title: NF-κB Mediates Mesenchymal Transition, Remodeling, and Pulmonary Fibrosis in Response to Chronic Inflammation by Viral RNA Patterns.
abstract: Airway remodeling is resultant of a complex multicellular response associated with a progressive decline of pulmonary function in patients with chronic airway disease. Here, repeated infections with respiratory viruses are linked with airway remodeling through largely unknown mechanisms. Although acute activation of the Toll-like receptor (TLR) 3 pathway by extracellular polyinosinic:polycytidylic acid (poly[I:C]) induces innate signaling through the NF-κB transcription factor in normal human small airway epithelial cells, prolonged (repetitive or tonic) poly(I:C) stimulation produces chronic stress fiber formation, mesenchymal transition, and activation of a fibrotic program. Chronic poly(I:C) stimulation enhanced the expression of core mesenchymal regulators Snail family zinc finger 1, zinc finger E-box binding homeobox, mesenchymal intermediate filaments (vimentin), and extracellular matrix proteins (fibronectin-1), and collagen 1A. This mesenchymal transition was prevented by silencing expression of NF-κB/RelA or administration of a small-molecule inhibitor of the IκB kinase, BMS345541. Acute poly(I:C) exposure in vivo induced profound neutrophilic airway inflammation. When administered repetitively, poly(I:C) resulted in enhanced fibrosis observed by lung micro-computed tomography, second harmonic generation microscopy of optically cleared lung tissue, and by immunohistochemistry. Epithelial flattening, expansion of the epithelial mesenchymal trophic unit, and enhanced Snail family zinc finger 1 and fibronectin 1 expression in airway epithelium were also observed. Repetitive poly(I:C)-induced airway remodeling, fibrosis, and epithelial-mesenchymal transition was inhibited by BMS345541 administration. Based on this novel model of viral inflammation-induced remodeling, we conclude that NF-κB is a major controller of epithelial-mesenchymal transition and pulmonary fibrosis, a finding that has potentially important relevance to airway remodeling produced by repetitive viral infections.
authors.affiliation: Departments of 1 Internal Medicine.|2 Sealy Center for Molecular Medicine.
authors.forename: Bing
authors.initials: B
authors.lastname: Tian
authors.affiliation: 3 Center for Biomedical Engineering.
authors.forename: Igor
authors.initials: I
authors.lastname: Patrikeev
authors.affiliation: 3 Center for Biomedical Engineering.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Ochoa
authors.affiliation: 3 Center for Biomedical Engineering.
authors.forename: Gracie
authors.initials: G
authors.lastname: Vargas
authors.affiliation: Departments of 1 Internal Medicine.|4 Department of Biochemistry and Molecular Biology, and.
authors.forename: KarryAnne K
authors.initials: KK
authors.lastname: Belanger
authors.affiliation: Departments of 1 Internal Medicine.|5 Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Julia
authors.initials: J
authors.lastname: Litvinov
authors.affiliation: 2 Sealy Center for Molecular Medicine.|6 Institute for Translational Sciences.|5 Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Istvan
authors.initials: I
authors.lastname: Boldogh
authors.affiliation: Departments of 1 Internal Medicine.|2 Sealy Center for Molecular Medicine.|6 Institute for Translational Sciences.
authors.forename: Bill T
authors.initials: BT
authors.lastname: Ameredes
authors.affiliation: 3 Center for Biomedical Engineering.
authors.forename: Massoud
authors.initials: M
authors.lastname: Motamedi
authors.affiliation: Departments of 1 Internal Medicine.|2 Sealy Center for Molecular Medicine.|6 Institute for Translational Sciences.
authors.forename: Allan R
authors.initials: AR
authors.lastname: Brasier
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D002908:Chronic Disease; D003094:Collagen / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006801:Humans; D008168:Lung / Q000473:pathology; D008648:Mesoderm / Q000187:drug effects / Q000473:pathology*; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D009504:Neutrophils / Q000473:pathology; D011014:Pneumonia / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology*; D011070:Poly I-C / Q000494:pharmacology; D011658:Pulmonary Fibrosis / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D012367:RNA, Viral / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D055114:X-Ray Microtomography
chemical_list: D016328:NF-kappa B; D012367:RNA, Viral; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D003094:Collagen; D011070:Poly I-C
keywords: Toll-like receptor 3; airway reprogramming; epithelial–mesenchymal transition; polyinosinic:polycytidylic acid; tissue clearing