A new short-term mouse model of chronic obstructive pulmonary disease identifies a role for mast cell tryptase in pathogenesis - 27/02/13
, Richard L. Stevens, PhD b, c, , Andrew G. Jarnicki, PhD a, , Richard Y. Kim, B Biomed Sci a, Irwan Hanish, BSc a, Nicole G. Hansbro, PhD a, Andrew Deane, BSc a, Simon Keely, PhD a, Jay C. Horvat, PhD a, Ming Yang, MD, PhD a, Brian G. Oliver, PhD d, Nico van Rooijen, PhD e, Mark D. Inman, MD, PhD f, Roberto Adachi, MD g, Roy J. Soberman, MD b, h, Sahar Hamadi c, Peter A. Wark, MD, PhD a, i, Paul S. Foster, PhD a, Philip M. Hansbro, PhD a, ⁎ 
Corresponding author: Philip M. Hansbro, PhD, Priority Research Centre for Asthma and Respiratory Disease and Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW 2308, Australia.Abstract |
Background |
Cigarette smoke–induced chronic obstructive pulmonary disease (COPD) is a life-threatening inflammatory disorder of the lung. The development of effective therapies for COPD has been hampered by the lack of an animal model that mimics the human disease in a short timeframe.
Objectives |
We sought to create an early-onset mouse model of cigarette smoke–induced COPD that develops the hallmark features of the human condition in a short time-frame. We also sought to use this model to better understand pathogenesis and the roles of macrophages and mast cells (MCs) in patients with COPD.
Methods |
Tightly controlled amounts of cigarette smoke were delivered to the airways of mice, and the development of the pathologic features of COPD was assessed. The roles of macrophages and MC tryptase in pathogenesis were evaluated by using depletion and in vitro studies and MC protease 6–deficient mice.
Results |
After just 8 weeks of smoke exposure, wild-type mice had chronic inflammation, mucus hypersecretion, airway remodeling, emphysema, and reduced lung function. These characteristic features of COPD were glucocorticoid resistant and did not spontaneously resolve. Systemic effects on skeletal muscle and the heart and increased susceptibility to respiratory tract infections also were observed. Macrophages and tryptase-expressing MCs were required for the development of COPD. Recombinant MC tryptase induced proinflammatory responses from cultured macrophages.
Conclusion |
A short-term mouse model of cigarette smoke–induced COPD was developed in which the characteristic features of the disease were induced more rapidly than in existing models. The model can be used to better understand COPD pathogenesis, and we show a requirement for macrophages and tryptase-expressing MCs.
Le texte complet de cet article est disponible en PDF.Key words : Cigarette smoke, chronic obstructive pulmonary disease, inflammation, emphysema, airway remodeling, lung function, macrophage, mast cell, protease, mouse mast cell protease 6, htryptase-β
Abbreviations used : B6, BALF, COPD, FEV100, FRC, FVC, htryptase-β, MC, mMCP, qPCR, TLC, WT
Plan
| Supported by grants from the National Health and Medical Research Council of Australia (510762, 569219, 1003565, 1003593, and 1023131), the US National Institutes of Health (AI065858 and AI059746), and the Harvard Club of Australia Foundation. |
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| Disclosure of potential conflict of interest: R. L. Stevens has been supported by one or more grants from the National Institutes of Health. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 131 - N° 3
P. 752 - mars 2013 Retour au numéro
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