title: Cigarette smoke-induced damage-associated molecular pattern release from necrotic neutrophils triggers proinflammatory mediator release.
abstract: Cigarette smoking, the major causative factor for the development of chronic obstructive pulmonary disease, is associated with neutrophilic airway inflammation. Cigarette smoke (CS) exposure can induce a switch from apoptotic to necrotic cell death in airway epithelium. Therefore, we hypothesized that CS promotes neutrophil necrosis with subsequent release of damage-associated molecular patterns (DAMPs), including high mobility group box 1 (HMGB1), alarming the innate immune system. We studied the effect of smoking two cigarettes on sputum neutrophils in healthy individuals and of 5-day CS or air exposure on neutrophil counts, myeloperoxidase, and HMGB1 levels in bronchoalveolar lavage fluid of BALB/c mice. In human peripheral blood neutrophils, mitochondrial membrane potential, apoptosis/necrosis markers, caspase activity, and DAMP release were studied after CS exposure. Finally, we assessed the effect of neutrophil-derived supernatants on the release of chemoattractant CXCL8 in normal human bronchial epithelial cells. Cigarette smoking caused a significant decrease in sputum neutrophil numbers after 3 hours. In mice, neutrophil counts were significantly increased 16 hours after repeated CS exposure but reduced 2 hours after an additional exposure. In vitro, CS induced necrotic neutrophil cell death, as indicated by mitochondrial dysfunction, inhibition of apoptosis, and DAMP release. Supernatants from CS-treated neutrophils significantly increased the release of CXCL8 in normal human bronchial epithelial cells. Together, these observations show, for the first time, that CS exposure induces neutrophil necrosis, leading to DAMP release, which may amplify CS-induced airway inflammation by promoting airway epithelial proinflammatory responses.
authors.affiliation: 1 Department of Pathology & Medical Biology.
authors.forename: Irene H
authors.initials: IH
authors.lastname: Heijink
authors.forename: Simon D
authors.initials: SD
authors.lastname: Pouwels
authors.forename: Carin
authors.initials: C
authors.lastname: Leijendekker
authors.forename: Harold G
authors.initials: HG
authors.lastname: de Bruin
authors.forename: G Jan
authors.initials: GJ
authors.lastname: Zijlstra
authors.forename: Hester
authors.initials: H
authors.lastname: van der Vaart
authors.forename: Nick H T
authors.initials: NH
authors.lastname: ten Hacken
authors.forename: Antoon J M
authors.initials: AJ
authors.lastname: van Oosterhout
authors.forename: Martijn C
authors.initials: MC
authors.lastname: Nawijn
authors.forename: Marco
authors.initials: M
authors.lastname: van der Toorn
mesh_terms: D000818:Animals; D017209:Apoptosis; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002478:Cells, Cultured; D018592:Cross-Over Studies; D005260:Female; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism*; D019570:Inhalation Exposure / Q000009:adverse effects; D016209:Interleukin-8 / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D053078:Membrane Potential, Mitochondrial; D008810:Mice, Inbred C57BL; D009336:Necrosis; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D010641:Phenotype; D011014:Pneumonia / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects* / Q000276:immunology / Q000378:metabolism; D013183:Sputum / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: C508606:CXCL8 protein, human; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D018836:Inflammation Mediators; D016209:Interleukin-8; D012906:Smoke; D009195:Peroxidase
keywords: chronic obstructive pulmonary disease; cigarette smoke; damage-associated molecular patterns; inflammation; neutrophils