A new short-term mouse model of chronic obstructive pulmonary disease identifies a role for mast cell tryptase in pathogenesis

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:131

Article

Beckett, Emma L.^1,2  Stevens, Richard L.^3,4  Jarnicki, Andrew G.^1,2  Kim, Richard Y.^1,2  Hanish, Irwan^1,2  Hansbro, Nicole G.^1,2  Deane, Andrew^1,2  Keely, Simon^1,2  Horvat, Jay C.^1,2  Yang, Ming^1,2  Oliver, Brian G.^5,6  van Rooijen, Nico⁷  Inman, Mark D.⁸  Adachi, Roberto⁹  Soberman, Roy J.^3,10  Hamadi, Sahar⁴  Wark, Peter A.^1,2,11  Foster, Paul S.^1,2  Hansbro, Philip M.^1,2 

[1] Univ Newcastle, Prior Res Ctr Asthma & Resp Dis, Newcastle, NSW 2308, Australia

[2] Univ Newcastle, Hunter Med Res Inst, Newcastle, NSW 2308, Australia

[3] Harvard Univ, Dept Med, Sch Med, Cambridge, MA 02138 USA

[4] Brigham & Womens Hosp, Boston, MA 02115 USA

[5] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia

[6] Univ Sydney, Woolcock Inst Med Res, Sydney, NSW 2006, Australia

[7] Vrije Univ, Dept Mol Cell Biol, Med Ctr, Amsterdam, Netherlands

[8] St Josephs Healthcare, Firestone Inst Resp Hlth, Hamilton, ON, Canada

[9] Univ Texas MD Anderson Canc Ctr, Dept Pulm Med, Houston, TX 77030 USA

[10] Massachusetts Gen Hosp, Boston, MA 02114 USA

[11] John Hunter Hosp, Dept Resp & Sleep Med, Newcastle, NSW, Australia

关键词: Cigarette smoke;    chronic obstructive pulmonary disease;    inflammation;    emphysema;    airway remodeling;    lung function;    macrophage;    mast cell;    protease;    mouse mast cell protease 6;    htryptase-beta;   

DOI  :  10.1016/j.jaci.2012.11.053

来源: Elsevier

【 摘 要 】

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. (J Allergy Clin Immunol 2013;131:752-62.)

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