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Pathogenesis of influenza virus-induced pneumonia: involvement of both nitric oxide and oxygen radicals
1Department of Microbiology, Kumamoto University School of Medicine, Japan.
Abstract:
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.
Insights
Nitric oxide (NO) contributes to influenza pneumonia severity in mice by forming peroxynitrite. Inhibiting NO production improved survival without compromising antiviral defenses.
Area of Science:
- Immunology
- Pathology
- Respiratory Medicine
Background:
- Influenza virus infection can lead to severe pneumonia.
- The precise mechanisms underlying influenza-induced lung injury are not fully understood.
- Nitric oxide (NO) is implicated in inflammatory responses but its specific role in influenza pneumonia requires clarification.
Purpose of the Study:
- To investigate the role of nitric oxide (NO) in the pathogenesis of influenza virus-induced pneumonia in mice.
- To determine the source and significance of NO production during influenza infection.
- To evaluate the therapeutic potential of inhibiting NO synthesis.
Main Methods:
- Induction of experimental influenza pneumonia in mice using influenza virus A/Kumamoto/Y5/67(H2N2).
- Measurement of nitric oxide synthase (NOS) activity and inducible NOS (iNOS) mRNA expression.
- Electron spin resonance (ESR) spectroscopy for in vivo NO detection.
- Immunohistochemistry using anti-nitrotyrosine antibody.
- Administration of N(omega)-monomethyl-L-arginine (L-NMMA) to inhibit NO synthesis.
Main Results:
- Increased NOS activity and iNOS mRNA in infected mouse lungs, mediated by interferon gamma.
- Significant in vivo NO generation detected in virus-infected lungs via ESR spectroscopy.
- Evidence of peroxynitrite formation through reaction of NO with superoxide (O2-), indicated by nitrotyrosine staining.
- L-NMMA administration improved survival rates in infected mice without impairing antiviral defenses.
Conclusions:
- Nitric oxide (NO), particularly when forming peroxynitrite with superoxide, is a key pathogenic factor in influenza virus-induced pneumonia in mice.
- Inhibition of NO synthesis represents a potential therapeutic strategy for influenza pneumonia.
- Interferon gamma plays a role in upregulating NO production during influenza infection.