Abstract
Disruption of the lower airway epithelial barrier plays a major role in the initiation and progression of chronic lung disease. Here, repetitive environmental insults produced by viral and allergens triggers metabolic adaptations, epithelial-mesenchymal plasticity (EMP) and airway remodeling. Epithelial plasticity disrupts epithelial barrier function, stimulates release of fibroblastic growth factors, and remodels the extracellular matrix (ECM). This review will focus on recent work demonstrating how the hexosamine biosynthetic pathway (HBP) links innate inflammation to airway remodeling. The HBP is a core metabolic pathway of the unfolded protein response (UPR) responsible for protein N-glycosylation, relief of proteotoxic stress and secretion of ECM modifiers. We will overview findings that the IκB kinase (IKK)-NFκB pathway directly activates expression of the SNAI-ZEB1 mesenchymal transcription factor module through regulation of the Bromodomain Containing Protein 4 (BRD4) chromatin modifier. BRD4 mediates transcriptional elongation of SNAI1-ZEB as well as enhancing chromatin accessibility and transcription of fibroblast growth factors, ECM and matrix metalloproteinases (MMPs). In addition, recent exciting findings that IKK cross-talks with the UPR by controlling phosphorylation and nuclear translocation of the autoregulatory XBP1s transcription factor are presented. HBP is required for N glycosylation and secretion of ECM components that play an important signaling role in airway remodeling. This interplay between innate inflammation, metabolic reprogramming and lower airway plasticity expands a population of subepithelial myofibroblasts by secreting fibroblastic growth factors, producing changes in ECM tensile strength, and fibroblast stimulation by MMP binding. Through these actions on myofibroblasts, EMP in lower airway cells produces expansion of the lamina reticularis and promotes airway remodeling. In this manner, metabolic reprogramming by the HBP mediates environmental insult-induced inflammation with remodeling in chronic airway diseases.
Highlights
THE TRANSITION ZONE OF THE AIRWAY MEDIATES RESPONSE TO ENVIRONMENTAL STRESSORSThis manuscript will focus on the role of specialized epithelium in the “transition zone” of the lower airway that is emerging as a major driver in the initiation and maintenance of inflammation and airway remodeling (Burgel, 2011; Zhao et al, 2017; Tian et al, 2018c; Brasier, 2019; Skibba et al, 2021)
Activation of epithelial plasticity by TGFβ produces substantial intracytoplasmic accumulation of N glycosylated proteins (Zhang et al, 2019). To further understand this process, we found that the key enzymes of the hexosamine biosynthetic pathway (HBP), Glutamine-fructose-6-phosphate transaminase (GFPT)-1, -2, Glucosamine-phosphate N-acetyltransferase (GNPNAT), and phosphoglucomutase (PGM3) were up-regulated in the TGFβ-induced epithelial-mesenchymal plasticity (EMP) state
Bromodomain Containing Protein 4 (BRD4) –SMAD3 complex plays a key role in TGFβinduced myofibroblast formation (Ijaz et al, 2017), and we have recently found that BRD4 forms complexes with members of the AP-1 complex (Mann et al, 2021)
Summary
This manuscript will focus on the role of specialized epithelium in the “transition zone” of the lower airway that is emerging as a major driver in the initiation and maintenance of inflammation and airway remodeling (Burgel, 2011; Zhao et al, 2017; Tian et al, 2018c; Brasier, 2019; Skibba et al, 2021). The “transition zone” is a region between the gas-conducting bronchioles and the gas-exchanging alveoli This zone is a pseudostratified columnar epithelium composed of at least five distinct epithelial phenotypes, as multi-ciliated cells, secretory/ “Club” cells, mucin-producing goblet cells, ionocytes and basal cells (Adams et al, 2020; Deprez et al, 2020; Zaragosi et al, 2020). These cells differ from one another in secretory functions, selfrenewal and mucociliary clearance properties. This unit is referred to as the “epithelial mesenchymal trophic unit” (EMTU). and is responsible for maintaining trophic effects on the epithelium (Figure 1) (Evans et al, 1999)
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