Extracellular DNA, Neutrophil Extracellular Traps, and Inflammasome Activation in Severe Asthma.

Autor: Lachowicz-Scroggins ME; 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, and.; 2 Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California., Dunican EM; 3 School of Medicine and St. Vincent's University Hospital, University College Dublin, Dublin, Ireland., Charbit AR; 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, and.; 2 Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California., Raymond W; 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, and.; 2 Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California., Looney MR; 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, and.; 2 Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California., Peters MC; 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, and.; 2 Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California., Gordon ED; 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, and.; 2 Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California., Woodruff PG; 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, and.; 2 Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California., Lefrançais E; 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, and.; 2 Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California., Phillips BR; 4 Division of Statistics and Bioinformatics, Department of Public Health Sciences, Pennsylvania State University, Hershey, Pennsylvania., Mauger DT; 4 Division of Statistics and Bioinformatics, Department of Public Health Sciences, Pennsylvania State University, Hershey, Pennsylvania., Comhair SA; 5 Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio., Erzurum SC; 5 Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio., Johansson MW; 6 Department of Biomolecular Chemistry and., Jarjour NN; 7 Section of Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, Wisconsin., Coverstone AM; 8 Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri., Castro M; 8 Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri., Hastie AT; 9 Pulmonary Section, Department of Internal Medicine, School of Medicine, Wake Forest University, Winston-Salem, North Carolina., Bleecker ER; 10 Division of Genetics, Genomics, and Precision Medicine, Department of Medicine, University of Arizona, Tucson, Arizona., Fajt ML; 11 Pulmonary, Allergy and Critical Care Medicine Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;and., Wenzel SE; 11 Pulmonary, Allergy and Critical Care Medicine Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;and., Israel E; 12 Division of Pulmonary and Critical Care Medicine, Brigham Research Institute, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts., Levy BD; 12 Division of Pulmonary and Critical Care Medicine, Brigham Research Institute, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts., Fahy JV; 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, and.; 2 Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California.
Jazyk: angličtina
Zdroj: American journal of respiratory and critical care medicine [Am J Respir Crit Care Med] 2019 May 01; Vol. 199 (9), pp. 1076-1085.
DOI: 10.1164/rccm.201810-1869OC
Abstrakt: Rationale: Extracellular DNA (eDNA) and neutrophil extracellular traps (NETs) are implicated in multiple inflammatory diseases. NETs mediate inflammasome activation and IL-1β secretion from monocytes and cause airway epithelial cell injury, but the role of eDNA, NETs, and IL-1β in asthma is uncertain. Objectives: To characterize the role of activated neutrophils in severe asthma through measurement of NETs and inflammasome activation. Methods: We measured sputum eDNA in induced sputum from 399 patients with asthma in the Severe Asthma Research Program-3 and in 94 healthy control subjects. We subdivided subjects with asthma into eDNA-low and -high subgroups to compare outcomes of asthma severity and of neutrophil and inflammasome activation. We also examined if NETs cause airway epithelial cell damage that can be prevented by DNase. Measurements and Main Results: We found that 13% of the Severe Asthma Research Program-3 cohort is "eDNA-high," as defined by sputum eDNA concentrations above the upper 95th percentile value in health. Compared with eDNA-low patients with asthma, eDNA-high patients had lower Asthma Control Test scores, frequent history of chronic mucus hypersecretion, and frequent use of oral corticosteroids for maintenance of asthma control (all P values <0.05). Sputum eDNA in asthma was associated with airway neutrophilic inflammation, increases in soluble NET components, and increases in caspase 1 activity and IL-1β (all P values <0.001). In in vitro studies, NETs caused cytotoxicity in airway epithelial cells that was prevented by disruption of NETs with DNase. Conclusions: High extracellular DNA concentrations in sputum mark a subset of patients with more severe asthma who have NETs and markers of inflammasome activation in their airways.
Databáze: MEDLINE