Dissertation
Mucus and ionocyte contributions to airway physiology and host defense
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Summer 2025
DOI: 10.25820/etd.008129
Abstract
The human bronchial tree comprises a complex network of successively-branching airways that extend from the trachea to alveolar sacs, where vital gas exchange oxygenates the bloodstream. This expansive network encompasses a surface area similar in size to a badminton court and is exposed to pathogens and particulate matter with every breath. As such, the airways are far from sterile – but instead, are in a perpetual state of sterilization.
Airway epithelial cells line the conducting airways and represent the first line of defense against potentially injurious exposures. These cells are covered by a thin layer of airway surface liquid (ASL) that hydrates a complex network of mucus. Through mucociliary transport (MCT), ciliated cells propel material trapped in this mucus network toward the larynx, where it is eventually swallowed or coughed out.
In this study, we focus on the interaction between ASL and the mucus networks that facilitate MCT. Dysregulation of ASL can lead to mucus abnormalities and promote disease. In cystic fibrosis (CF), failure to secrete Cl– through the cystic fibrosis transmembrane conductance regulator (CFTR) protein prevents mucus in the submucosal glands (SMGs) from detaching from the SMG duct. The result is airway mucus plugging that blocks air flow, promotes infection, and drives inflammation.
In Chapters 1 and 2, we focus on ionocytes, a rare airway epithelial cell type with high CFTR. We show that ionocytes do not correlate with chloride secretion, but instead, promote liquid absorption by facilitating chloride absorption. By adding IL-13, a cytokine involved in type-2 inflammation seen in asthma, we discovered that ionocytes lose CFTR and are reduced in abundance. The loss of ionocyte-mediated absorption promotes the secretory phenotype associated with type-2 inflammation.
In Chapter 3, we study the contributions of MUC5B to airway health. MUC5B is the major component of submucosal gland mucus, and therefore a major component of CF disease. However, SMG mucus is also required for initiating MCT. By genetically modifying the MUC5B gene in a pig, we hoped to better understand how MUC5B contributes to MCT and airway health. We found that MUC5B-knockout (KO) pigs showed increased expression and secretion of MUC19 from the SMGs, resulting in abnormal mucus strand formation. MUC5B-KO pigs had reduced MCT compared to wild type pigs, but not to the same degree as pigs that completely lacked submucosal glands, which exhibited almost no MCT. The ability to compensate for the loss of MUC5B illustrates the versatility of mucus networks that facilitate MCT.
In summary, this research bridges cellular contributions of ion transport to the physiology of mucus network abnormalities. On one hand, the ionocyte’s response to inflammatory signals implies that that airway host defenses are exceptionally fine-tuned. On the other hand, the ability of the airways to overcome loss of MUC5B underscores that the airways are adaptable and resilient. Both studies highlight the importance of the conducting airways to maintaining human health.
Details
- Title: Subtitle
- Mucus and ionocyte contributions to airway physiology and host defense
- Creators
- Guillermo Romano Ibarra
- Contributors
- David A. Stoltz (Advisor)John F Engelhardt (Committee Member)Josalyn L. Cho (Committee Member)Paul B. McCray (Committee Member)Joseph Zabner (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biomedical Science (Molecular Medicine)
- Date degree season
- Summer 2025
- DOI
- 10.25820/etd.008129
- Publisher
- University of Iowa
- Number of pages
- xvi, 127 pages
- Copyright
- Copyright 2023 Guillermo Romano Ibarra
- Comment
- This thesis has been optimized for improved web viewing. If you require the original version, contact the University Archives at the University of Iowa: https://www.lib.uiowa.edu/sc/contact/
- Language
- English
- Date submitted
- 05/03/2025
- Description illustrations
- Illustrations, graphs, charts, tables
- Description bibliographic
- Includes bibliographical references (pages 120-127).
- Public Abstract (ETD)
The airways of the human lung resemble a tree: with the trachea as the trunk, and millions of branches reaching tiny air sacs where oxygen enters the blood. This expansive surface is about the size of a badminton court. With every breath, we inhale particles and germs, forcing the lungs into a perpetual state of sterilization. Protecting the airways is a thin layer of airway surface liquid (ASL), a network of mucus, and a thin layer of cells. Some of these cells are covered with tiny hair-like projections that push anything trapped in the mucus network out of the airways. This process is called mucociliary transport (MCT). Disruptions to the ASL can disrupt the mucus network and lead to disease. Cystic fibrosis (CF), for instance, stems from the inability to release chloride through CFTR channels, resulting in thick mucus that gets stuck in the lungs, leading to chronic lung infections.
Our study focuses on interaction between the ASL and the mucus network. Chapters 1- 2 explore ionocytes, the rare cells with the most CFTR channels. We found these cells aid in liquid absorption. IL-13, which models asthma-related inflammation, stops ionocytes from absorbing liquid. This might explain why you get a runny nose during a cold. Chapter 3 investigates MUC5B, a key mucus component made in the glands that line the airways. This is the mucus that gets stuck in the lungs of people with CF, but it is also crucial for MCT. We found that pigs without MUC5B produce MUC19, which helps perform MCT. MUC19 is not as effective as MUC5B but helps when MUC5B is gone. This highlights the adaptability of our airways. In summary, our research describes the intricacies of ion transport and mucus networks. It emphasizes that our airways are finely tuned but exceedingly resilient, underscoring their vital role in maintaining human health.
- Academic Unit
- Biomedical Science Program
- Record Identifier
- 9984948341702771
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