Histone Deacetylase Inhibition Protects Mice Against Lethal Postinfluenza Pneumococcal Infection

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, Tomoko Betsuyaku

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

OBJECTIVES:: 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. DESIGN:: Prospective experimental study. SETTING:: University research laboratory. SUBJECTS:: C57BL/6 male mice. INTERVENTIONS:: 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. MEASUREMENTS AND MAIN RESULTS:: 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. CONCLUSIONS:: 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.

Original languageEnglish
JournalCritical Care Medicine
DOIs
Publication statusAccepted/In press - 2016 Jun 27

Fingerprint

Pneumococcal Infections
Histone Deacetylases
trichostatin A
Histone Deacetylase Inhibitors
Epigenomics
Pneumonia
Survival Rate
Bacterial Pneumonia
Lung
Influenza A virus
Bronchoalveolar Lavage Fluid
Adaptive Immunity
Virus Diseases
Acetylation
Streptococcus pneumoniae
Orthomyxoviridae
Interleukin-1
Innate Immunity
Natural Killer Cells
Histones

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Histone Deacetylase Inhibition Protects Mice Against Lethal Postinfluenza Pneumococcal Infection. / Yagi, Kazuma; Ishii, Makoto; Namkoong, Ho; Fujii, Hideki; Asami, Takahiro; Suzuki, Shoji; Asakura, Takanori; Mizoguchi, Kosuke; Kamo, Tetsuro; Tasaka, Sadatomo; Iwata, Satoshi; Kunkel, Steven L.; Hasegawa, Naoki; Betsuyaku, Tomoko.

In: Critical Care Medicine, 27.06.2016.

Research output: Contribution to journalArticle

Yagi, K, Ishii, M, Namkoong, H, Fujii, H, Asami, T, Suzuki, S, Asakura, T, Mizoguchi, K, Kamo, T, Tasaka, S, Iwata, S, Kunkel, SL, Hasegawa, N & Betsuyaku, T 2016, 'Histone Deacetylase Inhibition Protects Mice Against Lethal Postinfluenza Pneumococcal Infection', Critical Care Medicine. https://doi.org/10.1097/CCM.0000000000001821
Yagi, Kazuma ; Ishii, Makoto ; Namkoong, Ho ; Fujii, Hideki ; Asami, Takahiro ; Suzuki, Shoji ; Asakura, Takanori ; Mizoguchi, Kosuke ; Kamo, Tetsuro ; Tasaka, Sadatomo ; Iwata, Satoshi ; Kunkel, Steven L. ; Hasegawa, Naoki ; Betsuyaku, Tomoko. / Histone Deacetylase Inhibition Protects Mice Against Lethal Postinfluenza Pneumococcal Infection. In: Critical Care Medicine. 2016.
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AU - Yagi, Kazuma

AU - Ishii, Makoto

AU - Namkoong, Ho

AU - Fujii, Hideki

AU - Asami, Takahiro

AU - Suzuki, Shoji

AU - Asakura, Takanori

AU - Mizoguchi, Kosuke

AU - Kamo, Tetsuro

AU - Tasaka, Sadatomo

AU - Iwata, Satoshi

AU - Kunkel, Steven L.

AU - Hasegawa, Naoki

AU - Betsuyaku, Tomoko

PY - 2016/6/27

Y1 - 2016/6/27

N2 - OBJECTIVES:: 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. DESIGN:: Prospective experimental study. SETTING:: University research laboratory. SUBJECTS:: C57BL/6 male mice. INTERVENTIONS:: 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. MEASUREMENTS AND MAIN RESULTS:: 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. CONCLUSIONS:: 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.

AB - OBJECTIVES:: 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. DESIGN:: Prospective experimental study. SETTING:: University research laboratory. SUBJECTS:: C57BL/6 male mice. INTERVENTIONS:: 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. MEASUREMENTS AND MAIN RESULTS:: 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. CONCLUSIONS:: 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.

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