The tumor necrosis factor family member LIGHT is a target for asthmatic airway remodeling

• Published in: Nature medicine Vol. 17; no. 5; pp. 596 - 603
• Main Authors: Doherty, Taylor A, Soroosh, Pejman, Khorram, Naseem, Fukuyama, Satoshi, Rosenthal, Peter, Cho, Jae Youn, Norris, Paula S, Choi, Heonsik, Scheu, Stefanie, Pfeffer, Klaus, Zuraw, Bruce L, Ware, Carl F, Broide, David H, Croft, Michael
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2011; Nature Publishing Group
• Subjects: 631/250/127/1220; 631/250/251; 692/699/249/2510/31; Airway (Medicine); Airway Remodeling - physiology; Allergens; Animals; Asthma; Asthma - etiology; Asthma - pathology; Asthma - physiopathology; Biomedical and Life Sciences; Biomedicine; Cancer Research; Chronic illnesses; Disease Models, Animal; Families & family life; Humans; Infectious Diseases; Inflammation Mediators - physiology; Interleukin-13 - physiology; Lung - pathology; Lung - physiopathology; Lungs; Lymphotoxin alpha1, beta2 Heterotrimer - antagonists & inhibitors; Lymphotoxin alpha1, beta2 Heterotrimer - physiology; Metabolic Diseases; Mice; Mice, Knockout; Molecular Medicine; Neurosciences; Physiological aspects; Respiratory function; Signal Transduction; Transforming Growth Factor beta - physiology; Tumor necrosis factor; Tumor Necrosis Factor Ligand Superfamily Member 14 - antagonists & inhibitors; Tumor Necrosis Factor Ligand Superfamily Member 14 - deficiency; Tumor Necrosis Factor Ligand Superfamily Member 14 - genetics; Tumor Necrosis Factor Ligand Superfamily Member 14 - physiology; United States
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.2356

Chronic inflammation of the airways is associated with remodeling and fibrosis, leading to a progressive decline in lung function in people with severe asthma. Michael Croft and his colleagues report that in mouse models of allergic lung inflammation expression of the TNF family member LIGHT is induced. Blockade of LIGHT prevents remodeling, providing a therapeutic strategy to prevent asthmatic airway remodeling. Individuals with chronic asthma show a progressive decline in lung function that is thought to be due to structural remodeling of the airways characterized by subepithelial fibrosis and smooth muscle hyperplasia. Here we show that the tumor necrosis factor (TNF) family member LIGHT is expressed on lung inflammatory cells after allergen exposure. Pharmacological inhibition of LIGHT using a fusion protein between the IgG Fc domain and lymphotoxin β receptor (LTβR) reduces lung fibrosis, smooth muscle hyperplasia and airway hyperresponsiveness in mouse models of chronic asthma, despite having little effect on airway eosinophilia. LIGHT-deficient mice also show a similar impairment in fibrosis and smooth muscle accumulation. Blockade of LIGHT suppresses expression of lung transforming growth factor-β (TGF-β) and interleukin-13 (IL-13), cytokines implicated in remodeling in humans, whereas exogenous administration of LIGHT to the airways induces fibrosis and smooth muscle hyperplasia, Thus, LIGHT may be targeted to prevent asthma-related airway remodeling.