Pathogenesis of influenza virus-induced pneumonia: involvement of both nitric oxide and oxygen radicals

Proc Natl Acad Sci U S A. 1996 Mar 19;93(6):2448-53. doi: 10.1073/pnas.93.6.2448.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginine / analogs & derivatives
  • Arginine / pharmacology
  • Electron Spin Resonance Spectroscopy
  • Enzyme Induction
  • Enzyme Inhibitors / pharmacology
  • Free Radicals
  • Influenza A virus / pathogenicity
  • Interferon-gamma / physiology
  • Lung / metabolism
  • Male
  • Mice
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitric Oxide Synthase / biosynthesis
  • Pneumonia, Viral / physiopathology*
  • Reactive Oxygen Species / metabolism*
  • Superoxides / metabolism
  • omega-N-Methylarginine


  • Enzyme Inhibitors
  • Free Radicals
  • Reactive Oxygen Species
  • Superoxides
  • omega-N-Methylarginine
  • Nitric Oxide
  • Interferon-gamma
  • Arginine
  • Nitric Oxide Synthase