NF-κB mediates mesenchymal transition, remodeling, and pulmonary fibrosis in response to chronic inflammation by viral RNA patterns

Bing Tian, Igor Patrikeev, Lorenzo Ochoa, Gracie Vargas, Karry Anne K. Belanger, Julia Litvinov, Istvan Boldogh, Bill T. Ameredes, Massoud Motamedi, Allan R. Brasier

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


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-kB 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-kB/RelA or administration of a small-molecule inhibitor of the IkB 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-kB 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.

Original languageEnglish (US)
Pages (from-to)506-520
Number of pages15
JournalAmerican journal of respiratory cell and molecular biology
Issue number4
StatePublished - Apr 2017


  • Airway reprogramming
  • Epithelial-mesenchymal transition
  • Polyinosinic:polycytidylic acid
  • Tissue clearing
  • Toll-like receptor 3

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology


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