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
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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

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Figure 4

CPI-203 inhibits the production of Th17 cytokines and Th17 downstream chemokines and cytokines in vivo.

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CPI-203 inhibits the production of Th17 cytokines and Th17 downstream ch...
PAO1 was grown to log phase and then inoculated at a dose of 106 CFU by oropharyngeal inoculation into male C57Bl/6 mice (n = 5 per group). Mice were randomized to receive vehicle (Veh) or CPI-203 (CPI) (2.5 mg/kg) 60 minutes prior to infection and BID afterwards. (A) Lung bacterial burdens 24 hours after infection from control vehicle- and CPI-treated mice were determined by CFU and (B) BAL cell numbers were determined by quick-diff stain. (C) Gene expression in the lung was determined by RT-PCR and (D) total IL-17– and IFN-γ–producing cells were determined by intracellular staining. (E) Proinflammatory chemokines and cytokines in the whole-lung homogenates were determined by Luminex. P values were calculated by student t test.