Pathogenesis of influenza virus-induced pneumonia: involvement of both nitric oxide and oxygen radicals.
The role of nitric oxide (NO) in the pathogenesis of influenza virus-induced pneumonia in mice was investigated. Experimental influenza virus pneumonia was produced with influenza virus A/Kumamoto/Y5/67(H2N2). Both the enzyme activity of NO synthase (NOS) and mRNA expression of the inducible NOS were greatly increased in the mouse lungs; increases were mediated by interferon gamma. Excessive production of NO in the virus-infected lung was studied further by using electron spin resonance (ESR) spectroscopy. In vivo spin trapping with dithiocarbamate-iron complexes indicated that a significant amount of NO was generated in the virus-infected lung. Furthermore, an NO-hemoglobin ESR signal appeared in the virus-infected lung, and formation of NO-hemoglobin was significantly increased by treatment with superoxide dismutase and was inhibited by N(omega)-monomethyl-L-arginine (L-NMMA) administration. Immunohistochemistry with a specific anti-nitrotyrosine antibody showed intense staining of alveolar phagocytic cells such as macrophages and neutrophils and of intraalveolar exudate in the virus-infected lung. These results strongly suggest formation of peroxynitrite in the lung through the reaction of NO with O2-, which is generated by alveolar phagocytic cells and xanthine oxidase. In addition, administration of L-NMMA resulted in significant improvement in the survival rate of virus-infected mice without appreciable suppression of their antiviral defenses. On the basis of these data, we conclude that NO together with O2- which forms more reactive peroxynitrite may be the most important pathogenic factors in influenza virus-induced pneumonia in mice.
Akaike
T
T
Department of Microbiology, Kumamoto University School of Medicine, Japan.
Noguchi
Y
Y
Ijiri
S
S
Setoguchi
K
K
Suga
M
M
Zheng
Y M
YM
Dietzschold
B
B
Maeda
H
H
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D004578:Electron Spin Resonance Spectroscopy; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005609:Free Radicals; D009980:Influenza A virus / Q000472:pathogenicity; D007371:Interferon-gamma / Q000502:physiology; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011024:Pneumonia, Viral / Q000503:physiopathology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D019323:omega-N-Methylarginine
D004791:Enzyme Inhibitors; D005609:Free Radicals; D017382:Reactive Oxygen Species; D013481:Superoxides; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D007371:Interferon-gamma; D001120:Arginine; D019001:Nitric Oxide Synthase