title: 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 toPseudomonas aeruginosainfection. 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 theIL17locus. 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 acuteP. aeruginosalung 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: Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA.
authors: Kong
authors: K
authors: Chen
authors: Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA; University of Pittsburgh, Division of Pediatric Infectious Diseases, Department of Pediatrics, Pittsburgh, Pennsylvania, USA.
authors: Brian T
authors: BT
authors: Campfield
authors: University of Pittsburgh Asthma Institute at UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors: Sally E
authors: SE
authors: Wenzel
authors: Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA.
authors: Jeremy P
authors: JP
authors: McAleer
authors: Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: James L
authors: JL
authors: Kreindler
authors: Division of Pediatric Pulmonology, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors: Geoffrey
authors: G
authors: Kurland
authors: Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA.
authors: Radha
authors: R
authors: Gopal
authors: Division of Pulmonary Medicine, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors: Ting
authors: T
authors: Wang
authors: Division of Pulmonary Medicine, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors: Wei
authors: W
authors: Chen
authors: Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA.
authors: Taylor
authors: T
authors: Eddens
authors: Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA.
authors: Kathleen M
authors: KM
authors: Quinn
authors: Division of Pulmonary, Allergy, and Critical Care Medicine, UPMC, Pittsburgh, Pennsylvania, USA.
authors: Mike M
authors: MM
authors: Myerburg
authors: Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA.
authors: William T
authors: WT
authors: Horne
authors: Constellation Pharmaceuticals Inc., Cambridge, Massachusetts, USA.
authors: Jose M
authors: JM
authors: Lora
authors: Constellation Pharmaceuticals Inc., Cambridge, Massachusetts, USA.
authors: Brian K
authors: BK
authors: Albrecht
authors: Division of Pulmonary, Allergy, and Critical Care Medicine, UPMC, Pittsburgh, Pennsylvania, USA.
authors: Joseph M
authors: JM
authors: Pilewski
authors: Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA.
authors: Jay K
authors: JK
authors: Kolls