Selective Antagonists of the Bronchiolar Epithelial NF-κB-Bromodomain-Containing Protein 4 Pathway in Viral-Induced Airway Inflammation

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.