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: T J Haw, M R Starkey, P M Nair, S Pavlidis, G Liu, D H Nguyen, A C Hsu, I Hanish, R Y Kim, A M Collison, M D Inman, P A Wark, P S Foster, D A Knight, J Mattes, H Yagita, I M Adcock, J C Horvat, P M Hansbro
• Journal: Mucosal immunology (Mucosal Immunol) Vol. 9 Issue 4 Pg. 859-72 (07 2016) ISSN: 1935-3456 [Electronic] United States
• PMID: 26555706 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Inflammation Mediators
• RNA, Messenger
• TNF-Related Apoptosis-Inducing Ligand
• Tnfsf10 protein, mouse

Topics

• Animals
• Apoptosis
• Disease Models, Animal
• Female
• Humans
• Inflammation (immunology)
• Inflammation Mediators (metabolism)
• Lung (immunology)
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• Monocytes (immunology)
• Pulmonary Disease, Chronic Obstructive (immunology)
• RNA, Messenger (genetics)
• Respiratory Mucosa (physiology)
• Smoking (adverse effects)
• TNF-Related Apoptosis-Inducing Ligand (genetics, metabolism)
• Up-Regulation