• Kazuma Yagi, Makoto Ishii, Ho Namkoong, Hideki Fujii, Takahiro Asami, Shoji Suzuki, Takanori Asakura, Kosuke Mizoguchi, Tetsuro Kamo, Sadatomo Tasaka, Satoshi Iwata, Steven L Kunkel, Naoki Hasegawa, and Tomoko Betsuyaku.
• 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.
• Crit. Care Med. 2016 Oct 1; 44 (10): e980-7.

ObjectivesSecondary 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.DesignProspective experimental study.SettingUniversity research laboratory.SubjectsC57BL/6 male mice.InterventionsMice 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.Measurements And Main ResultsTrichostatin 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.ConclusionsThe 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.

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