Roflumilast inhibits respiratory syncytial virus infection in human differentiated bronchial epithelial cells.
Respiratory syncytial virus (RSV) causes acute exacerbations in COPD and asthma. RSV infects bronchial epithelial cells (HBE) that trigger RSV associated lung pathology. This study explores whether the phosphodiesterase 4 (PDE4) inhibitor Roflumilast N-oxide (RNO), alters RSV infection of well-differentiated HBE (WD-HBE) in vitro. WD-HBE were RSV infected in the presence or absence of RNO (0.1-100 nM). Viral infection (staining of F and G proteins, nucleoprotein RNA level), mRNA of ICAM-1, ciliated cell markers (digital high speed videomicroscopy, β-tubulin immunofluorescence, Foxj1 and Dnai2 mRNA), Goblet cells (PAS), mRNA of MUC5AC and CLCA1, mRNA and protein level of IL-13, IL-6, IL-8, TNFα, formation of H2O2 and the anti-oxidative armamentarium (mRNA of Nrf2, HO-1, GPx; total antioxidant capacity (TAC) were measured at day 10 or 15 post infection. RNO inhibited RSV infection of WD-HBE, prevented the loss of ciliated cells and markers, reduced the increase of MUC5AC and CLCA1 and inhibited the increase of IL-13, IL-6, IL-8, TNFα and ICAM-1. Additionally RNO reversed the reduction of Nrf2, HO-1 and GPx mRNA levels and consequently restored the TAC and reduced the H2O2 formation. RNO inhibits RSV infection of WD-HBE cultures and mitigates the cytopathological changes associated to this virus.
Research Foundation of the University General Hospital of Valencia, Valencia, Spain. mata_manroi@gva.es
Manuel
M
Mata
Isidoro
I
Martinez
Jose A
JA
Melero
Herman
H
Tenor
Julio
J
Cortijo
D000631:Aminopyridines / Q000494:pharmacology* / Q000627:therapeutic use*; D000975:Antioxidants / Q000378:metabolism; D056444:Axonemal Dyneins / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D001980:Bronchi / Q000473:pathology*; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects*; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism; D002923:Cilia / Q000187:drug effects / Q000378:metabolism; D003521:Cyclopropanes / Q000494:pharmacology / Q000627:therapeutic use; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology* / Q000821:virology*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020397:Goblet Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D008679:Metaplasia; D055271:Mucin 5AC / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy* / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000187:drug effects / Q000502:physiology; D014404:Tubulin / Q000378:metabolism; D019562:Viral Load / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
D000631:Aminopyridines; D000975:Antioxidants; D001549:Benzamides; D015415:Biomarkers; C492109:CLCA1 protein, human; D018118:Chloride Channels; D003521:Cyclopropanes; D016207:Cytokines; C425071:DNAI1 protein, human; C106349:FOXJ1 protein, human; D051858:Forkhead Transcription Factors; C524678:MUC5AC protein, human; D055271:Mucin 5AC; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014404:Tubulin; C424423:Roflumilast; D056444:Axonemal Dyneins; C517734:roflumilast N-oxide