RATIONALE: There is a need for new agents capable of suppressing the inflammatory response in chronic obstructive pulmonary disease. OBJECTIVES: This study evaluated the effects of roflumilast, a phosphodiesterase 4 (PDE4) inhibitor on acute lung inflammation and chronic lung changes in models of cigarette exposure in mice. METHODS: Roflumilast was given orally either at 1 mg/kg (R1) or at 5 mg/kg (R5). In the acute model (five cigarettes for 20 minutes), bronchoalveolar lavage fluid (BALF) changes were investigated at 4 and 24 hours. In the chronic model (three cigarettes/day for 7 months), morphometric and biochemical parameters were assessed at 7 months. MEASUREMENTS AND MAIN RESULTS: Acute exposure caused a fivefold increase in BALF neutrophils. Both doses of roflumilast partially prevented (by 30%) this increase. In addition, after smoke exposure, R1 increased BALF interleukin-10 by 79% and R5 by 129%. Chronic smoke exposure caused a 1.8-fold increase in lung macrophage density, emphysema, an increase of the mean linear intercept (+21%), a decrease of the internal surface area (-13%), and a drop (-13%) in lung desmosine content. R1 did not have any effect, whereas R5 prevented the increase in lung macrophage density by 70% and fully prevented the other changes. In addition, in the smoke-exposure group, 63% of the mice showed goblet cell metaplasia, and neither of the doses of roflumilast had any effect. CONCLUSIONS: This study shows for the first time that a PDE4 inhibitor partially ameliorates lung inflammation and fully prevents parenchymal destruction induced by cigarette smoke.
RATIONALE: There is a need for new agents capable of suppressing the inflammatory response in chronic obstructive pulmonary disease. OBJECTIVES: This study evaluated the effects of roflumilast, a phosphodiesterase 4 (PDE4) inhibitor on acute lung inflammation and chronic lung changes in models of cigarette exposure in mice. METHODS: Roflumilast was given orally either at 1 mg/kg (R1) or at 5 mg/kg (R5). In the acute model (five cigarettes for 20 minutes), bronchoalveolar lavage fluid (BALF) changes were investigated at 4 and 24 hours. In the chronic model (three cigarettes/day for 7 months), morphometric and biochemical parameters were assessed at 7 months. MEASUREMENTS AND MAIN RESULTS: Acute exposure caused a fivefold increase in BALF neutrophils. Both doses of roflumilast partially prevented (by 30%) this increase. In addition, after smoke exposure, R1 increased BALF interleukin-10 by 79% and R5 by 129%. Chronic smoke exposure caused a 1.8-fold increase in lung macrophage density, emphysema, an increase of the mean linear intercept (+21%), a decrease of the internal surface area (-13%), and a drop (-13%) in lung desmosine content. R1 did not have any effect, whereas R5 prevented the increase in lung macrophage density by 70% and fully prevented the other changes. In addition, in the smoke-exposure group, 63% of the mice showed goblet cell metaplasia, and neither of the doses of roflumilast had any effect. CONCLUSIONS: This study shows for the first time that a PDE4 inhibitor partially ameliorates lung inflammation and fully prevents parenchymal destruction induced by cigarette smoke.
Authors: Gloria S Forkuo; Hosu Kim; Vaidehi J Thanawala; Nour Al-Sawalha; Daniel Valdez; Radhika Joshi; Sergio Parra; Tonio Pera; Patricia A Gonnella; Brian J Knoll; Julia K L Walker; Raymond B Penn; Richard A Bond Journal: Am J Respir Cell Mol Biol Date: 2016-08 Impact factor: 6.914
Authors: Angie L Hertz; Andrew T Bender; Kimberly C Smith; Mark Gilchrist; Paul S Amieux; Alan Aderem; Joseph A Beavo Journal: Proc Natl Acad Sci U S A Date: 2009-12-03 Impact factor: 11.205
Authors: Wing-Yan Heidi Wan; Abigail Morris; Gillian Kinnear; William Pearce; Joanie Mok; Daniel Wyss; Christopher S Stevenson Journal: Respir Res Date: 2010-09-18