Severe lower respiratory tract infections (LRTIs) are associated with long-term reductions in pulmonary function, a highly significant indicator of chronic lung disease in adults. Work in our current funding period has elucidated the central role of the epigenetic coactivator bromodomain-containing protein 4 (BRD4) complexed with NF?B/RelA in mucosal inflammatory responses. Not only does the RelA?BRD4 complex activate inflammation, but it also activates the TGF?-mediated fibrotic program. We have demonstrated that small- molecule inhibition of BRD4 HAT prevents inflammation, fibrosis, and remodeling in mouse models of repetitive viral and allergen challenges. These findings provide the unifying mechanism linking the innate RelABRD4 complex with inflammation and airway remodeling. During the next funding period, we will test the hypothesis that the BRD4 histone acetyl transferase (HAT)-chromatin remodeling complex (CRC) is an epigenetic regulator that acutely activates the innate immune response and chronically activates airway remodeling. We will pursue three hypotheses that: 1) The NF?B/RelA-activated BRD4 HAT- CRC links RSV infection with the remodeling program. We will examine the role of RelA in activation and redistribution of the BRD4 HAT-CRC in fibrotic gene programs in primary human small airway epithelial cells (hSAECs) depleted of BRD4, complemented with BRD4 HAT mutations using air-liquid interface (ALI) cultures established by the Infant Bronchiolitis and Viral Core (IBVC). We will test the functional consequences of our original observations that BRD4 is in a dynamic complex with the SWI/SNF-related, Matrix-associated, Actin- dependent Regulator of Chromatin (SMARC) CRC in inflammation/remodeling. 2) RelA activates the epithelial BRD4 pathway to mediate RSV-induced disease and remodeling. We will use a novel RelA mouse knockout model to test the selective role of RelA signaling by tracheo-bronchiolar cells in RSV-induced inflammation and remodeling in vivo. We will test the effect of BRD4 silencing using BRD4CKO and a novel specific BRD4 inhibitor. We will measure TGF? fibrotic markers in nasopharyngeal samples from children with LRTI vs uncomplicated URI and normals. 3) RSV proteins restructure the RelA?BRD4 HAT-CRC complex to ?prime? allergic airway remodeling. In this aim, we will determine the functional consequences of our findings that RSV proteins interact with the RelA?BRD4 complex, and we will conduct experiments elucidating how RSV infection reprograms the RelA?BRD4 HAT-CRC to enhance (?prime?) allergen-induced myofibroblast expansion and airway remodeling. Our project is synergistic with the studies in RP2 to examine the role of RelA in the regulation of antioxidant genes/NRF2, and with RP3 to examine the role of 8-oxoguanine DNA glycosylase (OGG1) in RelA-activated remodeling. Our results will identify the BRD4 HAT-CRC as an important target in inflammation-remodeling, and they will provide proof-of-principle to advance small-molecule inhibitors to attenuate the long-term effects of RSV infections in humans.
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