Airway remodeling/fibrosis is an irreversible component of severe asthma and chronic obstructive pulmonary disease for which no effective therapy exists. Excessive production and secretion of collagens, fibronectin, and proteoglycans by resident mesenchymal cells leads to excessive extracellular matrix (ECM) deposition, remodeling, and reduced lung capacity. An important driver of airway fibrosis and remodeling is signaling via the morphogenic cytokine transforming growth factor (TGF)?, whose actions trigger fibrotic programs in airway epithelial cells and fibroblasts, producing myofibroblast foci. These processes result in coordinated production of ECM proteins (the ?matrisome?). The TGF? fibrotic response is thus a fundamental process that underlies airway remodeling, a characteristic of severe asthma, COPD and PF in humans, making this pathway a likely source for the identification of therapeutic targets for this unmet need. Our recent systems biology study revealed that TGF? triggers the X-box binding protein 1 (XBP1)-hexosamine biosynthesis pathway (HBP) axis, resulting in upregulation of N-linked protein glycosylation. The core matrisome components use the traditional secretory pathway, and are typically N-glycosylated. The relationship of the XBP1-HBP axis to the N-linked glycosylation, and secretion, of the matrisome/ECM in lung fibrosis has not been established. Our studies demonstrated that inhibition of the chromatin regulator bromodomain-containing protein 4 (BRD4) can block the TGF? fibrotic response, excessive ECM deposition, and lung fibrosis in a mouse model. Recent ChIP-Seq studies have revealed that BRD4 forms a super-enhancer upstream of XBP1, providing a unifying mechanism by which TGF?-induced epigenetic reprograming regulates the XBP1-HBP axis. We hypothesize that the TGF? fibrotic response and epigenetic reprograming activate the BRD4-XBP1-HBP axis and protein N- glycosylation of the matrisome, resulting in excessive ECM production and pulmonary fibrosis. The long-term objective of this R21 project is to determine the contribution of BRD4-XBP1-HBP to the pathomechanism underlying lung fibrosis. We seek to determine whether inhibition of the BRD4 or XBP1 can be used for therapeutic gain in lung fibrosis, another long-term goal. Our two specific aims will advance this objective:
Aim1 is to characterize how the BRD4-XBP1-HBP axis regulates intracellular proteostasis and matrisome N-glycosylation in human small airway epithelial cells during TGF?-induced fibrosis;
Aim2 is to characterize the link between BRD4-XBP1-HBP activation and matrisome N-glycosylation in TGF?-induced lung fibrosis. Upon completion of this study we will have identified a mechanism by which epithelial cells activate the BRD4-XBP1-HBP axis to restore proteostasis under stress conditions, and how the BRD4-XBP1- HBP axis contributes to the excessive production and secretion of ECM in pulmonary fibrosis. We also should have identified likely therapeutic target(s) for the treatment of pulmonary fibrosis, and in our future studies will test treatments aimed at these targets in an animal model.
Health Relevance. Pulmonary fibrosis represents a significant cause of morbidity, mortality and medical expense, but no effective therapies exist for this disease. Identifying new targets that regulate excessive extracellular matrix production and airway fibrosis will lead to the development of novel strategies to prevent or treat pulmonary fibrosis.
|Tian, Bing; Hosoki, Koa; Liu, Zhiqing et al. (2018) Mucosal bromodomain-containing protein 4 mediates aeroallergen-induced inflammation and remodeling. J Allergy Clin Immunol :|