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-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.