[en] Mucus plugs occlude airways to obstruct airflow in asthma. Studies in patients and in mouse models show that mucus plugs occur in the context of type 2 inflammation, and studies in human airway epithelial cells (HAECs) show that IL-13-activated cells generate pathologic mucus independently of immune cells. To determine how HAECs autonomously generate pathologic mucus, we used a magnetic microwire rheometer to characterize the viscoelastic properties of mucus secreted under varying conditions. We found that normal HAEC mucus exhibited viscoelastic liquid behavior and that mucus secreted by IL-13-activated HAECs exhibited solid-like behavior caused by mucin cross-linking. In addition, IL-13-activated HAECs shows increased peroxidase activity in apical secretions, and an overlaid thiolated polymer (thiomer) solution shows an increase in solid behavior that was prevented by peroxidase inhibition. Furthermore, gene expression for thyroid peroxidase (TPO), but not lactoperoxidase (LPO), was increased in IL-13-activated HAECs and both TPO and LPO catalyze the formation of oxidant acids that cross-link thiomer solutions. Finally, gene expression for TPO in airway epithelial brushings was increased in patients with asthma with high airway mucus plug scores. Together, our results show that IL-13-activated HAECs autonomously generated pathologic mucus via peroxidase-mediated cross-linking of mucin polymers.
Disciplines :
Immunology & infectious disease
Author, co-author :
Liégeois, Maude ; Université de Liège - ULiège > Département des sciences fonctionnelles (DSF) > Biochimie et biologie moléculaire ; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA
Braunreuther, Margaret; Department of Chemical Engineering, Stanford University, Stanford, California, USA
Charbit, Annabelle R; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA
Raymond, Wilfred W; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA
Tang, Monica; Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, UCSF, San Francisco, California, USA
Woodruff, Prescott G ; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA ; Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, UCSF, San Francisco, California, USA
Christenson, Stephanie A ; Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, UCSF, San Francisco, California, USA
Castro, Mario; Division of Pulmonary, Critical Care, and Sleep Medicine, University of Kansas School of Medicine, Kansas City, Kansas, USA
Erzurum, Serpil C; Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
Israel, Elliot; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
Jarjour, Nizar N; Division of Allergy, Pulmonary, and Critical Care Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
Levy, Bruce D ; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
Moore, Wendy C; Department of Internal Medicine, Section of Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
Wenzel, Sally E ; Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
Fuller, Gerald G; Department of Chemical Engineering, Stanford University, Stanford, California, USA
Fahy, John V; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA ; Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, UCSF, San Francisco, California, USA
NSF - National Science Foundation NIAID - National Institute of Allergy and Infectious Diseases NHLBI - National Heart Lung and Blood Institute
Funding text :
The authors thank Erin Gordon (UCSF) for providing human airway (tracheal) epithelial cells and the UCSF Genomic CoLab for their assistance with the sequencing data. The authors acknowledge Manuel Vazquez Villabeitia at the Institute of Material Science of Madrid, Spanish National Research Council (CSIC) for providing magnetic microwires. Javier Tajuelo is acknowledged for technical support of magnetic microwire procedures. The authors would like to thank the SARP clinical coordinators and laboratory personnel for their contribution to fulfilling SARP\u2019s scientific mission. The research findings resulting from SARP would not have been possible without their dedication and assistance with study visits, data collection, and biological sample processing. This work is supported in part by grants from the NIH National Heart Lung and Blood Institute grants (HL080414, HL107202, and AI077439). MB is supported by the Cystic Fibrosis Trust and the National Science Foundation Graduate Research Fellowship (NSF GRFP). The purchase of the Nikon SoRa microscope was funded by the NIH shared equipment grant S10OD028611-0.
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