Pneumococcal Infection Aggravates Elastase-Induced Emphysema via Matrix Metalloproteinase 12 Overexpression

Saeko Takahashi, Makoto Ishii, Ho Namkoong, Ahmed E. Hegab, Takahiro Asami, Kazuma Yagi, Mamoru Sasaki, Mizuha Haraguchi, Minako Sato, Naofumi Kameyama, Takanori Asakura, Shoji Suzuki, Sadatomo Tasaka, Satoshi Iwata, Naoki Hasegawa, Tomoko Betsuyaku

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background. Acute exacerbation of chronic obstructive pulmonary disease (COPD) - typically caused by bacterial or viral infection - is associated with poor prognosis and emphysema progression through unknown mechanisms. We aimed to elucidate the mechanisms responsible for the poor prognosis and emphysema progression associated with COPD exacerbation. Methods. We established a mouse model mimicking acute human COPD exacerbation, wherein mice with elastase-induced emphysema were intranasally infected with Streptococcus pneumoniae. Results. In mice with elastase-induced emphysema, infection with S. pneumoniae resulted in increased mortality, an increased number of inflammatory cells in bronchoalveolar lavage fluid (BALF), and increased matrix metalloproteinase 12 (MMP-12) production in the lungs, as well as enhanced emphysema progression. The increased MMP-12 production was mostly due to alveolar type II cells, alveolar macrophages, and lymphocytes that aggregated around vessels and bronchioles. Dexamethasone treatment suppressed the mortality rate and number of inflammatory cells in BALF but not emphysema progression, possibly owing to the failure of MMP-12 suppression in the lungs, whereas treatment with the MMP inhibitor ONO-4817 dramatically suppressed both mortality rate and emphysema progression. Conclusions. These results suggest that MMP-12 production during COPD exacerbation results in increased mortality and emphysema progression. Our study identifies MMP-12 as a target to prevent further aggravation of COPD.

Original languageEnglish
Pages (from-to)1018-1030
Number of pages13
JournalJournal of Infectious Diseases
Volume213
Issue number6
DOIs
Publication statusPublished - 2016 Mar 15

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Matrix Metalloproteinase 12
Pneumococcal Infections
Pancreatic Elastase
Emphysema
Chronic Obstructive Pulmonary Disease
Disease Progression
Mortality
Bronchoalveolar Lavage Fluid
Cell Count
Alveolar Epithelial Cells
Bronchioles
Lung
Matrix Metalloproteinase Inhibitors
Alveolar Macrophages
Virus Diseases
Streptococcus pneumoniae
Bacterial Infections
Dexamethasone
Lymphocytes

Keywords

  • chronic obstructive pulmonary disease exacerbation
  • matrix metalloproteinase-12
  • MMP inhibitor
  • Streptococcus pneumoniae

ASJC Scopus subject areas

  • Infectious Diseases
  • Immunology and Allergy

Cite this

Pneumococcal Infection Aggravates Elastase-Induced Emphysema via Matrix Metalloproteinase 12 Overexpression. / Takahashi, Saeko; Ishii, Makoto; Namkoong, Ho; Hegab, Ahmed E.; Asami, Takahiro; Yagi, Kazuma; Sasaki, Mamoru; Haraguchi, Mizuha; Sato, Minako; Kameyama, Naofumi; Asakura, Takanori; Suzuki, Shoji; Tasaka, Sadatomo; Iwata, Satoshi; Hasegawa, Naoki; Betsuyaku, Tomoko.

In: Journal of Infectious Diseases, Vol. 213, No. 6, 15.03.2016, p. 1018-1030.

Research output: Contribution to journalArticle

Takahashi, S, Ishii, M, Namkoong, H, Hegab, AE, Asami, T, Yagi, K, Sasaki, M, Haraguchi, M, Sato, M, Kameyama, N, Asakura, T, Suzuki, S, Tasaka, S, Iwata, S, Hasegawa, N & Betsuyaku, T 2016, 'Pneumococcal Infection Aggravates Elastase-Induced Emphysema via Matrix Metalloproteinase 12 Overexpression', Journal of Infectious Diseases, vol. 213, no. 6, pp. 1018-1030. https://doi.org/10.1093/infdis/jiv527
Takahashi, Saeko ; Ishii, Makoto ; Namkoong, Ho ; Hegab, Ahmed E. ; Asami, Takahiro ; Yagi, Kazuma ; Sasaki, Mamoru ; Haraguchi, Mizuha ; Sato, Minako ; Kameyama, Naofumi ; Asakura, Takanori ; Suzuki, Shoji ; Tasaka, Sadatomo ; Iwata, Satoshi ; Hasegawa, Naoki ; Betsuyaku, Tomoko. / Pneumococcal Infection Aggravates Elastase-Induced Emphysema via Matrix Metalloproteinase 12 Overexpression. In: Journal of Infectious Diseases. 2016 ; Vol. 213, No. 6. pp. 1018-1030.
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abstract = "Background. Acute exacerbation of chronic obstructive pulmonary disease (COPD) - typically caused by bacterial or viral infection - is associated with poor prognosis and emphysema progression through unknown mechanisms. We aimed to elucidate the mechanisms responsible for the poor prognosis and emphysema progression associated with COPD exacerbation. Methods. We established a mouse model mimicking acute human COPD exacerbation, wherein mice with elastase-induced emphysema were intranasally infected with Streptococcus pneumoniae. Results. In mice with elastase-induced emphysema, infection with S. pneumoniae resulted in increased mortality, an increased number of inflammatory cells in bronchoalveolar lavage fluid (BALF), and increased matrix metalloproteinase 12 (MMP-12) production in the lungs, as well as enhanced emphysema progression. The increased MMP-12 production was mostly due to alveolar type II cells, alveolar macrophages, and lymphocytes that aggregated around vessels and bronchioles. Dexamethasone treatment suppressed the mortality rate and number of inflammatory cells in BALF but not emphysema progression, possibly owing to the failure of MMP-12 suppression in the lungs, whereas treatment with the MMP inhibitor ONO-4817 dramatically suppressed both mortality rate and emphysema progression. Conclusions. These results suggest that MMP-12 production during COPD exacerbation results in increased mortality and emphysema progression. Our study identifies MMP-12 as a target to prevent further aggravation of COPD.",
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AU - Hegab, Ahmed E.

AU - Asami, Takahiro

AU - Yagi, Kazuma

AU - Sasaki, Mamoru

AU - Haraguchi, Mizuha

AU - Sato, Minako

AU - Kameyama, Naofumi

AU - Asakura, Takanori

AU - Suzuki, Shoji

AU - Tasaka, Sadatomo

AU - Iwata, Satoshi

AU - Hasegawa, Naoki

AU - Betsuyaku, Tomoko

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N2 - Background. Acute exacerbation of chronic obstructive pulmonary disease (COPD) - typically caused by bacterial or viral infection - is associated with poor prognosis and emphysema progression through unknown mechanisms. We aimed to elucidate the mechanisms responsible for the poor prognosis and emphysema progression associated with COPD exacerbation. Methods. We established a mouse model mimicking acute human COPD exacerbation, wherein mice with elastase-induced emphysema were intranasally infected with Streptococcus pneumoniae. Results. In mice with elastase-induced emphysema, infection with S. pneumoniae resulted in increased mortality, an increased number of inflammatory cells in bronchoalveolar lavage fluid (BALF), and increased matrix metalloproteinase 12 (MMP-12) production in the lungs, as well as enhanced emphysema progression. The increased MMP-12 production was mostly due to alveolar type II cells, alveolar macrophages, and lymphocytes that aggregated around vessels and bronchioles. Dexamethasone treatment suppressed the mortality rate and number of inflammatory cells in BALF but not emphysema progression, possibly owing to the failure of MMP-12 suppression in the lungs, whereas treatment with the MMP inhibitor ONO-4817 dramatically suppressed both mortality rate and emphysema progression. Conclusions. These results suggest that MMP-12 production during COPD exacerbation results in increased mortality and emphysema progression. Our study identifies MMP-12 as a target to prevent further aggravation of COPD.

AB - Background. Acute exacerbation of chronic obstructive pulmonary disease (COPD) - typically caused by bacterial or viral infection - is associated with poor prognosis and emphysema progression through unknown mechanisms. We aimed to elucidate the mechanisms responsible for the poor prognosis and emphysema progression associated with COPD exacerbation. Methods. We established a mouse model mimicking acute human COPD exacerbation, wherein mice with elastase-induced emphysema were intranasally infected with Streptococcus pneumoniae. Results. In mice with elastase-induced emphysema, infection with S. pneumoniae resulted in increased mortality, an increased number of inflammatory cells in bronchoalveolar lavage fluid (BALF), and increased matrix metalloproteinase 12 (MMP-12) production in the lungs, as well as enhanced emphysema progression. The increased MMP-12 production was mostly due to alveolar type II cells, alveolar macrophages, and lymphocytes that aggregated around vessels and bronchioles. Dexamethasone treatment suppressed the mortality rate and number of inflammatory cells in BALF but not emphysema progression, possibly owing to the failure of MMP-12 suppression in the lungs, whereas treatment with the MMP inhibitor ONO-4817 dramatically suppressed both mortality rate and emphysema progression. Conclusions. These results suggest that MMP-12 production during COPD exacerbation results in increased mortality and emphysema progression. Our study identifies MMP-12 as a target to prevent further aggravation of COPD.

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