RATIONALE: Emphysema is one component of chronic obstructive pulmonary disease (COPD), a respiratory disease currently increasing in prevalence worldwide. The mainstay therapy adopted to treat patients with COPD is glucocorticoids; unfortunately, this treatment has limited impact on disease symptoms or underlying airway inflammation. OBJECTIVE: There is an urgent need to develop therapies that modify both the underlying inflammation, thought to be involved in disease progression, and the structural changes in the emphysematous lung. METHODS: We have characterized an elastase-driven model of experimental emphysema in the rat that demonstrates COPD-like airway inflammation and determined the impact of a clinically relevant glucocorticoid. MEASUREMENTS AND MAIN RESULTS: We observed an increase in lung neutrophils, lymphomononuclear cells, mucus production, and inflammatory cytokines. Also present were increases in average air space area, which are associated with emphysema-like changes in lung function, such as increased residual volume and decreased flow; these increases in area were maintained for up to 10 weeks. In addition, we observed that elastase-induced airway neutrophilia is steroid resistant. Interestingly, the inflammation observed after elastase administration was found to be temporally associated with a lack of nuclear factor-kappaB pathway activation. This apparent nuclear factor-kappaB-independent inflammation may explain why treatment with a glucocorticoid was ineffective in this preclinical model and could suggest parallels in the steroid-resistant human disease. CONCLUSION: We believe that this model, in addition to its suitability for testing therapies that may modify existing emphysema, could be useful in the search for new therapies to reduce the steroid-resistant airway inflammation evident in COPD.
RATIONALE: Emphysema is one component of chronic obstructive pulmonary disease (COPD), a respiratory disease currently increasing in prevalence worldwide. The mainstay therapy adopted to treat patients with COPD is glucocorticoids; unfortunately, this treatment has limited impact on disease symptoms or underlying airway inflammation. OBJECTIVE: There is an urgent need to develop therapies that modify both the underlying inflammation, thought to be involved in disease progression, and the structural changes in the emphysematous lung. METHODS: We have characterized an elastase-driven model of experimental emphysema in the rat that demonstrates COPD-like airway inflammation and determined the impact of a clinically relevant glucocorticoid. MEASUREMENTS AND MAIN RESULTS: We observed an increase in lung neutrophils, lymphomononuclear cells, mucus production, and inflammatory cytokines. Also present were increases in average air space area, which are associated with emphysema-like changes in lung function, such as increased residual volume and decreased flow; these increases in area were maintained for up to 10 weeks. In addition, we observed that elastase-induced airway neutrophilia is steroid resistant. Interestingly, the inflammation observed after elastase administration was found to be temporally associated with a lack of nuclear factor-kappaB pathway activation. This apparent nuclear factor-kappaB-independent inflammation may explain why treatment with a glucocorticoid was ineffective in this preclinical model and could suggest parallels in the steroid-resistant human disease. CONCLUSION: We believe that this model, in addition to its suitability for testing therapies that may modify existing emphysema, could be useful in the search for new therapies to reduce the steroid-resistant airway inflammation evident in COPD.
Authors: David H McMillan; Carolyn J Baglole; Thomas H Thatcher; Sanjay Maggirwar; Patricia J Sime; Richard P Phipps Journal: Am J Pathol Date: 2011-05-05 Impact factor: 4.307
Authors: S A Tannu; L M Renzetti; N Tare; J D Ventre; D Lavelle; T A Lin; A Morschauser; J Paciorek; D R Bolin; H Michel; L Singer; M Hargaden; Id Knowles; P Gardiner; M Cazzola; L Calzetta; M G Matera; A Hicks Journal: Br J Pharmacol Date: 2010-11 Impact factor: 8.739
Authors: David M L Lilburn; Clémentine Lesbats; Joseph S Six; Eric Dubuis; Liang Yew-Booth; Dominick E Shaw; Maria G Belvisi; Mark A Birrell; Galina E Pavlovskaya; Thomas Meersmann Journal: J R Soc Interface Date: 2015-06-06 Impact factor: 4.118
Authors: Rajesh K Singh; Rebecca C Furze; Mark A Birrell; Sara M Rankin; Alistair N Hume; Miguel C Seabra Journal: BMC Cell Biol Date: 2014-10-31 Impact factor: 4.241