Published Online: March 1, 2013
Chronic obstructive pulmonary disease (COPD, a.k.a. emphysema) is the fourth leading cause of death, as determined by the World Health Organization (WHO). It presently is the sixth, third, and fifth leading killer in low-, middle-, and high-income countries, respectively. Thus, COPD is an immense health problem throughout the globe. Indeed, the number of people who recently died of COPD almost equaled that of AIDS and cancer combined. Alarmingly, the situation is rapidly deteriorating. The WHO predicts that ~10% of all deaths in the world by 2030 will be attributed to smoke-induced COPD unless something is done fairly soon. Unfortunately, there is no cure or effective therapy for COPD, and progress towards their development has been slow. This is due to deficiencies in our understanding at the molecular level of the factors and mechanisms that control the development of this life-threatening inflammatory disorder of the lung. The lack of an animal model that mimics the human disease in a short time-frame has also hindered our understanding of COPD.
In the Beckett et al. study in The Journal of Allergy and Clinical Immunology (JACI), Professors Hansbro and Stevens and their coworkers describe a new cigarette smoke-induced model of COPD.1 Mice that were exposed to cigarette smoke for 2.5 hours a day 5 days a week developed the hallmarks of the human disease in just 8 weeks (e.g., chronic inflammation, increased pulmonary expression of pro-inflammatory cytokines and chemokines, mucus hypersecretion, airway remodeling, emphysema, and impaired lung function). The characteristic features of COPD were glucocorticoid-resistant, and did not rapidly resolve once the animals ceased smoking. Also observed were systemic effects on skeletal muscle and the heart. In addition, the smoke-treated mice were more susceptible to respiratory infections. The experimental model can be used to elucidate the cellular, biochemical, immunological, and molecular mechanisms that underpin the pathogenesis of COPD, including the induction and progression phases of the disease. For example, increased numbers of activated macrophages are often found in the lungs of humans with COPD, and it has been concluded that these phagocytes have prominent adverse roles in the disease. Macrophages were also found to be important in the new experimental COPD model.
Human tryptase-beta is the major constituent of the secretory granules of pulmonary mast cells (MCs). Mouse MC protease-6 (mMCP-6) is its equivalent. It is now known that MCs and their exocytosed tetramer-forming tryptases have beneficial roles in bacterial and parasitic infections but adverse roles in inflammatory arthritis and colitis. Professor Stevens and his coworkers created an mMCP-6-deficient mouse line in 2007. Professors Hansbro and Stevens and their team then showed in the Beckett et al. study that cigarette smoke-induced COPD was significantly reduced in these transgenic mice. In support of the in vivo data, these investigators demonstrated that recombinant human tryptase-beta induced cultured macrophages to markedly increase their expression of numerous pro-inflammatory chemokines and cytokines. The mechanism by which MC tryptases induce macrophages to increase their expression of cytokines and chemokines remains to be determined at the molecular level. Nevertheless, the collective data suggest that mMCP-6 and human tryptase-beta are associated with macrophage accumulation and macrophage-dependent inflammation, remodeling, and emphysema in COPD. The Beckett et al. study raises the possibility that synthetic inhibitors of human tryptase-beta might be of therapeutic benefit in the treatment of patients with COPD.
1. Beckett EL, Stevens RL, Jarnicki AG, Kim RY, Hanish I, Hansbro NG, et al. A short-term model of COPD identifies a role for mast cell tryptase. J Allergy Clin Immunol 2013;000:000-000
The Journal of Allergy and Clinical Immunology is an official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.