UP-REGULATION 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 fac tors on in vivo XDH/XO expression, and their contribution to lung inju ry, are poorly understood. Rats were exposed to normoxia or hypoxia fo r 24 h after treatment with LPS (1 mg/kg) and IL-1 beta (100 mu g/kg) or sterile saline. Lungs were then harvested for measurement of XDH/XO enzymatic activity and gene expression, and pulmonary edema was asses sed by measurement of the wet/dry lung weight ratio (W/D). Although tr eatment with LPS + IL-1 beta or hypoxia independently produced a 2-fol d elevation (p < 0.05 versus exposure to normoxia and treatment with s aline) in lung XDH/XO activity and mRNA, the combination of LPS + IL-1 beta and hypoxia caused a 4- and 3.5-fold increase in these values, r espectively. XDH/XO protein expression was increased 2-fold by hypoxia alone and 1.3-fold by treatment with LPS + IL-1 beta alone or combina tion treatment. Compared with normoxic lungs, W/D was significantly in creased by exposure to hypoxia, LPS + IL-1 beta, or combination treatm ent. This increase was prevented by treatment of the animals with tung sten, which abrogated lung XDH/XO activity. In conclusion, LPS, IL-1 b eta, and hypoxia significantly upregulate lung XDH/XO expression in vi vo. The present data support a role for this enzyme in the pathogenesi s of acute lung injury.