title: A pathogenic role for tumor necrosis factor-related apoptosis-inducing ligand in chronic obstructive pulmonary disease.
abstract: Chronic obstructive pulmonary disease (COPD) is a life-threatening inflammatory respiratory disorder, often induced by cigarette smoke (CS) exposure. The development of effective therapies is impaired by a lack of understanding of the underlining mechanisms. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine with inflammatory and apoptotic properties. We interrogated a mouse model of CS-induced experimental COPD and human tissues to identify a novel role for TRAIL in COPD pathogenesis. CS exposure of wild-type mice increased TRAIL and its receptor messenger RNA (mRNA) expression and protein levels, as well as the number of TRAIL(+)CD11b(+) monocytes in the lung. TRAIL and its receptor mRNA were also increased in human COPD. CS-exposed TRAIL-deficient mice had decreased pulmonary inflammation, pro-inflammatory mediators, emphysema-like alveolar enlargement, and improved lung function. TRAIL-deficient mice also developed spontaneous small airway changes with increased epithelial cell thickness and collagen deposition, independent of CS exposure. Importantly, therapeutic neutralization of TRAIL, after the establishment of early-stage experimental COPD, reduced pulmonary inflammation, emphysema-like alveolar enlargement, and small airway changes. These data provide further evidence for TRAIL being a pivotal inflammatory factor in respiratory diseases, and the first preclinical evidence to suggest that therapeutic agents that target TRAIL may be effective in COPD therapy.
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.|School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia.
authors.forename: T J
authors.initials: TJ
authors.lastname: Haw
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.|School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia.
authors.forename: M R
authors.initials: MR
authors.lastname: Starkey
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.|School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia.
authors.forename: P M
authors.initials: PM
authors.lastname: Nair
authors.affiliation: The Airways Disease Section, National Heart & Lung Institute, Imperial College London, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Pavlidis
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.|School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia.
authors.forename: G
authors.initials: G
authors.lastname: Liu
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.|School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia.
authors.forename: D H
authors.initials: DH
authors.lastname: Nguyen
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.|School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia.
authors.forename: A C
authors.initials: AC
authors.lastname: Hsu
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.|School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia.|Department of Microbiology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia.
authors.forename: I
authors.initials: I
authors.lastname: Hanish
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.|School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia.
authors.forename: R Y
authors.initials: RY
authors.lastname: Kim
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.|School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia.
authors.forename: A M
authors.initials: AM
authors.lastname: Collison
authors.affiliation: Department of Medicine, Firestone Institute for Respiratory Health, St. Joseph's Healthcare, McMaster University, Hamilton, Ontario, Canada.
authors.forename: M D
authors.initials: MD
authors.lastname: Inman
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.|School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia.
authors.forename: P A
authors.initials: PA
authors.lastname: Wark
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.|School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia.
authors.forename: P S
authors.initials: PS
authors.lastname: Foster
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.|School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia.
authors.forename: D A
authors.initials: DA
authors.lastname: Knight
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.|School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Mattes
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yagita
authors.affiliation: The Airways Disease Section, National Heart & Lung Institute, Imperial College London, London, UK.
authors.forename: I M
authors.initials: IM
authors.lastname: Adcock
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.|School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia.
authors.forename: J C
authors.initials: JC
authors.lastname: Horvat
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.|School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia.
authors.forename: P M
authors.initials: PM
authors.lastname: Hansbro
mesh_terms: D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics*; D020545:Respiratory Mucosa / Q000502:physiology*; D012907:Smoking / Q000009:adverse effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D018836:Inflammation Mediators; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse