title: Assessment of Brd4 inhibition in idiopathic pulmonary fibrosis lung fibroblasts and in vivo models of lung fibrosis.
abstract: Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease of high unmet medical need. Although bromodomain (Brd) and extra terminal domain isoforms have recently been implicated in mediating inflammatory and oncologic indications, their roles in lung fibrosis have not been comprehensively assessed. We investigated the role of Brd on the profibrotic responses of lung fibroblasts (LFs) in patients with rapidly progressing IPF and a mouse bleomycin model of lung fibrosis. The enhanced migration, proliferation, and IL-6 release observed in LFs from patients with rapidly progressing IPF are attenuated by pharmacologic inhibition of Brd4. These changes are accompanied by enhanced histone H4 lysine5 acetylation and association of Brd4 with genes involved in the profibrotic responses in IPF LFs as demonstrated using chromatin immunoprecipitation and quantitative PCR. Oral administration of 200 mg/kg per day Brd4 inhibitor JQ1 in a therapeutic dosing regimen substantially attenuated lung fibrosis induced by bleomycin in C57BL/6 mice. In conclusion, this study shows that the Brd4 inhibitor JQ1, administered in a therapeutic dosage, is capable of inhibiting the profibrotic effects of IPF LFs and attenuates bleomycin-induced lung fibrosis in mice. These results suggest that Brd4 inhibitors may represent a novel therapy for the treatment of rapidly progressing IPF.
authors.affiliation: Inflammation Discovery Therapeutic Area, Hoffmann-La Roche Inc., Nutley, New Jersey, USA.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Tang
authors.forename: Ruoqi
authors.initials: R
authors.lastname: Peng
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Phillips
authors.forename: Jeremy
authors.initials: J
authors.lastname: Deguzman
authors.forename: Yonglin
authors.initials: Y
authors.lastname: Ren
authors.forename: Subramanium
authors.initials: S
authors.lastname: Apparsundaram
authors.forename: Qi
authors.initials: Q
authors.lastname: Luo
authors.forename: Carla M
authors.initials: CM
authors.lastname: Bauer
authors.forename: Maria E
authors.initials: ME
authors.lastname: Fuentes
authors.forename: Julie A
authors.initials: JA
authors.lastname: DeMartino
authors.forename: Gaurav
authors.initials: G
authors.lastname: Tyagi
authors.forename: Rosario
authors.initials: R
authors.lastname: Garrido
authors.forename: Cory M
authors.initials: CM
authors.lastname: Hogaboam
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Denton
authors.forename: Alan M
authors.initials: AM
authors.lastname: Holmes
authors.forename: Christopher
authors.initials: C
authors.lastname: Kitson
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Stevenson
authors.forename: David C
authors.initials: DC
authors.lastname: Budd
mesh_terms: D000107:Acetylation; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D001381:Azepines / Q000494:pharmacology; D001761:Bleomycin / Q000633:toxicity; D018797:Cell Cycle Proteins; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D006133:Growth Substances / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000473:pathology*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D012867:Skin / Q000166:cytology; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D014230:Triazoles / Q000494:pharmacology; D000092468:Bromodomain Containing Proteins
chemical_list: D000893:Anti-Inflammatory Agents; D000903:Antibiotics, Antineoplastic; D001381:Azepines; D001761:Bleomycin; D018797:Cell Cycle Proteins; D055513:Connective Tissue Growth Factor; D016207:Cytokines; D006133:Growth Substances; D006657:Histones; D015850:Interleukin-6; D009687:Nuclear Proteins; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C486694:Brd4 protein, mouse