title: Bromodomain and Extra-Terminal Protein Inhibition Attenuates Neutrophil-dominant Allergic Airway Disease.
abstract: Atopic asthma is a prevalent respiratory disease that is characterized by inflammation, mucus hypersecretion, and airway hyperresponsiveness. The complexity of this heterogeneous disorder has commanded the need to better define asthma phenotypes based on underlying molecular mechanisms of disease. Although classically viewed as a type 2-regulated disease, type 17 helper T (Th17) cells are known to be influential in asthma pathogenesis, predominantly in asthmatics with neutrophilia and severe refractory disease. Bromodomain and extra-terminal domain (BET) chromatin adaptors serve as immunomodulators by directly regulating Th17 responses and Th17-mediated pathology in murine models of autoimmunity and infection. Based on this, we hypothesized that BET proteins may also play an essential role in neutrophil-dominant allergic airway disease. Using a murine model of neutrophil-dominant allergic airway disease, we demonstrate that BET inhibition limits pulmonary inflammation and alters the Th17-related inflammatory milieu in the lungs. In addition, inhibition of BET proteins improved lung function (specifically quasi-static lung compliance and tissue elastance) and reduced mucus production in airways. Overall, these studies show that BET proteins may have a critical role in asthma pathogenesis by altering type 17 inflammation, and thus interfering with BET-dependent chromatin signaling may provide clinical benefits to patients suffering from asthma.
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA USA.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Manni
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA USA.
authors.forename: Sivanarayana
authors.initials: S
authors.lastname: Mandalapu
authors.affiliation: Constellation Pharmaceuticals, Inc., Cambridge, MA USA.
authors.forename: Andres
authors.initials: A
authors.lastname: Salmeron
authors.affiliation: Constellation Pharmaceuticals, Inc., Cambridge, MA USA.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Lora
authors.affiliation: Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA USA.
authors.forename: Jay K
authors.initials: JK
authors.lastname: Kolls
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Alcorn
mesh_terms: D000818:Animals; D001249:Asthma / Q000473:pathology*; D004195:Disease Models, Animal; D007249:Inflammation / Q000473:pathology; D008168:Lung / Q000473:pathology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C486765:Dner protein, mouse; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D014157:Transcription Factors