TY - JOUR
T1 - Inhibitory effects of theophylline on the peroxynitrite-augmented release of matrix metalloproteinases by lung fibroblasts
AU - Sugiura, Hisatoshi
AU - Kawabata, Hiroki
AU - Ichikawa, Tomohiro
AU - Koarai, Akira
AU - Yanagisawa, Satoru
AU - Kikuchi, Takashi
AU - Minakata, Yoshiaki
AU - Matsunaga, Kazuto
AU - Nakanishi, Masanori
AU - Hirano, Tsunahiko
AU - Akamatsu, Keiichiro
AU - Furukawa, Kanako
AU - Ichinose, Masakazu
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2012/4/15
Y1 - 2012/4/15
N2 - The anti-inflammatory effects of theophylline have been reported to include inhibition of the release of proinflammatory mediators from macrophages and neutrophils. Overproduction of reactive nitrogen species (RNS) has been reported in the airways of patients with chronic obstructive pulmonary disease (COPD), and this causes tissue inflammation and injury. We investigated whether peroxynitrite stimulated the release of matrix metalloproteinases 2 and 9 (MMP-2 and -9; gelatinases) from human fetal lung fibroblasts (HFL-1 cell line) and whether theophylline inhibited the peroxynitrite-augmented release of MMPs. HFL-1 cells and primary lung fibroblasts were treated with peroxynitrite (an RNS), and gelatinases levels were evaluated by gelatin zymography. The inhibitory effect of theophylline on the peroxynitrite-augmented release of MMP-2 and MMP-9 was also investigated. To explore the cell signaling pathways involved in the peroxynitrite-induced gelatinases release and the inhibitory effect of theophylline, transforming growth factor-β 1 (TGF-β 1), nuclear factor- κB (NF- κB), and histone deacetylase (HDAC) were measured. Peroxynitrite significantly augmented the release of MMP-2 and MMP-9 by fibroblasts (P < 0.01), as well as TGF-β 1 release (P < 0.01), NF- κB activation (P <0.01), and HDAC2 inactivation (P<0.01). An NF- κB inhibitor diminished the RNS-augmented release of MMPs and TGF-β 1 (P < 0.01), and a neutralizing TGF-β antibody also diminished MMP release (P < 0.01). Theophylline significantly inhibited the peroxynitrite-augmented release of MMP-2 and MMP-9 in HFL-1 cells and normal adult lung fibroblasts, and it also inhibited the peroxynitrite-mediated HDAC2 inactivation, NF- κB activation, and TGF-1 release in HFL-1 cells (all P < 0.01). These results suggest that peroxynitrite can influence tissue remodeling by promoting gelatinases release, while theophylline suppresses peroxynitrite-induced tissue remodeling via pathways involving NF- κB/TGF-β1 and/or HDAC in the HFL-1 cell line.
AB - The anti-inflammatory effects of theophylline have been reported to include inhibition of the release of proinflammatory mediators from macrophages and neutrophils. Overproduction of reactive nitrogen species (RNS) has been reported in the airways of patients with chronic obstructive pulmonary disease (COPD), and this causes tissue inflammation and injury. We investigated whether peroxynitrite stimulated the release of matrix metalloproteinases 2 and 9 (MMP-2 and -9; gelatinases) from human fetal lung fibroblasts (HFL-1 cell line) and whether theophylline inhibited the peroxynitrite-augmented release of MMPs. HFL-1 cells and primary lung fibroblasts were treated with peroxynitrite (an RNS), and gelatinases levels were evaluated by gelatin zymography. The inhibitory effect of theophylline on the peroxynitrite-augmented release of MMP-2 and MMP-9 was also investigated. To explore the cell signaling pathways involved in the peroxynitrite-induced gelatinases release and the inhibitory effect of theophylline, transforming growth factor-β 1 (TGF-β 1), nuclear factor- κB (NF- κB), and histone deacetylase (HDAC) were measured. Peroxynitrite significantly augmented the release of MMP-2 and MMP-9 by fibroblasts (P < 0.01), as well as TGF-β 1 release (P < 0.01), NF- κB activation (P <0.01), and HDAC2 inactivation (P<0.01). An NF- κB inhibitor diminished the RNS-augmented release of MMPs and TGF-β 1 (P < 0.01), and a neutralizing TGF-β antibody also diminished MMP release (P < 0.01). Theophylline significantly inhibited the peroxynitrite-augmented release of MMP-2 and MMP-9 in HFL-1 cells and normal adult lung fibroblasts, and it also inhibited the peroxynitrite-mediated HDAC2 inactivation, NF- κB activation, and TGF-1 release in HFL-1 cells (all P < 0.01). These results suggest that peroxynitrite can influence tissue remodeling by promoting gelatinases release, while theophylline suppresses peroxynitrite-induced tissue remodeling via pathways involving NF- κB/TGF-β1 and/or HDAC in the HFL-1 cell line.
KW - Chronic obstructive pulmonary disease
KW - Fibroblast
KW - Phosphodiesterase inhibitor
KW - Proteinase
KW - Reactive nitrogen species
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U2 - 10.1152/ajplung.00342.2011
DO - 10.1152/ajplung.00342.2011
M3 - Article
C2 - 22287608
AN - SCOPUS:84859778323
VL - 302
SP - L764-L774
JO - American Journal of Physiology
JF - American Journal of Physiology
SN - 1040-0605
IS - 8
ER -