title: Roflumilast increases Clara cell secretory protein in cigarette smoke-exposed mice.
abstract: Decreased Clara cell secretory protein (CCSP) levels have been found in smokers and chronic obstructive pulmonary disease (COPD) patients, which may be related to the development of COPD. A phosphodiesterase-4 (PDE4) inhibitor, roflumilast, appears to have therapeutic value for COPD. However, its effect on CCSP in cigarette smoke (CS)-exposed lungs has not been investigated. AKR/J mice were treated as follows: air control, CS, roflumilast plus CS, and roflumilast. Mice underwent four weeks of air or CS exposure. Roflumilast was administrated at 5mg/kg via gavage once daily for the duration of the study. CCSP levels in bronchoalveolar lavage (BAL) fluid and ERK1/2 activation in lungs were examined. CS exposure tended to decrease CCSP levels in BAL fluid compared to air controls. Treatment with roflumilast significantly reversed CS-induced downward trend of CCSP in BAL fluid. Roflumilast significantly inhibited CS-induced upward trend of ERK1/2 activation in lungs, and the levels of activated ERK1/2 in lungs negatively correlated with CCSP levels of BAL fluid in CS, and CS plus roflumilast groups. Our results demonstrate that one of the therapeutic mechanisms of roflumilast is to reverse CS-induced downward trend in CCSP levels of BAL fluid, which may be mediated by down-regulating ERK1/2 activity.
authors.affiliation: Department of Medicine, National Jewish Health and the University of Colorado Denver, Denver, CO 80206, USA. gexn@umn.edu
authors.forename: Xiao Na
authors.initials: XN
authors.lastname: Ge
authors.forename: Hong Wei
authors.initials: HW
authors.lastname: Chu
authors.forename: Maisha N
authors.initials: MN
authors.lastname: Minor
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: Case
authors.forename: David G
authors.initials: DG
authors.lastname: Bosch
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Martin
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D003521:Cyclopropanes / Q000494:pharmacology; D015536:Down-Regulation; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy; D012907:Smoking / Q000009:adverse effects*; D018709:Statistics, Nonparametric; D014598:Uteroglobin / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; D010726:Phosphodiesterase Inhibitors; D018809:Proliferating Cell Nuclear Antigen; C556390:Scgb1a1 protein, mouse; C424423:Roflumilast; D014598:Uteroglobin; D020928:Mitogen-Activated Protein Kinases