T. Akaike et al., PATHOGENESIS OF INFLUENZA VIRUS-INDUCED PNEUMONIA - INVOLVEMENT OF BOTH NITRIC-OXIDE AND OXYGEN RADICALS, Proceedings of the National Academy of Sciences of the United Statesof America, 93(6), 1996, pp. 2448-2453
The role of nitric oxide (NO) in the pathogenesis of influenza virus-i
nduced pneumonia in mice was investigated, Experimental influenza viru
s pneumonia was produced with influenza virus A/Kumamoto/Y5/67(H2N2).
Both the enzyme activity of NO synthase (NOS) and mRNA expression of t
he inducible NOS were greatly increased in the mouse lungs; increases
were mediated by interferon gamma, Excessive production of NO in the v
irus-infected lung was studied further by using electron spin resonanc
e (ESR) spectroscopy, In vivo spin trapping with dithiocarbamate-iron
complexes indicated that a significant amount of NO was generated in t
he virus-infected lung, Furthermore, an NO-hemoglobin ESR signal appea
red in the virus-infected lung, and formation of NO-hemoglobin was sig
nificantly increased by treatment with superoxide dismutase and was in
hibited by N-omega-monomethyl-L-arginine (L-NMMA) administration, Immu
nohistochemistry with a specific anti-nitrotyrosine antibody showed in
tense staining of alveolar phagocytic cells such as macrophages and ne
utrophils and of intraalveolar exudate in the virus-infected lung, The
se results strongly suggest formation of peroxynitrite in the lung thr
ough the reaction of NO with O-2(-), which is generated by alveolar ph
agocytic 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 defe
nses, On the basis of these data, we conclude that NO together with O-
2(-) which forms more reactive peroxynitrite may be the most important
pathogenic factors in influenza virus-induced pneumonia in mice.