Wednesday, March 12, 2025
3/12/2025
Mucociliary Innate Defense Mechanism in the Human Distal Airway Project summary Airway mucociliary clearance (MCC) is a critical innate defense system for maintenance of lung health. Failed mucus transport is common to the pathogenesis of muco-obstructive lung diseases (MOLDs). Mucociliary transport (MCT) rates, governed by cilial and mucus properties, are reportedly slower in vivo in distal airways, reflecting in part shorter cilia and reduced ciliary cell density. Mucus concentration is another key parameter that determines MCT. However, mechanisms that integrate regional cilial and mucus properties into MCT are not understood. This question is particularly important in small airways (< 2 mm in diameter), as they are the earliest and most affected region in MOLDs. Our prior studies have demonstrated reduced mucin secretion with robust CFTR-mediated fluid secretion in small airways, both activities dominated by secretory club cells, suggesting that mucus is less concentrated in the small airways relative to proximal airways in health. Basic physiology questions include: 1) why do small airways exhibit slower MCT; 2) how is slower MCT produced by integrated small airway epithelial cellular activities; and 3) what is the cost for the slower MCT with less concentrated mucus to the small airway region? Answers to these questions likely relate in part to the exponential decrease in surface area from distal to proximal airways. Accordingly, we hypothesize that mucus production and clearance in small airways is tightly regulated to achieve a balance between airway protection and efficient intraregional mucus clearance. Small airway epithelia produce a relatively dilute mucus that is transported at relatively slow rates to prevent accumulation in central airways. While this property is necessary to accommodate decrease in surface area from distal to proximal airways, the dilute mucus layer and slower clearance rates also lead to increased vulnerability to inhaled toxicants in small airway regions. To test this central hypothesis, we propose the following aims: 1) Identify region- and cell type- specific regulatory mechanisms for the MCT in human airways. We will identify region-specific MCC regulatory mechanisms, utilizing human large and small airway cell and tissue explant culture models. We will then relate region-specific MCC functions to epigenetic regulatory elements determining region-specific airway epithelial cell types, utilizing multi-omics approaches. 2) Identify pathways determining the distal airway secretory club cell as a multi-dimensional ion/mucin regulatory cell that controls small airway mucus properties. 3) Identify mechanisms that produce failure of mucociliary innate defense systems in the distal airway in MOLDs. We will test whether failure of the transcriptional regulation required to maintain distal airway specificity causes local MCC dysfunction in small airway epithelia. Our overarching goal is to generate mechanistic insights into region-specific mucociliary innate defense mechanisms with a focus on small airways. Achievement of our goal should provide a new paradigm to understand MCC in the normal lung and how to approach novel therapies for MOLDs.
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