title: Histone Deacetylase Inhibition Protects Mice Against Lethal Postinfluenza Pneumococcal Infection.
abstract: Secondary bacterial pneumonia following influenza virus infection is associated with high mortality, but the mechanism is largely unknown. Epigenetic gene regulation appears to play key roles in innate and adaptive immunity. We hypothesized that histone acetylation, a major epigenetic mechanism associated with transcriptionally active chromatin, might contribute to the poor outcome of postinfluenza pneumonia.
  
  
  
  Prospective experimental study.
  
  
  
  University research laboratory.
  
  
  
  C57BL/6 male mice.
  
  
  
  Mice were infected intranasally with 1.0 × 10 colony-forming units of Streptococcus pneumoniae, 7 days after intranasal inoculation with five plaque-forming units of influenza virus A/H1N1/PR8/34. The mice were intraperitoneally injected with the histone deacetylase inhibitor trichostatin A (1 mg/kg) or vehicle once a day from 1 hour after pneumococcal infection throughout the course of the experiment. The primary outcome was survival rate.
  
  
  
  Trichostatin A significantly suppressed histone deacetylase activity and significantly improved the survival rate of mice (56.3%) after postinfluenza pneumococcal infection when compared with vehicle-treated mice (20.0%), which was associated with a significant decrease in the total cell count of the bronchoalveolar lavage fluid. The interleukin-1β level in the serum and the number of natural killer cells in the lungs were significantly lower in the trichostatin A-treated group.
  
  
  
  The histone deacetylase inhibitor trichostatin A protects mice against postinfluenza pneumonia possibly through multiple factors, including decreasing local cell recruitment into the lungs and suppressing systemic inflammation.
authors.affiliation: 1Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.2Department of Immunology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.3Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan.4Department of Infectious Diseases, Keio University School of Medicine, Tokyo, Japan.5Center for Infectious Diseases and Infection Control, Keio University School of Medicine, Tokyo, Japan.6Department of Pathology, University of Michigan Medical School, Ann Arbor, MI.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Yagi
authors.forename: Makoto
authors.initials: M
authors.lastname: Ishii
authors.forename: Ho
authors.initials: H
authors.lastname: Namkoong
authors.forename: Hideki
authors.initials: H
authors.lastname: Fujii
authors.forename: Takahiro
authors.initials: T
authors.lastname: Asami
authors.forename: Shoji
authors.initials: S
authors.lastname: Suzuki
authors.forename: Takanori
authors.initials: T
authors.lastname: Asakura
authors.forename: Kosuke
authors.initials: K
authors.lastname: Mizoguchi
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Kamo
authors.forename: Sadatomo
authors.initials: S
authors.lastname: Tasaka
authors.forename: Satoshi
authors.initials: S
authors.lastname: Iwata
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kunkel
authors.forename: Naoki
authors.initials: N
authors.lastname: Hasegawa
authors.forename: Tomoko
authors.initials: T
authors.lastname: Betsuyaku
mesh_terms: D000818:Animals; D058491:Bacterial Load; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016207:Cytokines / Q000096:biosynthesis; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D053118:Influenza A Virus, H1N1 Subtype; D007251:Influenza, Human / Q000150:complications*; D053583:Interleukin-1beta / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000378:metabolism; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011018:Pneumonia, Pneumococcal / Q000150:complications* / Q000473:pathology; D011446:Prospective Studies
chemical_list: D016207:Cytokines; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D053583:Interleukin-1beta; C012589:trichostatin A