title: Pneumococcal Infection Aggravates Elastase-Induced Emphysema via Matrix Metalloproteinase 12 Overexpression.
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.
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine.
authors.forename: Saeko
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ishii
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine.
authors.forename: Ho
authors.initials: H
authors.lastname: Namkoong
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine.
authors.forename: Ahmed E
authors.initials: AE
authors.lastname: Hegab
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Asami
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Yagi
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Sasaki
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine.
authors.forename: Mizuha
authors.initials: M
authors.lastname: Haraguchi
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine.
authors.forename: Minako
authors.initials: M
authors.lastname: Sato
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine.
authors.forename: Naofumi
authors.initials: N
authors.lastname: Kameyama
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine.
authors.forename: Takanori
authors.initials: T
authors.lastname: Asakura
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine.
authors.forename: Shoji
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine.
authors.forename: Sadatomo
authors.initials: S
authors.lastname: Tasaka
authors.affiliation: Department of Infectious Diseases Center for Infectious Disease and Infection Control, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Iwata
authors.affiliation: Center for Infectious Disease and Infection Control, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Hasegawa
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Betsuyaku
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000627:therapeutic use; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D008214:Lymphocytes / Q000502:physiology; D008264:Macrophages / Q000502:physiology; D053508:Matrix Metalloproteinase 12 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000502:physiology; D010196:Pancreatic Elastase / Q000633:toxicity*; D010647:Phenyl Ethers / Q000494:pharmacology; D011008:Pneumococcal Infections / Q000150:complications* / Q000378:metabolism; D011656:Pulmonary Emphysema / Q000139:chemically induced* / Q000150:complications / Q000473:pathology; D013296:Streptococcus pneumoniae
chemical_list: D016207:Cytokines; C414368:N-hydroxy-5-ethoxymethyloxy-2-methyl-4-(4-phenoxybenzoyl)aminopentanamide; D010647:Phenyl Ethers; D003907:Dexamethasone; D010196:Pancreatic Elastase; D053508:Matrix Metalloproteinase 12
keywords: MMP inhibitor; Streptococcus pneumoniae; chronic obstructive pulmonary disease exacerbation; matrix metalloproteinase-12