Antiinflammatory effects of bromodomain and extraterminal domain inhibition in cystic fibrosis lung inflammation
Kong Chen, Brian T. Campfield, Sally E. Wenzel, Jeremy P. McAleer, James L. Kreindler, Geoffrey Kurland, Radha Gopal, Ting Wang, Wei Chen, Taylor Eddens, Kathleen M. Quinn, Mike M. Myerburg, William T. Horne, Jose M. Lora, Brian K. Albrecht, Joseph M. Pilewski, Jay K. Kolls
Kong Chen, Brian T. Campfield, Sally E. Wenzel, Jeremy P. McAleer, James L. Kreindler, Geoffrey Kurland, Radha Gopal, Ting Wang, Wei Chen, Taylor Eddens, Kathleen M. Quinn, Mike M. Myerburg, William T. Horne, Jose M. Lora, Brian K. Albrecht, Joseph M. Pilewski, Jay K. Kolls
View: Text | PDF
Research Article Inflammation Therapeutics

Antiinflammatory effects of bromodomain and extraterminal domain inhibition in cystic fibrosis lung inflammation

Abstract

Significant morbidity in cystic fibrosis (CF) results from chronic lung inflammation, most commonly due to Pseudomonas aeruginosa infection. Recent data suggest that IL-17 contributes to pathological inflammation in the setting of abnormal mucosal immunity, and type 17 immunity–driven inflammatory responses may represent a target to block aberrant inflammation in CF. Indeed, transcriptomic analysis of the airway epithelium from CF patients undergoing clinical bronchoscopy revealed upregulation of IL-17 downstream signature genes, implicating a substantial contribution of IL-17–mediated immunity in CF lungs. Bromodomain and extraterminal domain (BET) chromatin modulators can regulate T cell responses, specifically Th17-mediated inflammation, by mechanisms that include bromodomain-dependent inhibition of acetylated histones at the IL17 locus. Here, we show that, in vitro, BET inhibition potently suppressed Th17 cell responses in explanted CF tissue and inhibited IL-17–driven chemokine production in human bronchial epithelial cells. In an acute P. aeruginosa lung infection murine model, BET inhibition decreased inflammation, without exacerbating infection, suggesting that BET inhibition may be a potential therapeutic target in patients with CF.

Authors

Kong Chen, Brian T. Campfield, Sally E. Wenzel, Jeremy P. McAleer, James L. Kreindler, Geoffrey Kurland, Radha Gopal, Ting Wang, Wei Chen, Taylor Eddens, Kathleen M. Quinn, Mike M. Myerburg, William T. Horne, Jose M. Lora, Brian K. Albrecht, Joseph M. Pilewski, Jay K. Kolls

×

Figure 5

CPI-203 does not exacerbate fungal infection.

Options: View larger image (or click on image) Download as PowerPoint
CPI-203 does not exacerbate fungal infection. Female 6- to 8-week-old mi...
Female 6- to 8-week-old mice (n = 5 per group) were randomized to treatment with vehicle or compound by i.p. administration followed by inoculation with A. fumigatus conidia. Mice were infected with A. fumigatus via o.p. aspiration (107 organisms). As a positive control for susceptibility, mice underwent neutrophil depletion by i.p. injection of antibody clone RB6-8C5 (0.6 mg per mouse) 1 day prior to infection. (A) Survival and (B) weight loss of the animals were monitored for 4 days. (C) Fungal burden measured by primers and probes specifically detecting 18s RNA on day 2 after infection and cytokine gene expression in the lungs were determined by real-time RT-PCR. Data were combined from 2 independent experiments. *P < 0.05 by ANOVA.