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: Hiroaki Mori, Takashi Nose, Kouki Ishitani, Satoshi Kasagi, Sanae Souma, Taeko Akiyoshi, Yuzo Kodama, Takanori Mori, Miwa Kondo, Shinichi Sasaki, Akihiko Iwase, Kazuhisa Takahashi, Yoshinosuke Fukuchi, Kuniaki Seyama
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 294 Issue 2 Pg. L196-204 (Feb 2008) ISSN: 1040-0605 [Print] United States
• PMID: 17993591 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aerosols
• Enzyme Inhibitors
• GPD-1116
• Lipopolysaccharides
• Naphthyridines
• Phosphodiesterase 4 Inhibitors
• Tumor Necrosis Factor-alpha
• Vascular Endothelial Growth Factor A
• Matrix Metalloproteinase 12

Topics

• Aerosols
• Aging (drug effects)
• Animals
• Apoptosis (drug effects)
• Body Weight (drug effects)
• Bronchoalveolar Lavage Fluid (cytology)
• Cell Line
• Enzyme Inhibitors (chemistry, pharmacology)
• Leukocytes (cytology, drug effects)
• Lipopolysaccharides (pharmacology)
• Lung (drug effects, enzymology, metabolism, pathology)
• Matrix Metalloproteinase 12 (metabolism)
• Mice
• Mice, Inbred Strains
• Naphthyridines (chemistry, pharmacology)
• Phosphodiesterase 4 Inhibitors
• Pulmonary Emphysema (chemically induced, enzymology, prevention & control)
• Smoking
• Subcellular Fractions
• Tumor Necrosis Factor-alpha (metabolism)
• Vascular Endothelial Growth Factor A (metabolism)