Histone deacetylase inhibitors suppress RSV infection and alleviate virus-induced airway inflammation

Autor: Qiuqin Feng, Man Tian, Long Yi, Hongwei Wang, Bin Zhang, Hui Χu, Zhonglan Su, Shiyu Song
Rok vydání: 2016
Předmět:
0301 basic medicine
respiratory syncytial virus
viruses
medicine.medical_treatment
Respiratory System
Histone Deacetylase 2
Hydroxamic Acids
0302 clinical medicine
Interferon
oxidative stress
Mice
Inbred BALB C
Vorinostat
education.field_of_study
Histone deacetylase 2
NF-kappa B
Articles
General Medicine
respiratory system
Respiratory Syncytial Viruses
Cytokine
030220 oncology & carcinogenesis
Host-Pathogen Interactions
Cytokines
Female
Mitogen-Activated Protein Kinases
medicine.symptom
medicine.drug
STAT3 Transcription Factor
Blotting
Western
Population
Bronchi
Inflammation
Respiratory Syncytial Virus Infections
Biology
Cell Line
03 medical and health sciences
Cell Line
Tumor
Genetics
medicine
Animals
Humans
education
Epithelial Cells
Pneumonia
Histone Deacetylase Inhibitors
030104 developmental biology
Trichostatin A
Cyclooxygenase 2
histone deacetylase
Immunology
Cancer research
Histone deacetylase
Zdroj: International Journal of Molecular Medicine
ISSN: 1791-244X
1107-3756
Popis: Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants and young children. However, the majority of RSV-infected patients only show mild symptoms. Different severities of infection and responses among the RSV-infected population indicate that epigenetic regulation as well as personal genetic background may affect RSV infectivity. Histone deacetylase (HDAC) is an important epigenetic regulator in lung diseases. The present study aimed to explore the possible connection between HDAC expression and RSV-induced lung inflammation. To address this question, RSV-infected airway epithelial cells (BEAS‑2B) were prepared and a mouse model of RSV infection was established, and then treated with various concentrations of HDAC inhibitors (HDACis), namely trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA). Viral replication and markers of virus-induced airway inflammation or oxidative stress were assessed. The activation of the nuclear factor-κB (NF-κB), cyclo-oxygenase-2 (COX-2), mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling pathways was evaluated by western blot analysis. Our results showed that RSV infection in airway epithelial cells (AECs) significantly decreased histone acetylation levels by altering HDAC2 expression. The treatment of RSV-infected AECs with HDACis significantly restricted RSV replication by upregulating the interferon-α (IFN-α) related signaling pathways. The treatment of RSV-infected AECs with HDACis also significantly inhibited RSV-induced pro-inflammatory cytokine release [interleukin (IL)-6 and IL-8] and oxidative stress-related molecule production [malondialdehyde (MDA), and nitrogen monoxide (NO)]. The activation of NF-κB, COX-2, MAPK and Stat3, which orchestrate pro‑inflammatory gene expression and oxidative stress injury, was also significantly inhibited. Our in vivo study using a mouse model of RSV infection validated these results. Treatment with HDACis alleviated airway inflammation and reduced in vivo RSV replication. Our data demonstrated that RSV reduced histone acetylation by enhancing HDAC2 expression. Treatment with HDACis (TSA/SAHA) significantly inhibited RSV replication and decreased RSV-induced airway inflammation and oxidative stress. Therefore, the inhibition of HDACs represents a novel therapeutic approach in modulating RSV-induced lung disease.
Databáze: OpenAIRE
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