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  • Title: Selective Antagonists of the Bronchiolar Epithelial NF-κB-Bromodomain-Containing Protein 4 Pathway in Viral-Induced Airway Inflammation.
    Author: Tian B, Liu Z, Yang J, Sun H, Zhao Y, Wakamiya M, Chen H, Rytting E, Zhou J, Brasier AR.
    Journal: Cell Rep; 2018 Apr 24; 23(4):1138-1151. PubMed ID: 29694891.
    Abstract:
    The mechanisms by which the mammalian airway detects invading viral pathogens to trigger protective innate neutrophilic inflammation are incompletely understood. We observe that innate activation of nuclear factor κB (NF-κB)/RelA transcription factor indirectly activates atypical BRD4 histone acetyltransferase (HAT) activity, RNA polymerase II (Pol II) phosphorylation, and secretion of neutrophilic chemokines. To study this pathway in vivo, we developed a conditional knockout of RelA in distal airway epithelial cells; these animals have reduced mucosal BRD4/Pol II activation and neutrophilic inflammation to viral patterns. To further understand the role of BRD4 in vivo, two potent, highly selective small-molecule BRD4 inhibitors were developed. These well-tolerated inhibitors disrupt the BRD4 complex with Pol II and histones, completely blocking inducible epithelial chemokine production and neutrophilia. We conclude that RelA-BRD4 signaling in distal tracheobronchiolar epithelial cells mediates acute inflammation in response to luminal viral patterns. These potent BRD4 antagonists are versatile pharmacological tools for investigating BRD4 functions in vivo.
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