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7 results on '"Elex S. Harris"'

1. Reduced sialylation of airway mucin impairs mucus transport by altering the biophysical properties of mucin

Author

Elex S. Harris, Hannah J. McIntire, Marina Mazur, Hinnerk Schulz-Hildebrandt, Hui Min Leung, Guillermo J. Tearney, Stefanie Krick, Steven M. Rowe, and Jarrod W. Barnes

Subjects
Medicine, Science
Abstract

Abstract Mucus stasis is a pathologic hallmark of muco-obstructive diseases, including cystic fibrosis (CF). Mucins, the principal component of mucus, are extensively modified with hydroxyl (O)-linked glycans, which are largely terminated by sialic acid. Sialic acid is a negatively charged monosaccharide and contributes to the biochemical/biophysical properties of mucins. Reports suggest that mucin sialylation may be altered in CF; however, the consequences of reduced sialylation on mucus clearance have not been fully determined. Here, we investigated the consequences of reduced sialylation on the charge state and conformation of the most prominent airway mucin, MUC5B, and defined the functional consequences of reduced sialylation on mucociliary transport (MCT). Reduced sialylation contributed to a lower charged MUC5B form and decreased polymer expansion. The inhibition of total mucin sialylation de novo impaired MCT in primary human bronchial epithelial cells and rat airways, and specific α-2,3 sialylation blockade was sufficient to recapitulate these findings. Finally, we show that ST3 beta-galactoside alpha-2,3-sialyltransferase (ST3Gal1) expression is downregulated in CF and partially restored by correcting CFTR via Elexacaftor/Tezacaftor/Ivacaftor treatment. Overall, this study demonstrates the importance of mucin sialylation in mucus clearance and identifies decreased sialylation by ST3Gal1 as a possible therapeutic target in CF and potentially other muco-obstructive diseases.

Published
2024
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2. Fibroblast Growth Factor Receptor 4 Deficiency Mediates Airway Inflammation in the Adult Healthy Lung?

Author

Molly Easter, Jaleesa Garth, Elex S. Harris, Ren-Jay Shei, Eric S. Helton, Yuhua Wei, Rebecca Denson, Rennan Zaharias, Steven M. Rowe, Patrick Geraghty, Christian Faul, Jarrod W. Barnes, and Stefanie Krick

Subjects
fibroblast growth factor receptor 4, lung, inflammation, bronchial epithelium, interleukin 6, airway surface liquid volume, Medicine (General), R5-920
Abstract

Fibroblast growth factor receptor (FGFR) 4 has been shown to mediate pro-inflammatory signaling in the liver and airway epithelium in chronic obstructive pulmonary disease. In past reports, FGFR4 knockout (Fgfr4−/−) mice did not show any lung phenotype developmentally or at birth, unless FGFR3 deficiency was present simultaneously. Therefore, we wanted to know whether the loss of FGFR4 had any effect on the adult murine lung. Our results indicate that adult Fgfr4−/− mice demonstrate a lung phenotype consisting of widened airway spaces, increased airway inflammation, bronchial obstruction, and right ventricular hypertrophy consistent with emphysema. Despite downregulation of FGF23 serum levels, interleukin (IL) 1β and IL-6 in the Fgfr4−/− lung, and abrogation of p38 signaling, primary murine Fgfr4−/− airway cells showed increased expression of IL-1β and augmented secretion of IL-6, which correlated with decreased airway surface liquid depth as assessed by micro-optical coherence tomography. These findings were paralleled by increased ERK phosphorylation in Fgfr4−/− airway cells when compared with their control wild-type cells. Analysis of a murine model with constitutive activation of FGFR4 showed attenuation of pro-inflammatory mediators in the lung and airway epithelium. In conclusion, we are the first to show an inflammatory and obstructive airway phenotype in the adult healthy murine Fgfr4−/− lung, which might be due to the upregulation of ERK phosphorylation in the Fgfr4−/− airway epithelium.

Published
2020
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3. Airway remodeling in ferrets with cigarette smoke-induced COPD using µCT imaging

Author

Stephen A. Byzek, Trenton R. Schoeb, Harrison Kim, Hrudaya Nath, Elex S Harris, S. Vamsee Raju, Denise Stanford, Jennifer LaFontaine, Surya P. Bhatt, Steven M. Rowe, and Sandeep Bodduluri

Subjects
Pulmonary and Respiratory Medicine, COPD, Pathology, medicine.medical_specialty, Chronic bronchitis, Bronchial wall, Physiology, business.industry, Pulmonary disease, Cell Biology, respiratory system, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Airway wall, Physiology (medical), medicine, Cigarette smoke, 030212 general & internal medicine, Airway, business, Research Article
Abstract

Structural changes to airway morphology, such as increased bronchial wall thickness (BWT) and airway wall area, are cardinal features of chronic obstructive pulmonary disease (COPD). Ferrets are a recently established animal model uniquely exhibiting similar clinical and pathological characteristics of COPD as humans, including chronic bronchitis. Our objective was to develop a microcomputed tomography (µCT) method for evaluating structural changes to the airways in ferrets and assess whether the effects of smoking induce changes consistent with chronic bronchitis in humans. Ferrets were exposed to mainstream cigarette smoke or air control twice daily for 6 mo. µCT was conducted in vivo at 6 mo; a longitudinal cohort was imaged monthly. Manual measurements of BWT, luminal diameter (LD), and BWT-to-LD ratio (BWT/LD) were conducted and confirmed by a semiautomated algorithm. The square root of bronchial wall area (√WA) versus luminal perimeter was determined on an individual ferret basis. Smoke-exposed ferrets reproducibly demonstrated 34% increased BWT ( P < 0.001) along with increased LD and BWT/LD versus air controls. Regression indicated that the effect of smoking on BWT persisted despite controlling for covariates. Semiautomated measurements replicated findings. √WA for the theoretical median airway luminal perimeter of 4 mm (Pi4) was elevated 4.4% in smoke-exposed ferrets ( P = 0.015). Increased BWT and Pi4 developed steadily over time. µCT-based airway measurements in ferrets are feasible and reproducible. Smoke-exposed ferrets develop increased BWT and Pi4, changes similar to humans with chronic bronchitis. µCT can be used as a significant translational platform to measure dynamic airway morphological changes.

Published
2020

4. 566: Accelerated aging pathways are activated in cystic fibrosis airway disease

Author

M. Hirsch, S. Birket, Jarrod W. Barnes, Stefanie Krick, M. Easter, Elex S Harris, E. Helton, and G. Bollar

Subjects
Pulmonary and Respiratory Medicine, Pathology, medicine.medical_specialty, Airway disease, business.industry, Pediatrics, Perinatology and Child Health, Medicine, business, medicine.disease, Cystic fibrosis, Accelerated aging
Published
2021

6. Airway Remodeling in Ferrets with Cigarette Smoke Induced COPD using µCT Imaging Supplement File

Author

Stanford, Denise, Kim, Harrison, Bodduluri, Sandeep, LaFontaine, Jennifer, Byzek, Stephen A., Schoeb, Trenton R., Elex S. Harris, Hrudaya P. Nath, Bhatt, Surya P., S. Vamsee Raju, and Rowe, Steven M.

Subjects
respiratory system
Abstract

RATIONALE: Structural changes to airway morphology such as increased bronchial wall thickness (BWT) and airway wall area are cardinal features of chronic obstructive pulmonary disease (COPD). Ferrets are a recently established animal model uniquely exhibiting similar clinical and pathological characteristics of COPD as humans, including chronic bronchitis. OBJECTIVES: Develop a µCT method for evaluating structural changes to the airways in ferrets, and assess whether the effects of smoking induce changes consistent with chronic bronchitis in humans. METHODS: Ferrets were exposed to mainstream cigarette smoke or air control twice daily for 6 months. µCT was conducted in vivo at 6 months; a longitudinal cohort was imaged monthly. Manual measurements of BWT, luminal diameter (LD), and BWT:LD ratio were conducted, and confirmed by a semi-automated algorithm. The square root of bronchial wall area (WA) vs. luminal perimeter was determined on an individual ferret basis. MEASUREMENTS AND MAIN RESULTS: Smoke exposed ferrets reproducibly demonstrated 34% increased BWT (P CONCLUSIONS: µCT-based airway measurements in ferrets are feasible and reproducible. Smoke exposed ferrets develop increased BWT and Pi4, changes similar to humans with chronic bronchitis. µCT can be used as a significant translational platform to measure dynamic airway morphological changes.

Published
2020
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