title: Phosphodiesterase 4 inhibitor GPD-1116 markedly attenuates the development of cigarette smoke-induced emphysema in senescence-accelerated mice P1 strain.
abstract: Phosphodiesterase 4 (PDE4) is an intracellular enzyme specifically degrading cAMP, a second messenger exerting inhibitory effects on many inflammatory cells. To investigate whether GPD-1116 (a PDE4 inhibitor) prevents murine lungs from developing cigarette smoke-induced emphysema, the senescence-accelerated mouse (SAM) P1 strain was exposed to either fresh air or cigarette smoke for 8 wk with or without oral administration of GPD-1116. We confirmed the development of smoke-induced emphysema in SAMP1 [air vs. smoke (means +/- SE); the mean linear intercepts (MLI), 52.9 +/- 0.8 vs. 68.4 +/- 4.2 microm, P < 0.05, and destructive index (DI), 4.5% +/- 1.3% vs. 16.0% +/- 0.4%, P < 0.01]. Emphysema was markedly attenuated by GPD-1116 (MLI = 57.0 +/- 1.4 microm, P < 0.05; DI = 8.2% +/- 0.6%, P < 0.01) compared with smoke-exposed SAMP1 without GPD-1116. Smoke-induced apoptosis of lung cells were also reduced by administration of GPD-1116. Matrix metalloproteinase (MMP)-12 activity in bronchoalveolar lavage fluid (BALF) was increased by smoke exposure (air vs. smoke, 4.1 +/- 1.1 vs. 40.5 +/- 16.2 area/microg protein; P < 0.05), but GPD-1116 significantly decreased MMP-12 activity in smoke-exposed mice (5.3 +/- 2.1 area/microg protein). However, VEGF content in lung tissues and BALF decreased after smoke exposure, and the decrease was not markedly restored by oral administration of GPD-1116. Our study suggests that GPD-1116 attenuates smoke-induced emphysema by inhibiting the increase of smoke-induced MMP-12 activity and protecting lung cells from apoptosis, but is not likely to alleviate cigarette smoke-induced decrease of VEGF in SAMP1 lungs.
authors.affiliation: Department of Respiratory Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo 113-8421, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mori
authors.forename: Takashi
authors.initials: T
authors.lastname: Nose
authors.forename: Kouki
authors.initials: K
authors.lastname: Ishitani
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kasagi
authors.forename: Sanae
authors.initials: S
authors.lastname: Souma
authors.forename: Taeko
authors.initials: T
authors.lastname: Akiyoshi
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Kodama
authors.forename: Takanori
authors.initials: T
authors.lastname: Mori
authors.forename: Miwa
authors.initials: M
authors.lastname: Kondo
authors.forename: Shinichi
authors.initials: S
authors.lastname: Sasaki
authors.forename: Akihiko
authors.initials: A
authors.lastname: Iwase
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Takahashi
authors.forename: Yoshinosuke
authors.initials: Y
authors.lastname: Fukuchi
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Seyama
mesh_terms: D000336:Aerosols; D000375:Aging / Q000187:drug effects*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009287:Naphthyridines / Q000737:chemistry / Q000494:pharmacology*; D058988:Phosphodiesterase 4 Inhibitors; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000201:enzymology* / Q000517:prevention & control*; D012907:Smoking; D013347:Subcellular Fractions; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000336:Aerosols; D004791:Enzyme Inhibitors; C527262:GPD-1116; D008070:Lipopolysaccharides; D009287:Naphthyridines; D058988:Phosphodiesterase 4 Inhibitors; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D053508:Matrix Metalloproteinase 12