期刊
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
卷 64, 期 1, 页码 69-78出版社
AMER THORACIC SOC
DOI: 10.1165/rcmb.2020-0168OC
关键词
macrorheology; microrheology; multiple particle tracking; muco-inert nanoparticles; respiratory tract diseases
资金
- U.S. National Institutes of Health [1R01HL139673, P30CA016059, R01EY027827, DA048768]
- U.S. Food and Drug Administration [HHSF223201810114C]
- Cystic Fibrosis Foundation Postdoctal Research Fellowship [CHAI20F0]
- George and Lavinia Blick Research Fund
- Janivo Foundation (the Netherlands)
- C.J. Vaillant Foundation (the Netherlands)
- European Respiratory Society Long-Term Research Fellowship
- Amsterdam University Medical Center PhD Graduate School Scholarship
This study suggests that the release of neutrophil extracellular traps (NETs) may contribute to airway mucus obstruction by increasing mucus viscoelasticity, and that this effect is partly due to oxidative stress.
Mucus obstruction is a key feature of many inflammatory airway diseases. Neutrophil extracellular traps (NETs) are released upon neutrophil stimulation and consist of extracellular chromatin networks studded with cytotoxic proteins. When released in the airways, these NETs can become part of the airway mucus. We hypothesized that the extracellular DNA and/or oxidative stress (e.g., by the release of reactive oxygen species and myeloperoxidase during NETs formation in the airways) would increase mucus viscoelasticity. We collected human airway mucus from endotracheal tubes of healthy patients admitted for elective surgery and coincubated these samples with NETs from phorbol 12-myristate 13-acetate-stimulated neutrophils. Unstimulated neutrophils served as controls, and blocking experiments were performed with dornase alfa for extracellular DNA and the free radical scavenger dimethylthiourea for oxidation. Compared with controls, the coincubation of mucus with NETs resulted in 1) significantly increased mucus viscoelasticity (macrorheology) and 2) significantly decreased mesh pore size of the mucus and decreased movement of muco-inert nanoparticles through the mucus (microrheology), but 3) NETs did not cause visible changes in the microstructure of the mucus by scanning EM. Incubation with either dornase alfa or dimethylthiourea attenuated the observed changes in macrorheology and microrheology. This suggests that the release of NETs may contribute to airway mucus obstruction by increasing mucus viscoelasticity and that this effect is not solely due to the release of DNA but may in part be due to oxidative stress.
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