Upregulation of Xanthine Oxidase by Lipopolysaccharide, Interleukin-1, and Hypoxia

Abstract

LPS and selected cytokines upregulate xanthine dehydrogenase/xanthine oxidase (XDH/XO) in cellu- lar systems. However, the effect of these factors on in vivo XDH/XO expression, and their contribu- tion 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-1 b (100 m g/kg) or sterile saline. Lungs were then harvested for measurement of XDH/XO enzymatic activity and gene expression, and pulmonary edema was as- sessed by measurement of the wet/dry lung weight ratio (W/D). Although treatment with LPS 1 IL-1 b 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 1 IL-1 b and hy- poxia 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 1 IL-1 b alone or combination treatment. Compared with normoxic lungs, W/D was significantly increased by exposure to hypoxia, LPS 1 IL-1 b , or combination treatment. This increase was prevented by treatment of the animals with tungsten, which abrogated lung XDH/XO activity. In conclusion, LPS, IL-1 b , 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 PM, Yu F-S, Cote CG, Zulueta JJ, Sawhney R, Skinner KA, Skinner HB, Parks DA, Lanzillo JJ. Upregulation of xanthine oxidase by lipopolysaccha- ride, interleukin-1, and hypoxia: role in acute lung injury. AM J RESPIR CRIT CARE MED 1998;158:299-305.