NF-κB Mediates Mesenchymal Transition, Remodeling, and Pulmonary Fibrosis in Response to Chronic Inflammation by Viral RNA Patterns
| Autor: | Julia Litvinov, Gracie Vargas, Igor Patrikeev, Massoud Motamedi, Istvan Boldogh, Bill T. Ameredes, Lorenzo Ochoa, Allan R. Brasier, Karry Anne K. Belanger, Bing Tian |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Pathology medicine.medical_specialty Epithelial-Mesenchymal Transition Neutrophils Pulmonary Fibrosis Clinical Biochemistry Vimentin IκB kinase Biology Mesoderm 03 medical and health sciences chemistry.chemical_compound Fibrosis Pulmonary fibrosis medicine Animals Humans Epithelial–mesenchymal transition Lung Molecular Biology Original Research NF-kappa B Epithelial Cells Pneumonia X-Ray Microtomography Cell Biology medicine.disease Toll-Like Receptor 3 Cell biology Mice Inbred C57BL Poly I-C 030104 developmental biology chemistry Polyinosinic:polycytidylic acid Chronic Disease biology.protein Airway Remodeling RNA Viral Respiratory epithelium Collagen Signal transduction Bronchoalveolar Lavage Fluid Signal Transduction |
| Zdroj: | American Journal of Respiratory Cell and Molecular Biology. 56:506-520 |
| ISSN: | 1535-4989 1044-1549 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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