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 Ameredes, Massoud Motamedi, Allan R. Brasier

Research output: Contribution to journalArticle

15 Citations (Scopus)

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-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
Volume56
Issue number4
DOIs
StatePublished - Apr 1 2017

Fingerprint

Pulmonary Fibrosis
Viral RNA
Airway Remodeling
Poly I-C
NF-kappa B
Inflammation
Epithelial-Mesenchymal Transition
Zinc Fingers
Snails
Fibronectins
Lung
Zinc
Fibrosis
Toll-Like Receptor 3
Stress Fibers
Intermediate Filaments
Extracellular Matrix Proteins
Vimentin
Virus Diseases
Respiratory Tract Infections

Keywords

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

ASJC Scopus subject areas

  • Medicine(all)
  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

NF-κB mediates mesenchymal transition, remodeling, and pulmonary fibrosis in response to chronic inflammation by viral RNA patterns. / Tian, Bing; Patrikeev, Igor; Ochoa, Lorenzo; Vargas, Gracie; Belanger, Karry Anne K.; Litvinov, Julia; Boldogh, Istvan; Ameredes, Bill; Motamedi, Massoud; Brasier, Allan R.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 56, No. 4, 01.04.2017, p. 506-520.

Research output: Contribution to journalArticle

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AU - Litvinov, Julia

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