Dependence on O2- generation by xanthine oxidase of pathogenesis of influenza virus infection in mice.

Abstract

We evaluated various biochemical parameters in influenza virus-infected mice and focused on adenosine catabolism in the supernatant of bronchoalveolar lavage fluid (s-BALF), lung tissue, and serum (plasma). The activities of adenosine deaminase (ADA) and xanthine oxidase (XO), which generates O2 were elevated in the s-BALF, lung tissue homogenate, and serum (plasma). The elevations were most remarkable in s-BALF and in lung tissue: We found a 170-fold increase in ADA activity and a 400-fold increase in XO activity as measured per volume of alveolar lavage fluid. The ratio of activity of XO to activity of xanthine dehydrogenase in s-BALF increased from 0.15±0.05 (control; no infection) to 1.06±0.13 on day 6 after viral infection. Increased levels of various adenosine catabolites (i.e., inosine, hypoxanthine, xanthine, and uric acid) in serum and s-BALF were confirmed. We also identified 02 generation from XO in s-BALF obtained on days 6 and 8 after infection, and the generation of°2 was enhanced remarkably in the presence of adenosine. Lastly, treatment with allopurinol (an inhibitor of XO) and with chemically modified superoxide dismutase (a scavenger of O°) improved the survival rate of influenza virus-infected mice. These results indicate that generation of oxygen-free radicals by XO, coupled with catabolic supply of hypoxanthine from adenosine catabolism, is a pathogenic principle in influenza virus infection in mice and that a therapeutic approach by elhimination of oxygen radicals thus seems possible. (J. Clin. Invest. 1990.85:739-745.) viral pathogenesis -free radicals * xanthine oxidase * SOD

N-acetyl-l-cysteine (NAC) inhibit mucin synthesis and pro-inflammatory mediators in alveolar type II epithelial cells infected with influenza virus A and B and with respiratory syncytial virus (RSV)

“…The mechanisms used by respiratory viruses to cause exacerbations remain under investigation. Some studies support the role of Reactive Oxygen Intermediates (ROIs) as mediators of virus induced epithelial damage in influenza infected mice [8]. The source of these oxidants may be leukocytes, xanthine oxidase, which is increased in influenza-M a n u s c r i p t 4 infected lungs [8], or lung epithelial cells themselves [9,10].…”

“…Some studies support the role of Reactive Oxygen Intermediates (ROIs) as mediators of virus induced epithelial damage in influenza infected mice [8]. The source of these oxidants may be leukocytes, xanthine oxidase, which is increased in influenza-M a n u s c r i p t 4 infected lungs [8], or lung epithelial cells themselves [9,10]. Oxidative stress is one of the components of the pathophysiology of COPD [11].…”

Cloning of the cDNAs Coding for Two Novel Molybdo-flavoproteins Showing High Similarity with Aldehyde Oxidase and Xanthine Oxidoreductase

“…XOR is the key enzyme in the catabolism of purines oxidizing hypoxanthine to xanthine and xanthine to uric acid, although the physiological function of this protein may be more complex than anticipated (23,24). Because of its ability to produce toxic superoxide anions, the oxidase form of XOR (25) has been implicated as a possible mediator of tissue damage in a number of pathological situations, such as ischemia (26), inflammation (27), and infection (28). AO is much less studied, and a physiological substrate for the enzyme has not yet been established, although there are reports indicating that the enzyme oxidizes retinaldehyde into retinoic acid (29) and is involved in the catabolism of the monoamine neurotransmitters (30).…”

Cerebral Oxidative Stress and Mitochondrial Dysfunction in Oxonate-Induced Hyperuricemic Mice

“…---Measurement of uric acid concentration in deproteinized plasma of mouse blood was carried out by the use of Hitachi HPLC apparatus (pump, L-6000; UV detector, L-4000; chromatointegrator, D-2500; Hitachi Co., Tokyo, Japan) according to the method of Akaike et al 16) Detection limit of uric acid in this method was 1 µM or more. Measurement of Antioxidant Enzyme Activities ---Cumene hydroperoxide was used as the substrate to eliminate the effect of catalase contamination in the sample solution on the measurement of GPx activity in cerebrum.…”