TY - JOUR
T1 - Phosphodiesterase 4 inhibitor cilomilast inhibits fibroblast-mediated collagen gel degradation induced by tumor necrosis factor-α and neutrophil elastase
AU - Kohyama, Tadashi
AU - Liu, Xiangde
AU - Yun, Kui Zhu
AU - Wen, Fu Qiang
AU - Hang, Jun Wang
AU - Fang, Qiuhong
AU - Kobayashi, Tetsu
AU - Rennard, Stephen I.
N1 - Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2002/10
Y1 - 2002/10
N2 - Tissue destruction, resulting in emphysema, can be a consequence of several pathologic processes. The current study evaluated the effects of the phosphodiesterase (PDE)4 inhibitor, cilomilast, and other PDE inhibitors on the ability of fibroblasts to degrade extracellular matrix. Using the three-dimensional collagen gel culture system, fibroblasts (HFL-1) were cultured with tumor necrosis factor (TNF)-α, known to induce matrix metalloproteinase (MMP) release, and/or neutrophil elastase (NE), which can induce MMP activation. On Day 4, gels containing TNF-α and NE were significantly degraded (20.8 ± 2.9% of original collagen content). Cilomilast (10 μM) inhibited this degradation (84.4 ± 8.4%). Amrinone, a PDE3 inhibitor, and zaprinast, a PDE5 inhibitor, had no effect. Gelatin zymography and immunoblotting revealed that fibroblasts cultured with TNF-α released increased amounts of latent MMP-1 and -9. The addition of NE resulted in the conversion of MMP-1 and -9 to their active forms, indicative of collagen degradation. Cilomilast inhibited the release of MMP-1 and -9, as well as conversion of MMP-1 to its active form. Using real-time PCR analysis, cilomilast's effect on MMP-1 release was not associated with the proteinase's mRNA expression, suggesting that the inhibition of release is regulated at the post-transcriptional level. These results suggest that cilomilast may be a potentially effective therapeutic agent in diseases characterized by excessive tissue destruction, such as emphysema.
AB - Tissue destruction, resulting in emphysema, can be a consequence of several pathologic processes. The current study evaluated the effects of the phosphodiesterase (PDE)4 inhibitor, cilomilast, and other PDE inhibitors on the ability of fibroblasts to degrade extracellular matrix. Using the three-dimensional collagen gel culture system, fibroblasts (HFL-1) were cultured with tumor necrosis factor (TNF)-α, known to induce matrix metalloproteinase (MMP) release, and/or neutrophil elastase (NE), which can induce MMP activation. On Day 4, gels containing TNF-α and NE were significantly degraded (20.8 ± 2.9% of original collagen content). Cilomilast (10 μM) inhibited this degradation (84.4 ± 8.4%). Amrinone, a PDE3 inhibitor, and zaprinast, a PDE5 inhibitor, had no effect. Gelatin zymography and immunoblotting revealed that fibroblasts cultured with TNF-α released increased amounts of latent MMP-1 and -9. The addition of NE resulted in the conversion of MMP-1 and -9 to their active forms, indicative of collagen degradation. Cilomilast inhibited the release of MMP-1 and -9, as well as conversion of MMP-1 to its active form. Using real-time PCR analysis, cilomilast's effect on MMP-1 release was not associated with the proteinase's mRNA expression, suggesting that the inhibition of release is regulated at the post-transcriptional level. These results suggest that cilomilast may be a potentially effective therapeutic agent in diseases characterized by excessive tissue destruction, such as emphysema.
UR - http://www.scopus.com/inward/record.url?scp=0036787848&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036787848&partnerID=8YFLogxK
U2 - 10.1165/rcmb.4818
DO - 10.1165/rcmb.4818
M3 - Article
C2 - 12356583
AN - SCOPUS:0036787848
VL - 27
SP - 487
EP - 494
JO - American Journal of Respiratory Cell and Molecular Biology
JF - American Journal of Respiratory Cell and Molecular Biology
SN - 1044-1549
IS - 4
ER -