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.

RSV Reprograms the CDK9•BRD4 Chromatin Remodeling Complex to Couple Innate Inflammation to Airway Remodeling

“…In contrast, intracellular viral PAMPs are detected by dsRNA helicases and kinases of the retinoic acid inducible gene -I (RIG-I)/melanoma differentiation-associated protein (MDA5) family. Upon binding their cognate PAMPs, PRR-mediated signaling produces acute oxidative injury [14], disruption of cilia function, epithelial apoptosis, disruption of epithelial barrier function [15], and activation of IIR signaling, resulting in rapid neutrophilic inflammation [16]. These pathways have been extensively reviewed [17] and modeled mathematically [18].…”

“…As with the rapid activation of immediate-early IIR genes, NFκB binding recruits BRD4 to the SNAI/ZEB1/TWIST promoters and mediates ECM production and airway fibrosis [61]. Several studies have shown that small molecule BRD4 inhibitors block mesenchymal transition [16,85].…”

Osteopontin contributes to late-onset asthma phenotypes in adult asthma patients

“…Interestingly, compared with younger mice with asthma, older mice with asthma displayed a higher expression of pSmad3 42 , an important pathway of TGF-β1-mediated fibrosis 43 , which was also strongly enhanced by poly(I:C). Chronic poly(I:C) stimulation can stimulate NF-κB expression and epithelial-mesenchymal transition, fibrosis, and airway remodeling 44 . Taken together, these findings suggest that viral exposure could amplify the age-dependent increase in OPN, which enables airway inflammation and TGF-β1mediated remodeling and contributes to presenting a more severe phenotype of asthma of LOA.…”

Imaging of Murine Whole Lung Fibrosis by Large Scale 3D Microscopy aided by Tissue Optical Clearing

“…For this study, we used a fibrosis model driven by chronic TLR3 activation induced by repetitive administration of the poly(I:C) agonist, the model representative of a viral-induced fibrosis. This innate epithelial activation model has been shown to cause significant, chronic airway fibrosis and remodeling within a 30 day period 31 . Previous assessment of this model involved histology of regional areas of the lung.…”

“…A repetitive poly(I:C) challenge murine model of airway remodeling and subepithelial fibrosis served as the lung fibrosis model 31 . Animal experiments were performed according to the NIH Guide for Care and Use of Experimental Animals and approved by the University of Texas Medical Branch (UTMB) Institutional Animal Care and Use Committee (approval no.…”