Alpha-1 antitrypsin limits neutrophil extracellular trap disruption of airway epithelial barrier function
Neutrophil extracellular traps contribute to lung injury in cystic fibrosis and asthma, but the mechanisms are poorly understood. We sought to understand the impact of human NETs on barrier function in primary human bronchial epithelial and a human airway epithelial cell line. We demonstrate that NE...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.1023553/full |
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| author | K. M. Hudock K. M. Hudock K. M. Hudock M. S. Collins M. A. Imbrogno E. L. Kramer E. L. Kramer J. J. Brewington J. J. Brewington A. Ziady A. Ziady N. Zhang N. Zhang J. Snowball Y. Xu Y. Xu Y. Xu B. C. Carey B. C. Carey Y. Horio Y. Horio S. M. O’Grady S. M. O’Grady E. J. Kopras J. Meeker H. Morgan A. J. Ostmann E. Skala M. E. Siefert C. L. Na C. R. Davidson K. Gollomp K. Gollomp N. Mangalmurti N. Mangalmurti B. C. Trapnell B. C. Trapnell B. C. Trapnell J. P. Clancy |
| author_facet | K. M. Hudock K. M. Hudock K. M. Hudock M. S. Collins M. A. Imbrogno E. L. Kramer E. L. Kramer J. J. Brewington J. J. Brewington A. Ziady A. Ziady N. Zhang N. Zhang J. Snowball Y. Xu Y. Xu Y. Xu B. C. Carey B. C. Carey Y. Horio Y. Horio S. M. O’Grady S. M. O’Grady E. J. Kopras J. Meeker H. Morgan A. J. Ostmann E. Skala M. E. Siefert C. L. Na C. R. Davidson K. Gollomp K. Gollomp N. Mangalmurti N. Mangalmurti B. C. Trapnell B. C. Trapnell B. C. Trapnell J. P. Clancy |
| author_sort | K. M. Hudock |
| collection | DOAJ |
| description | Neutrophil extracellular traps contribute to lung injury in cystic fibrosis and asthma, but the mechanisms are poorly understood. We sought to understand the impact of human NETs on barrier function in primary human bronchial epithelial and a human airway epithelial cell line. We demonstrate that NETs disrupt airway epithelial barrier function by decreasing transepithelial electrical resistance and increasing paracellular flux, partially by NET-induced airway cell apoptosis. NETs selectively impact the expression of tight junction genes claudins 4, 8 and 11. Bronchial epithelia exposed to NETs demonstrate visible gaps in E-cadherin staining, a decrease in full-length E-cadherin protein and the appearance of cleaved E-cadherin peptides. Pretreatment of NETs with alpha-1 antitrypsin (A1AT) inhibits NET serine protease activity, limits E-cadherin cleavage, decreases bronchial cell apoptosis and preserves epithelial integrity. In conclusion, NETs disrupt human airway epithelial barrier function through bronchial cell death and degradation of E-cadherin, which are limited by exogenous A1AT. |
| first_indexed | 2024-04-10T23:49:45Z |
| format | Article |
| id | doaj.art-f5f449250f9b4c29852fec5e049dfdcd |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-10T23:49:45Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-f5f449250f9b4c29852fec5e049dfdcd2023-01-10T21:37:58ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-01-011310.3389/fimmu.2022.10235531023553Alpha-1 antitrypsin limits neutrophil extracellular trap disruption of airway epithelial barrier functionK. M. Hudock0K. M. Hudock1K. M. Hudock2M. S. Collins3M. A. Imbrogno4E. L. Kramer5E. L. Kramer6J. J. Brewington7J. J. Brewington8A. Ziady9A. Ziady10N. Zhang11N. Zhang12J. Snowball13Y. Xu14Y. Xu15Y. Xu16B. C. Carey17B. C. Carey18Y. Horio19Y. Horio20S. M. O’Grady21S. M. O’Grady22E. J. Kopras23J. Meeker24H. Morgan25A. J. Ostmann26E. Skala27M. E. Siefert28C. L. Na29C. R. Davidson30K. Gollomp31K. Gollomp32N. Mangalmurti33N. Mangalmurti34B. C. Trapnell35B. C. Trapnell36B. C. Trapnell37J. P. Clancy38Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United StatesDivision of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United StatesDepartment of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United StatesDivision of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United StatesDivision of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United StatesDepartment of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United StatesDivision of Pediatric Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United StatesDepartment of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United StatesDivision of Pediatric Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United StatesDepartment of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United StatesDivision of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United StatesDepartment of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United StatesDivision of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United StatesDivision of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United StatesDivision of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United StatesDepartment of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United StatesDivisions of Biomedical Informatics, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United StatesDepartment of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United StatesTranslational Pulmonary Science Center, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United StatesDivision of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United StatesDepartment of Respiratory Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto-shi, Kumamoto, Japan0Departments of Animal Science, University of Minnesota, St. Paul, MN, United States1Department of Integrative Biology and Physiology, University of Minnesota, St. Paul, MN, United StatesDivision of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United StatesDivision of Pediatric Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United StatesDivision of Pediatric Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United StatesDivision of Pediatric Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United StatesDivision of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United StatesDivision of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United StatesDivision of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United StatesDivision of Pediatric Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States2Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States3Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States4Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States5Pennsylvania Lung Biology Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United StatesDivision of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United StatesDepartment of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United StatesTranslational Pulmonary Science Center, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States6Cystic Fibrosis Foundation, Bethesda, MD, United StatesNeutrophil extracellular traps contribute to lung injury in cystic fibrosis and asthma, but the mechanisms are poorly understood. We sought to understand the impact of human NETs on barrier function in primary human bronchial epithelial and a human airway epithelial cell line. We demonstrate that NETs disrupt airway epithelial barrier function by decreasing transepithelial electrical resistance and increasing paracellular flux, partially by NET-induced airway cell apoptosis. NETs selectively impact the expression of tight junction genes claudins 4, 8 and 11. Bronchial epithelia exposed to NETs demonstrate visible gaps in E-cadherin staining, a decrease in full-length E-cadherin protein and the appearance of cleaved E-cadherin peptides. Pretreatment of NETs with alpha-1 antitrypsin (A1AT) inhibits NET serine protease activity, limits E-cadherin cleavage, decreases bronchial cell apoptosis and preserves epithelial integrity. In conclusion, NETs disrupt human airway epithelial barrier function through bronchial cell death and degradation of E-cadherin, which are limited by exogenous A1AT.https://www.frontiersin.org/articles/10.3389/fimmu.2022.1023553/fullNETs (neutrophil extracellular traps)alpha-1 antitrypsin (A1AT)barrier functionbronchial epitheliaE-cadherin (CDH1) |
| spellingShingle | K. M. Hudock K. M. Hudock K. M. Hudock M. S. Collins M. A. Imbrogno E. L. Kramer E. L. Kramer J. J. Brewington J. J. Brewington A. Ziady A. Ziady N. Zhang N. Zhang J. Snowball Y. Xu Y. Xu Y. Xu B. C. Carey B. C. Carey Y. Horio Y. Horio S. M. O’Grady S. M. O’Grady E. J. Kopras J. Meeker H. Morgan A. J. Ostmann E. Skala M. E. Siefert C. L. Na C. R. Davidson K. Gollomp K. Gollomp N. Mangalmurti N. Mangalmurti B. C. Trapnell B. C. Trapnell B. C. Trapnell J. P. Clancy Alpha-1 antitrypsin limits neutrophil extracellular trap disruption of airway epithelial barrier function Frontiers in Immunology NETs (neutrophil extracellular traps) alpha-1 antitrypsin (A1AT) barrier function bronchial epithelia E-cadherin (CDH1) |
| title | Alpha-1 antitrypsin limits neutrophil extracellular trap disruption of airway epithelial barrier function |
| title_full | Alpha-1 antitrypsin limits neutrophil extracellular trap disruption of airway epithelial barrier function |
| title_fullStr | Alpha-1 antitrypsin limits neutrophil extracellular trap disruption of airway epithelial barrier function |
| title_full_unstemmed | Alpha-1 antitrypsin limits neutrophil extracellular trap disruption of airway epithelial barrier function |
| title_short | Alpha-1 antitrypsin limits neutrophil extracellular trap disruption of airway epithelial barrier function |
| title_sort | alpha 1 antitrypsin limits neutrophil extracellular trap disruption of airway epithelial barrier function |
| topic | NETs (neutrophil extracellular traps) alpha-1 antitrypsin (A1AT) barrier function bronchial epithelia E-cadherin (CDH1) |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.1023553/full |
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