About

Professor Brian Button's research primarily focuses on the physiology and pathophysiology of airway mucus clearance and airway surface liquid regulation. His work extensively explores the mechanisms underlying mucociliary transport, airway surface hydration, and the role of mechanical stress in maintaining airway health. He has contributed to understanding the biophysical and biochemical properties of mucus and the periciliary layer, including the impact of mucus hyperconcentration in chronic bronchitis and cystic fibrosis. His studies have elucidated the role of ion transport, ATP release, and mechanical forces in regulating airway surface liquid volume and mucus clearance rates, which are critical for lung health and defense against infections. Professor Button's research also involves mathematical and computational modeling to describe airway epithelial cell function and nucleotide regulation, providing insights into airway homeostasis and disease mechanisms. His work has significant implications for developing therapeutic strategies targeting airway hydration and mucus clearance in respiratory diseases.

Research topics

• Biology
• Genetics
• Immunology
• Medicine
• Anatomy
• Anesthesia
• Ecology
• Pathology
• Virology
• Physiology

Selected publications

• Cilia-independent gas–liquid transport, a third mechanism mediating airway mucus clearance

  Journal of Clinical Investigation · 2026-03-17

  articleOpen accessSenior author

  Airway mucus clearance from the lungs occurs by 2 widely recognized mechanisms: cilia-mediated clearance and high-velocity airflow-mediated cough clearance. However, a potentially important third mechanism of mucus clearance, referred to as cilia-independent gas-liquid transport (GLT), was proposed based on in vitro model systems to occur during normal tidal breathing but has largely been overlooked. We conducted in vitro and in vivo studies to investigate the role of tidal breathing airflow rates in mucus clearance. An in vitro airway culture bead-tracking model demonstrated airflow-dependent mucus transport at tidal breathing flow rates. As with other modes of mucus clearance, GLT was critically dependent on mucus concentration. In vivo studies in cilial beat-deficient mice demonstrated that GLT-mediated mucus clearance occurs during tidal breathing in the absence of cough, and the rate of GLT mucus clearance was dependent on breathing frequency and body orientation. These studies demonstrated that GLT is a third mechanism of mucus clearance and likely represents a significant mode of clearance in persons with cilial dysfunction. These findings indicate that increasing breathing rates through exercise, using mucus rehydrating agents or mucolytics, or combining these approaches may restore clinically and physiologically meaningful airway clearance in these patients.

  PublisherDOI

• Heat waves elevate risks of airway hypersensitivity that inhaled endogenous ions reduce

  Research Square · 2025-10-06

  preprintOpen access
  PublisherOA PDFDOI

• Author Correction: Global warming risks dehydrating and inflaming human airways

  Communications Earth & Environment · 2025-03-28

  articleOpen accessSenior author
  PublisherOA PDFDOI

• Regulation of normal and cystic fibrosis airway surface liquid volume by phasic shear stress

  UNC Libraries · 2025-08-16

  articleOpen access

  The physical removal of viruses and bacteria on the mucociliary escalator is an important aspect of the mammalian lung's innate defense mechanism. The volume of airway surface liquid (ASL) present in the respiratory tract is a critical determinant of both mucus hydration and the rate of mucus clearance from the lung. ASL volume is maintained by the predominantly ciliated epithelium via coordinated regulation of (a) absorption, by the epithelial Na+ channel, and (b) secretion, by the Ca2+ -activated Cl- channel (CaCC) and CFTR. This review provides an update on our current understanding of how shear stress regulates ASL volume height in normal and cystic fibrosis (CF) airway epithelia through extracellular ATP- and adenosine (ADO)-mediated pathways that modulate ion transport and ASL volume homeostasis. We also discuss (a) how derangement of the ADO-CFTR pathway renders CF airways vulnerable to viral infections that deplete ASL volume and produce mucus stasis, and (b) potential shear stress-dependent therapies for CF.

  PublisherDOI

• STAT3-Dependent Regulation of CFTR and Ciliogenesis Is Essential for Mucociliary Clearance and Innate Airway Defense in Hyper-IgE Syndrome

  American Journal of Respiratory and Critical Care Medicine · 2025-06-13 · 3 citations

  articleOpen access

  Abstract Rationale Hyper-IgE syndrome (STAT3-HIES), also known as Job’s syndrome, is a rare immunodeficiency disease typically caused by dominant-negative STAT3 mutations. STAT3-HIES is characterized by chronic pulmonary infection and inflammation, suggesting impaired innate host defense. Objectives To identify airway epithelial host defense defects caused by STAT3 mutations that, together with immune dysfunction, contribute to recurrent pulmonary infections in STAT3-HIES. Methods STAT3-HIES sputum was analyzed for biochemical and biophysical properties. STAT3-HIES excised lungs were harvested for histology, and bronchial brush samples were collected for RNA sequencing and in vitro culture. A STAT3-HIES–specific R382W mutation, expressed via lentivirus, and STAT3 knockout (CRISPR/Cas9) were studied in normal human bronchial epithelial cells under basal or inflammatory (IL1β)-stimulated conditions. Effects of STAT3 deficiency on transcriptomics, epithelial ion channel, secretory, antimicrobial, and ciliary functions were assessed. Measurements and Main Results STAT3-HIES sputum showed increased mucus concentration and viscoelasticity. STAT3-HIES excised lungs exhibited mucus obstruction and elevated IL1β expression. STAT3 mutations reduced CFTR mRNA and protein amounts, impaired CFTR-dependent fluid and mucin secretion, suppressed antimicrobial peptide, cytokine, and chemokine expression, and acidified airway surface liquid at baseline and after IL1β exposure. Notably, mutant STAT3 suppressed IL1R1 expression. Furthermore, STAT3 mutations impaired multiciliogenesis by blocking commitment to ciliated cell lineages through inhibition of HES6, leading to defective mucociliary transport. Administration of a γ-secretase inhibitor restored HES6 expression and improved ciliogenesis in STAT3 R382W mutant cells. Conclusions STAT3 dysfunction leads to multicomponent defects in airway epithelial innate defense, which, in conjunction with immune deficiency, contributes to chronic pulmonary infection in STAT3-HIES.

  PublisherOA PDFDOI

• Global warming risks dehydrating and inflaming human airways

  Communications Earth & Environment · 2025-03-17 · 9 citations

  articleOpen accessSenior author

  Global warming increases water evaporation rates from planetary ecosystems. Here, we show that evaporation rates encountered during human breathing in dehydrating atmospheres promote airway inflammation and potentially exacerbate lung diseases. Continuum mathematical analysis predicts that water evaporation thins airway mucus layers and compresses epithelial cells during tidal breathing. Experiments using human tracheal-bronchial cells confirm that exposure to air with progressive degrees of dryness (relative humidities of 95%, 60%, and 30% at 37 °C) causes the mucus layer to progressively thin (by 5%, 35%, and 58%). Associated compression of epithelial cells elevates secretion of inflammatory cytokines (TNF-α, IL-33, and IL-6). Exposing mice with a muco-inflammatory phenotype to intermittent dry air for 14 days results in histopathological changes and alteration of inflammatory infiltrates. Together with climate model simulations, these findings suggest that most of the United States will be at elevated risk of airway inflammation by the latter half of this century. Exposure of human upper respiratory tracts to dry atmospheres promotes airway inflammation and aggravates lung diseases, according to an analysis of water efflux in human breathing, epithelial cell and mouse experiments, and climate model simulations

  PublisherOA PDFDOI

• Effect of hypertonic saline on mucociliary clearance and clinical outcomes in chronic bronchitis

  UNC Libraries · 2025-08-13

  articleOpen access

  BACKGROUND: Mucus dehydration and impaired mucus clearance are common features of cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). In CF, inhaled hypertonic saline (HS) improves lung function and produces sustained increases in mucociliary clearance (MCC). We hypothesised that administration of HS (7% NaCl) twice daily for 2 weeks would improve clinical outcomes and produce sustained increases in MCC in COPD subjects with a chronic bronchitis (CB) phenotype. METHODS: Twenty-two CB subjects completed a double-blinded, crossover study comparing inhaled HS to a hypotonic control solution (0.12% saline) administered <em>via</em> nebuliser twice daily for 2 weeks. Treatment order was randomised. During each treatment period, symptoms and spirometry were measured. MCC was measured at baseline, shortly after initial study agent administration, and approximately 12 h after the final dose. RESULTS: HS was safe and well tolerated but overall produced no significant improvements in spirometry or patient-reported outcomes. CB subjects had slower baseline MCC than healthy subjects. The MCC rates over 60 min (Ave60Clr) in CB subjects following 2 weeks of HS were not different from 0.12% saline but were slower than baseline (Ave60Clr was 9.1&plusmn;6.3% at baseline <em>versus</em> 5.3&plusmn;6.9% after HS; p&lt;0.05). Subgroup analyses determined that subjects with residual baseline central lung clearance (14 subjects) had improved spirometry and symptoms following treatment with HS, but not 0.12% saline, treatment. CONCLUSIONS: Inhaled HS appeared to be safe in a general CB population. A specific phenotypic subgroup may benefit from HS but requires additional study.

  PublisherDOI

• Hyaluronan Ameliorates Viral Pneumonia in Mice and Humans by Inhibiting Transcription Factor E2F1

  American Journal of Respiratory Cell and Molecular Biology · 2025-07-28 · 2 citations

  articleOpen access

  Viral lung infections are a major cause of morbidity and mortality worldwide. Despite significant advances in vaccines and antivirals, there remains a tremendous need for broadly applicable treatments that can be utilized across viral infections. Before infecting epithelial cells, viruses interact with the epithelial glycocalyx, which contains high-molecular weight hyaluronan (HMWHA), a glycosaminoglycan that has beneficial effects in lung injury. In this study, we sought to determine the role of HMWHA in viral pneumonia. We infected mice with influenza or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and treated them with prophylactic or therapeutic doses of HMWHA or saline control. We performed in vitro experiments of infection with viruses of respiratory and nonrespiratory human and animal cells and evaluated the effect of HMWHA on infection. We analyzed existing databases for expression of hyaluronan and the transcription factor E2F1. Finally, we performed a clinical trial with HMWHA in patients with severe coronavirus disease (COVID-19). Exogenously applied HMWHA improved survival in SARS-CoV-2 and influenza infection in mice by ameliorating inflammation through the inhibition of E2F1. In a clinical study, inhaled HMWHA improved outcomes in patients with severe COVID-19. Furthermore, airway epithelia naturally express HMWHA, which is induced during viral infection and prevents infection through the macromolecular crowding of viruses. Our data provide a mechanistic justification for the use of HMWHA as a broadly effective prophylactic and therapeutic agent in viral airway infection.

  PublisherDOI

• Physiology and pathophysiology of human airway mucus

  UNC Libraries · 2025-07-31

  articleOpen access1st authorCorresponding

  The mucus clearance system is the dominant mechanical host defense system of the human lung. Mucus is cleared from the lung by cilia and airflow, including both two-phase gas-liquid pumping and cough-dependent mechanisms, and mucus transport rates are heavily dependent on mucus concentration. Importantly, mucus transport rates are accurately predicted by the gel-on-brush model of the mucociliary apparatus from the relative osmotic moduli of the mucus and periciliary-glycocalyceal (PCL-G) layers. The fluid available to hydrate mucus is generated by transepithelial fluid transport. Feedback interactions between mucus concentrations and cilia beating, via purinergic signaling, coordinate Na⁺ absorptive vs Cl^- secretory rates to maintain mucus hydration in health. In disease, mucus becomes hyperconcentrated (dehydrated). Multiple mechanisms derange the ion transport pathways that normally hydrate mucus in muco-obstructive lung diseases, e.g., cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), non-CF bronchiectasis (NCFB), and primary ciliary dyskinesia (PCD). A key step in muco-obstructive disease pathogenesis is the osmotic compression of the mucus layer onto the airway surface with the formation of adherent mucus plaques and plugs, particularly in distal airways. Mucus plaques create locally hypoxic conditions and produce airflow obstruction, inflammation, infection, and, ultimately, airway wall damage. Therapies to clear adherent mucus with hydrating and mucolytic agents are rational, and strategies to develop these agents are reviewed.

  PublisherDOI

• Transgenic hCFTR expression fails to correct β -ENaC mouse lung disease

  UNC Libraries · 2025-08-16

  articleOpen access

  The relationships between airway epithelial Cl -secretion-Na + absorption balance, airway surface liquid (ASL) homeostasis, and lung disease were investigated in selected transgenic mice. 1) To determine if transgenic overexpression of wild-type (WT) human CFTR (hCFTR) accelerated Cl - secretion and regulated Na + absorption in murine airways, we utilized a Clara cell secretory protein (CCSP)-specific promoter to generate mice expressing airway-specific hCFTR. Ussing chamber studies revealed significantly (~2.5-fold) elevated basal Cl - secretory currents in CCSP-hCFTR transgenic mouse airways. Endogenous murine airway Na + absorption was not regulated by hCFTR, and these mice exhibited no lung disease. 2) We tested whether hCFTR, transgenically expressed on a transgenic mouse background overexpressing the β-subunit of the epithelial Na + channel (β-ENaC), restored ion transport balance and ASL volume homeostasis and ameliorated lung disease. Both transgenes were active in CCSP-hCFTR/ β -ENaC transgenic mouse airways, which exhibited an elevated basal Cl - secretion and Na + hyperabsorption. However, the airway disease characteristic of β -ENaC mice persisted. Confocal studies of ASL volume homeostasis in cultured tracheal cells revealed ASL autoregulation to a height of ~6 μm in WT and CCSP-hCFTR cultures, whereas ASL was reduced to <4 μm in β -ENaC and CCSP-hCFTR/ β -ENaC cultures. We conclude that 1) hCFTR overexpression increases basal Cl - secretion but does not regulate Na+ transport in WT mice and 2) transgenic hCFTR produces increased Cl - secretion, but not regulation of Na + channels, in β -ENaC mouse airways and does not ameliorate β -ENaC mouse lung disease.

  PublisherDOI

Recent grants

• NIH Grant K01DK080847

  NIH · $301k · 2011

• The role of mucus and pulmonary surface interactions in lung defense

  NIH · $378k · 2015–2019

• The role of mucus and pulmonary surface interactions in lung defense

  NIH · $2.7M · 2015–2025

• Core D: Pharmacokinetics/Pharmacodynamics Core

  NIH · $42.6M · 2017–2024

• Core B: Molecular/Functional Measurement Core

  NIH · $2.3M · 2003–2020

Frequent coauthors

• Richard C. Boucher

  University of North Carolina at Chapel Hill

  101 shared

• David B. Hill

  North Carolina State University

  60 shared

• Camille Ehré

  University of North Carolina at Chapel Hill

  38 shared

• Alessandra Livraghi-Butrico

  38 shared

• Mehmet Kesımer

  University of North Carolina at Chapel Hill

  38 shared

• Barbara R. Grubb

  37 shared

• Wanda K. O’Neal

  University of North Carolina at Chapel Hill

  34 shared

• Troy D. Rogers

  30 shared

Labs

• UNC Department of Biochemistry and BiophysicsPI