Abstract
Idiopathic pulmonary fibrosis is a lethal disease driven by myofibroblast expansion. Currently no therapies exist that target the epigenetic mechanisms controlling myofibroblast transdifferentiation, which is responsible for unregulated extracellular matrix (ECM) production. We have recently shown that bromodomain-containing protein 4 (BRD4), an epigenetic regulator that forms a scaffold for nuclear activators and transcription factors, is essential for TGFβ-induced myofibroblast transdifferentiation. However, its role in the development and progression of pulmonary fibrosis in vivo has not been established. Here, we evaluate the hypothesis that BRD4 bromodomain interactions mediate myofibroblast expansion and fibrosing disease in vivo. C57BL/6J mice challenged with intratracheal bleomycin were systemically treated with a selective allosteric inhibitor of the BRD4 bromodomain 1 (BD1), ZL0591 (10 mg/kg), during the established fibrotic phase (14 days post-bleomycin) in a rigorous therapeutic paradigm. Eleven days after initiation of ZL0591 treatment (25 days post-bleomycin), we detected a significant improvement in blood O2 saturation compared to bleomycin/vehicle control. Twenty-eight days post-bleomycin, we observed a reduction in the volumetric Hounsfield Unit (HU) density by micro computed tomography (μCT) in the ZL0591-treated group, as well as a reduction in collagen deposition (hydroxyproline content) and severity of injury (Ashcroft scoring). Myofibroblast transdifferentiation was measured by smooth muscle α-actin (αSMA) staining, indicating a loss of this cell population in the ZL0591-treated group, and corresponded to reduced transcript levels of myofibroblast-associated extracellular matrix genes, tenascin-C and collagen 1α1. We conclude that BRD4 BD1 interactions are critical for myofibroblast transdifferentiation and fibrotic progression in a mouse model of pulmonary fibrosis.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease that leads to death within 3–5 years of diagnosis (Ley et al, 2011)
We found that blood O2 saturation and heart rate were reduced in the bleomycin-treated group compared to uninjured controls, while the respiratory rate was unchanged between the two groups (Figures 1A–C)
bromodomain-containing protein 4 (BRD4) is a member of the bromodomain and extraterminal domain (BET) family that serves as a multifunctional chromatin regulator and plays key roles in cell cycle progression, DNA damage-repair, innate inflammation and cell-state transition processes driving oncogenic transformation and hypertrophic diseases (Devaiah et al, 2016b; Donati et al, 2018)
Summary
Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease that leads to death within 3–5 years of diagnosis (Ley et al, 2011). Transdifferentiation of mesenchymal fibroblasts in IPF involves the coordinated activation and suppression of hundreds of genes These processes lead to increased cell motility/invasiveness, contractility and increased expression of ECM proteins (Kis et al, 2011; Torr et al, 2015). While p300/CBP has been implicated in TGFβ-induced collagen (Col) expression, a non-selective inhibitor of all members of the BET family, JQ1when given at pharmacological concentrations during the acute inflammatory phase-diminished bleomycin-induced pulmonary fibrosis in mice (Tang et al, 2013). This suggests an important role for BET proteins in the development of pulmonary fibrosis, the individual role of BET family members in myofibroblast transdifferentation and IPF remains unclear
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