title: A new short-term mouse model of chronic obstructive pulmonary disease identifies a role for mast cell tryptase in pathogenesis.
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.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors: Priority Research Centre for Asthma and Respiratory Disease and Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia.
authors: Emma L
authors: EL
authors: Beckett
authors: Richard L
authors: RL
authors: Stevens
authors: Andrew G
authors: AG
authors: Jarnicki
authors: Richard Y
authors: RY
authors: Kim
authors: Irwan
authors: I
authors: Hanish
authors: Nicole G
authors: NG
authors: Hansbro
authors: Andrew
authors: A
authors: Deane
authors: Simon
authors: S
authors: Keely
authors: Jay C
authors: JC
authors: Horvat
authors: Ming
authors: M
authors: Yang
authors: Brian G
authors: BG
authors: Oliver
authors: Nico
authors: N
authors: van Rooijen
authors: Mark D
authors: MD
authors: Inman
authors: Roberto
authors: R
authors: Adachi
authors: Roy J
authors: RJ
authors: Soberman
authors: Sahar
authors: S
authors: Hamadi
authors: Peter A
authors: PA
authors: Wark
authors: Paul S
authors: PS
authors: Foster
authors: Philip M
authors: PM
authors: Hansbro
mesh_terms: D056151:Airway Remodeling; D000818:Animals; D004195:Disease Models, Animal; D008264:Macrophages / Q000276:immunology; D008407:Mast Cells / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D012129:Respiratory Function Tests; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana; D053802:Tryptases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*
chemical_list: D012906:Smoke; C509190:Tpsb2 protein, mouse; D053802:Tryptases
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