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Chronic obstructive pulmonary disease (COPD) and chronic asthma clinically manifest with sputum production and cough, which correlate with pathologic features such as mucin hypersecretion and airway lumenal mucus accumulation (1, 2). Increased mucin and mucus concentration is closely related to cigarette smoke and chronic bronchitis symptoms; for example, cough and sputum production, slowed mucociliary clearance (MCC), and COPD severity (3, 4). Twomajor secreted airway mucins, MUC5AC andMUC5B, constitute the airway mucus layer, and the presence of two “similar” gel-forming mucins in the lungs has been a conundrum for decades that can be summarized by several major questions: 1) What are the macromolecular, structural differences that may couple with biophysical properties of their gels? 2) What are the individual roles and functions of these two in the airways, and what are the consequences of not having either one of them? 3) What is their distribution throughout the airways, and how are they regulated? 4) Are they being made in the same cells, and if so, are they stored in the same or in separate secretory granules? The more we reveal the answers to these questions, the closer we will get to finding strategies to manipulate mucins therapeutically to treat mucus abnormalities. First, although MUC5AC and MUC5B share domain similarities as different gene products, recent studies indicated that their multimeric organization could be distinct and linked to their structural differences (5). Individually, MUC5AC and MUC5B form a distinct network infrastructure on the epithelial surfaces: MUC5AC forms tightly organized and branched networks, whereas MUC5B forms linear and occasionally branched networks (5). Furthermore,MUC5ACbinds significantlymore to hydrophobic surfaces, whereasMUC5AC layers aremore rigid and viscoelastic than those ofMUC5B (5). Second, MUC5B is essential for lung homeostasis and defense (6), whereas MUC5AC is a necessary player in allergic airway response and is responsible for mucus plugging and impairedMCC (7, 8). MUC5B is the dominant mucin in health; and in disease, bothMUC5B andMUC5AC increase, but MUC5AC increases disproportionately (3) and becomes closely associated to pathologic airway measures such as small airway abnormalities, airway obstruction, and increased exacerbation frequencies (9). In addition to MUC5AC’s potential as a sensitive biomarker for the initiation and progression of chronic bronchitis and COPD (9), genomewide association studies highlighted the causative role of increased MUC5AC expression in the pathogenesis of moderate and severe asthma (10, 11). Therefore, selectively targeting MUC5AC production and secretion has been of therapeutic interest. Third, studies on the airway regional distribution of MUC5AC andMUC5B indicated that MUC5B is expressed in both the superficial epithelium and the glands. In contrast, MUC5AC is only expressed in the superficial epithelium (12). MUC5B is expressed in the trachea, bronchi, and bronchioles, whereas MUC5AC expression is concentrated in relatively large airways, including the trachea and bronchi, but not in the distal bronchioles in healthy lungs. It is also notable that neither mucin is expressed in the terminal bronchioles in healthy lungs (12), suggesting that the presence and accumulation of these mucins in this region is a manifestation of airway disease. The difference in regional distribution betweenMUC5B andMUC5AC could also provide an insight into the distinct properties of the two mucins. Last, we have had no information as to whether they are made in the same airway cells and packaged together or separately in the secretory granules. In this issue of the Journal, a detailed, elegant study by Hoang and colleagues (pp. 1081–1095) addresses this fundamental information gap by observing both mouse and human airway tissues and primary airway cell cultures using state-of-the-art, high-resolution light microscopy techniques (13). The authors aimed to understand the packaging of MUC5AC andMUC5Bmucins in the secretory granules in the secretory cells of mouse and human airways. They stimulated mouse airways with either IL-1b or IL-13, representing type 1 and type 2 inflammation, respectively. After IL-1b stimulation, approximately half of the cells in the mouse axial bronchus hadMuc5b andMuc5ac together, whereas the other half had only Muc5b expression. After IL-13 stimulation, approximately three-fourths of the cells had bothMuc5b andMuc5ac together, whereas the others had either only Muc5b orMuc5ac. When the authors quantitated the secretory granule populations after these challenges, the vast majority of the granules contained either both mucins or Muc5b alone, whereas Muc5ac-only granules were not more than 15%. Similar results were obtained in the tissues from human airways; the majority of the cells in the proximal and distal airways expressed bothMUC5B andMUC5AC. The amount of MUC5B-only cells in the distal airways was three times higher than in the proximal airways. This observation is consistent with a previous study that foundMUC5B predominantly expressed in the distal airway superficial epithelium (12). Most (three-fourths) of the cells in the distal airways expressed both mucins. Although the amount was much lower, MUC5AC-only cells were also present in the distal This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0. For commercial usage and reprints, please e-mail Diane Gern ([email protected]).