Am. J. Respir. Crit. Care Med., Volume 158, Number 1, July 1998, 299-305

Upregulation of Xanthine Oxidase by Lipopolysaccharide, Interleukin-1, and Hypoxia
Role in Acute Lung Injury

PAUL M. HASSOUN, FENG-SHENG YU, CLAUDIA G. COTE, JAVIER J. ZULUETA, RANEETA SAWHNEY, KELLY A. SKINNER, HENRY B. SKINNER, DALE A. PARKS, and JOSEPH J. LANZILLO

Department of Medicine, Pulmonary and Critical Care Division and Tupper Research Institute, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts; and Departments of Anesthesiology, Physiology and Biophysics, and Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama

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-1 (100 µg/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-1 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-1 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-1 alone or combination treatment. Compared with normoxic lungs, W/D was significantly increased by exposure to hypoxia, LPS + IL-1, 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, 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.

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