HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 294/2/L196    most recent 00173.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Mori, H. Articles by Seyama, K. Search for Related Content PubMed PubMed Citation Articles by Mori, H. Articles by Seyama, K.

Phosphodiesterase 4 inhibitor GPD-1116 markedly attenuates the development of cigarette smoke-induced emphysema in senescence-accelerated mice P1 strain

¹Department of Respiratory Medicine, Juntendo University School of Medicine and ²Pharmacological Research Department, Developmental Research Center, Aska Pharmaceutical, Tokyo; ³The First Division of Internal Medicine, Urayasu Juntendo University Hospital, Chiba; and ⁴Department of Respiratory Medicine, Tokyo Metropolitan Koto Geriatric Medical Center, Tokyo, Japan

Submitted 30 April 2007 ; accepted in final form 29 October 2007

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 µm, 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 µm, 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/µg protein; P < 0.05), but GPD-1116 significantly decreased MMP-12 activity in smoke-exposed mice (5.3 ± 2.1 area/µg 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.

protease; aging; apoptosis; oxidative stress; vascular endothelial growth factor

This article has been cited by other articles:

				A. Churg, M. Cosio, and J. L. Wright Mechanisms of cigarette smoke-induced COPD: insights from animal models Am J Physiol Lung Cell Mol Physiol, April 1, 2008; 294(4): L612 - L631. [Abstract] [Full Text] [PDF]