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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

Premedication with Clarithromycin Is Effective against Secondary Bacterial Pneumonia during Influenza Virus Infection in a Pulmonary Emphysema Mouse Model

Tatsuhiko Harada, Yuji Ishimatsu, Atsuko Hara, Towako Morita, Shota Nakashima, Tomoyuki Kakugawa, Noriho Sakamoto, Kosuke Kosai, Koichi Izumikawa, Katsunori Yanagihara, Hiroshi Mukae and Shigeru Kohno
Journal of Pharmacology and Experimental Therapeutics September 2016, 358 (3) 457-463; DOI: https://doi.org/10.1124/jpet.116.233932
Tatsuhiko Harada
Department of Infectious Diseases, Unit of Molecular Microbiology and Immunology (T.H., K.I.), Department of Cardiopulmonary Rehabilitation Sciences (Y.I.), Department of Respiratory Medicine (N.S., H.M.), and Department of Laboratory Medicine (K.K, K.Y.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan (T.H., A.H., T.M., S.N., T.K., N.S., H.M., S.K.)
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Yuji Ishimatsu
Department of Infectious Diseases, Unit of Molecular Microbiology and Immunology (T.H., K.I.), Department of Cardiopulmonary Rehabilitation Sciences (Y.I.), Department of Respiratory Medicine (N.S., H.M.), and Department of Laboratory Medicine (K.K, K.Y.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan (T.H., A.H., T.M., S.N., T.K., N.S., H.M., S.K.)
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Atsuko Hara
Department of Infectious Diseases, Unit of Molecular Microbiology and Immunology (T.H., K.I.), Department of Cardiopulmonary Rehabilitation Sciences (Y.I.), Department of Respiratory Medicine (N.S., H.M.), and Department of Laboratory Medicine (K.K, K.Y.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan (T.H., A.H., T.M., S.N., T.K., N.S., H.M., S.K.)
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Towako Morita
Department of Infectious Diseases, Unit of Molecular Microbiology and Immunology (T.H., K.I.), Department of Cardiopulmonary Rehabilitation Sciences (Y.I.), Department of Respiratory Medicine (N.S., H.M.), and Department of Laboratory Medicine (K.K, K.Y.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan (T.H., A.H., T.M., S.N., T.K., N.S., H.M., S.K.)
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Shota Nakashima
Department of Infectious Diseases, Unit of Molecular Microbiology and Immunology (T.H., K.I.), Department of Cardiopulmonary Rehabilitation Sciences (Y.I.), Department of Respiratory Medicine (N.S., H.M.), and Department of Laboratory Medicine (K.K, K.Y.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan (T.H., A.H., T.M., S.N., T.K., N.S., H.M., S.K.)
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Tomoyuki Kakugawa
Department of Infectious Diseases, Unit of Molecular Microbiology and Immunology (T.H., K.I.), Department of Cardiopulmonary Rehabilitation Sciences (Y.I.), Department of Respiratory Medicine (N.S., H.M.), and Department of Laboratory Medicine (K.K, K.Y.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan (T.H., A.H., T.M., S.N., T.K., N.S., H.M., S.K.)
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Noriho Sakamoto
Department of Infectious Diseases, Unit of Molecular Microbiology and Immunology (T.H., K.I.), Department of Cardiopulmonary Rehabilitation Sciences (Y.I.), Department of Respiratory Medicine (N.S., H.M.), and Department of Laboratory Medicine (K.K, K.Y.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan (T.H., A.H., T.M., S.N., T.K., N.S., H.M., S.K.)
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Kosuke Kosai
Department of Infectious Diseases, Unit of Molecular Microbiology and Immunology (T.H., K.I.), Department of Cardiopulmonary Rehabilitation Sciences (Y.I.), Department of Respiratory Medicine (N.S., H.M.), and Department of Laboratory Medicine (K.K, K.Y.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan (T.H., A.H., T.M., S.N., T.K., N.S., H.M., S.K.)
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Koichi Izumikawa
Department of Infectious Diseases, Unit of Molecular Microbiology and Immunology (T.H., K.I.), Department of Cardiopulmonary Rehabilitation Sciences (Y.I.), Department of Respiratory Medicine (N.S., H.M.), and Department of Laboratory Medicine (K.K, K.Y.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan (T.H., A.H., T.M., S.N., T.K., N.S., H.M., S.K.)
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Katsunori Yanagihara
Department of Infectious Diseases, Unit of Molecular Microbiology and Immunology (T.H., K.I.), Department of Cardiopulmonary Rehabilitation Sciences (Y.I.), Department of Respiratory Medicine (N.S., H.M.), and Department of Laboratory Medicine (K.K, K.Y.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan (T.H., A.H., T.M., S.N., T.K., N.S., H.M., S.K.)
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Hiroshi Mukae
Department of Infectious Diseases, Unit of Molecular Microbiology and Immunology (T.H., K.I.), Department of Cardiopulmonary Rehabilitation Sciences (Y.I.), Department of Respiratory Medicine (N.S., H.M.), and Department of Laboratory Medicine (K.K, K.Y.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan (T.H., A.H., T.M., S.N., T.K., N.S., H.M., S.K.)
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Shigeru Kohno
Department of Infectious Diseases, Unit of Molecular Microbiology and Immunology (T.H., K.I.), Department of Cardiopulmonary Rehabilitation Sciences (Y.I.), Department of Respiratory Medicine (N.S., H.M.), and Department of Laboratory Medicine (K.K, K.Y.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan (T.H., A.H., T.M., S.N., T.K., N.S., H.M., S.K.)
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Abstract

Secondary bacterial pneumonia (SBP) during influenza increases the severity of chronic obstructive pulmonary disease (COPD) and its associated mortality. Macrolide antibiotics, including clarithromycin (CAM), are potential treatments for a variety of chronic respiratory diseases owing to their pharmacological activities, in addition to antimicrobial action. We examined the efficacy of CAM for the treatment of SBP after influenza infection in COPD. Specifically, we evaluated the effect of CAM in elastase-induced emphysema mice that were inoculated with influenza virus (strain A/PR8/34) and subsequently infected with macrolide-resistant Streptococcus pneumoniae. CAM was administered to the emphysema mice 4 days prior to influenza virus inoculation. Premedication with CAM improved pathologic responses and bacterial load 2 days after S. pneumoniae inoculation. Survival rates were higher in emphysema mice than control mice. While CAM premedication did not affect viral titers or exert antibacterial activity against S. pneumoniae in the lungs, it enhanced host defense and reduced inflammation, as evidenced by the significant reductions in total cell and neutrophil counts and interferon (IFN)-γ levels in bronchoalveolar lavage fluid and lung homogenates. These results suggest that CAM protects against SBP during influenza in elastase-induced emphysema mice by reducing IFN-γ production, thus enhancing immunity to SBP, and by decreasing neutrophil infiltration into the lung to prevent injury. Accordingly, CAM may be an effective strategy to prevent secondary bacterial pneumonia in COPD patients in areas in which vaccines are inaccessible or limited.

Footnotes

    • Received March 28, 2016.
    • Accepted July 6, 2016.
  • This work was supported by Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research (KAKENHI) (Grant No. 23791139].

  • dx.doi.org/10.1124/jpet.116.233932.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 358 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 358, Issue 3
1 Sep 2016
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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

Effect of CAM on SBP during Influenza in Emphysema Mice

Tatsuhiko Harada, Yuji Ishimatsu, Atsuko Hara, Towako Morita, Shota Nakashima, Tomoyuki Kakugawa, Noriho Sakamoto, Kosuke Kosai, Koichi Izumikawa, Katsunori Yanagihara, Hiroshi Mukae and Shigeru Kohno
Journal of Pharmacology and Experimental Therapeutics September 1, 2016, 358 (3) 457-463; DOI: https://doi.org/10.1124/jpet.116.233932

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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

Effect of CAM on SBP during Influenza in Emphysema Mice

Tatsuhiko Harada, Yuji Ishimatsu, Atsuko Hara, Towako Morita, Shota Nakashima, Tomoyuki Kakugawa, Noriho Sakamoto, Kosuke Kosai, Koichi Izumikawa, Katsunori Yanagihara, Hiroshi Mukae and Shigeru Kohno
Journal of Pharmacology and Experimental Therapeutics September 1, 2016, 358 (3) 457-463; DOI: https://doi.org/10.1124/jpet.116.233932
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