Published ahead of print on September 25, 2003, doi:10.1165/rcmb.2003-0309OC
© 2004 American Thoracic Society DOI: 10.1165/rcmb.2003-0309OC Mononuclear Phagocyte Xanthine Oxidoreductase Contributes to Cytokine-Induced Acute Lung InjuryWebb-Waring Institute for Cancer, Aging and Antioxidant Research; School of Medicine, Department of Pulmonary Sciences; and Department of Physiology and Biophysics, University of Colorado Health Sciences Center, Denver, Colorado Address correspondence to: Dr. Richard M. Wright, Webb-Waring Institute, Campus Box C-322, 4200 East 9th Ave. Denver, CO 80262. E-mail: richard.m.wright{at}uchsc.edu Acute lung injury (ALI) is characterized by increased alveolar cytokines, inflammatory cell infiltration, oxidative stress, and alveolar cell apoptosis. Previous work suggested that xanthine oxidoreductase (XOR) may contribute to oxidative stress in ALI as a product of the vascular endothelial cell. We present evidence that cytokine induced lung inflammation and injury involves activation of XOR in the newly recruited mononuclear phagocytes (MNP). We found that XOR was increased predominantly in the MNP that increase rapidly in the lungs of rats that develop ALI following intratracheal cytokine insufflation. XOR was recovered from the MNP largely converted to its oxygen radical generating, reversible O-form, and alveolar MNP exhibited increased oxidative stress as evidenced by increased nitrotyrosine staining. Cytokine insufflation also increased alveolar cell apoptosis. A functional role for XOR in cytokine-induced inflammation was demonstrated when feeding rats two different XOR inhibitors, tungsten and allopurinol, decreased MNP XOR induction, nitrotyrosine staining, inflammatory cell infiltration, and alveolar cell apoptosis. Transfer of control or allopurinol treated MNP into rat lungs confirmed a specific role for MNP XOR in promoting lung inflammation. These data indicate that XOR can contribute to lung inflammation by its expression and conversion in a highly mobile inflammatory cell population.
Abbreviations: acute lung injury, ALI • bronchoalveolar lavage fluid, BALF • fluorescence-activated cell sorter, FACS • interferon- This article has been cited by other articles:
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