title: Double-stranded RNA induces molecular and inflammatory signatures that are directly relevant to COPD.
abstract: Polyinosinic:polycytidylic acid (poly I:C) is a synthetic analogue of double-stranded (ds)RNA, a molecular pattern associated with viral infections, that is used to exacerbate inflammation in lung injury models. Despite its frequent use, there are no detailed studies of the responses elicited by a single topical administration of poly I:C to the lungs of mice. Our data provides the first demonstration that the molecular responses in the airways induced by poly I:C correlate to those observed in the lungs of chronic obstructive pulmonary disease (COPD) patients. These expression data also revealed three distinct phases of response to poly I:C, consistent with the changing inflammatory cell infiltrate in the airways. Poly I:C induced increased numbers of neutrophils and natural killer cells in the airways, which were blocked by CXCR2 and CCR5 antagonists, respectively. Using gene set variation analysis on representative clinical data sets, gene sets defined by poly I:C-induced differentially expressed genes were enriched in the molecular profiles of COPD but not idiopathic pulmonary fibrosis patients. Collectively, these data represent a new approach for validating the clinical relevance of preclinical animal models and demonstrate that a dual CXCR2/CCR5 antagonist may be an effective treatment for COPD patients.
authors.affiliation: DTA Inflammation, Hoffmann-La Roche Inc., pRED, Pharma Research and Early Development, Nutley, New Jersey, USA.
authors.forename: P
authors.initials: P
authors.lastname: Harris
authors.forename: S
authors.initials: S
authors.lastname: Sridhar
authors.forename: R
authors.initials: R
authors.lastname: Peng
authors.forename: J E
authors.initials: JE
authors.lastname: Phillips
authors.forename: R G
authors.initials: RG
authors.lastname: Cohn
authors.forename: L
authors.initials: L
authors.lastname: Burns
authors.forename: J
authors.initials: J
authors.lastname: Woods
authors.forename: M
authors.initials: M
authors.lastname: Ramanujam
authors.forename: M
authors.initials: M
authors.lastname: Loubeau
authors.forename: G
authors.initials: G
authors.lastname: Tyagi
authors.forename: J
authors.initials: J
authors.lastname: Allard
authors.forename: M
authors.initials: M
authors.lastname: Burczynski
authors.forename: P
authors.initials: P
authors.lastname: Ravindran
authors.forename: D
authors.initials: D
authors.lastname: Cheng
authors.forename: H
authors.initials: H
authors.lastname: Bitter
authors.forename: J S
authors.initials: JS
authors.lastname: Fine
authors.forename: C M T
authors.initials: CM
authors.lastname: Bauer
authors.forename: C S
authors.initials: CS
authors.lastname: Stevenson
mesh_terms: D000818:Animals; D002465:Cell Movement; D004195:Disease Models, Animal; D005240:Feasibility Studies; D053263:Gene Regulatory Networks / Q000276:immunology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000276:immunology; D011070:Poly I-C / Q000276:immunology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000276:immunology*; D012330:RNA, Double-Stranded / Q000276:immunology; D019713:Receptors, CCR5 / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D059467:Transcriptome / Q000276:immunology; D014777:Virus Diseases / Q000235:genetics* / Q000276:immunology*
chemical_list: D018836:Inflammation Mediators; D012330:RNA, Double-Stranded; D019713:Receptors, CCR5; D023063:Receptors, Interleukin-8B; D011070:Poly I-C