title: Respiratory syncytial virus infections enhance cigarette smoke induced COPD in mice.
abstract: Respiratory syncytial viral (RSV) infections are a frequent cause of chronic obstructive pulmonary disease (COPD) exacerbations, which are a major factor in disease progression and mortality. RSV is able to evade antiviral defenses to persist in the lungs of COPD patients. Though RSV infection has been identified in COPD, its contribution to cigarette smoke-induced airway inflammation and lung tissue destruction has not been established. Here we examine the long-term effects of cigarette smoke exposure, in combination with monthly RSV infections, on pulmonary inflammation, protease production and remodeling in mice. RSV exposures enhanced the influx of macrophages, neutrophils and lymphocytes to the airways of cigarette smoke exposed C57BL/6J mice. This infiltration of cells was most pronounced around the vasculature and bronchial airways. By itself, RSV caused significant airspace enlargement and fibrosis in mice and these effects were accentuated with concomitant smoke exposure. Combined stimulation with both smoke and RSV synergistically induced cytokine (IL-1α, IL-17, IFN-γ, KC, IL-13, CXCL9, RANTES, MIF and GM-CSF) and protease (MMP-2, -8, -12, -13, -16 and cathepsins E, S, W and Z) expression. In addition, RSV exposure caused marked apoptosis within the airways of infected mice, which was augmented by cigarette smoke exposure. RSV and smoke exposure also reduced protein phosphatase 2A (PP2A) and protein tyrosine phosphates (PTP1B) expression and activity. This is significant as these phosphatases counter smoke-induced inflammation and protease expression. Together, these findings show for the first time that recurrent RSV infection markedly enhances inflammation, apoptosis and tissue destruction in smoke-exposed mice. Indeed, these results indicate that preventing RSV transmission and infection has the potential to significantly impact on COPD severity and progression.
authors.affiliation: St. Luke's Roosevelt Hospital, Mount Sinai Health System, Division of Pulmonary and Critical Care Medicine, New York, New York, United States of America.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Foronjy
authors.affiliation: St. Luke's Roosevelt Hospital, Mount Sinai Health System, Division of Pulmonary and Critical Care Medicine, New York, New York, United States of America.
authors.forename: Abdoulaye J
authors.initials: AJ
authors.lastname: Dabo
authors.affiliation: Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom.
authors.forename: Clifford C
authors.initials: CC
authors.lastname: Taggart
authors.affiliation: Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom.
authors.forename: Sinead
authors.initials: S
authors.lastname: Weldon
authors.affiliation: St. Luke's Roosevelt Hospital, Mount Sinai Health System, Division of Pulmonary and Critical Care Medicine, New York, New York, United States of America.
authors.forename: Patrick
authors.initials: P
authors.lastname: Geraghty
mesh_terms: D000818:Animals; D017209:Apoptosis; D002403:Cathepsins / Q000378:metabolism; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D054884:Host-Pathogen Interactions; D006801:Humans; D015151:Immunoblotting; D008168:Lung / Q000378:metabolism / Q000503:physiopathology / Q000821:virology; D008810:Mice, Inbred C57BL; D010447:Peptide Hydrolases / Q000378:metabolism; D011014:Pneumonia / Q000378:metabolism / Q000503:physiopathology / Q000821:virology; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000503:physiopathology* / Q000821:virology; D018357:Respiratory Syncytial Virus Infections / Q000209:etiology / Q000503:physiopathology* / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana / Q000737:chemistry*
chemical_list: D016207:Cytokines; D012906:Smoke; D054648:Protein Phosphatase 2; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse; D002403:Cathepsins; D010447:Peptide Hydrolases; C028217:cathepsin S