-1beta, or combination treatment. This increase was prevented by treatment of the animals with tungsten, which abrogated lung XDH/XO activity. In conclusion, LPS, IL-1beta, and hypoxia significantly upregulate lung XDH/XO expression in vivo. The present data support a role for this enzyme in the pathogenesis of acute lung injury.
Hassoun
P M
PM
Department of Medicine, Pulmonary and Critical Care Division and Tupper Research Institute, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA. paul.hassoun@es.nemc.org
Yu
F S
FS
Cote
C G
CG
Zulueta
J J
JJ
Sawhney
R
R
Skinner
K A
KA
Skinner
H B
HB
Parks
D A
DA
Lanzillo
J J
JJ
D000818:Animals; D015153:Blotting, Western; D000860:Hypoxia / Q000503:physiopathology*; D007375:Interleukin-1 / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D008297:Male; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation; D014969:Xanthine Oxidase / Q000378:metabolism*
D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014969:Xanthine Oxidase