Dependence on O2- generation by xanthine oxidase of pathogenesis of influenza virus infection in mice.
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 O2- generation from XO in s-BALF obtained on days 6 and 8 after infection, and the generation of O2- 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 O2-) 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 elimination of oxygen radicals thus seems possible.
Akaike
T
T
Department of Microbiology, Kumamoto University, Japan.
Ando
M
M
Oda
T
T
Doi
T
T
Ijiri
S
S
Araki
S
S
Maeda
H
H
D000241:Adenosine / Q000378:metabolism; D000243:Adenosine Deaminase / Q000032:analysis; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000378:metabolism; D008297:Male; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000209:etiology* / Q000378:metabolism; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*; D014779:Virus Replication; D014969:Xanthine Oxidase / Q000032:analysis / Q000502:physiology*
D013481:Superoxides; D000493:Allopurinol; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase; D000243:Adenosine Deaminase; D000241:Adenosine