Inhibitory effects of theophylline on the peroxynitrite-augmented release of matrix metalloproteinases by lung fibroblasts

Hisatoshi Sugiura, Hiroki Kawabata, Tomohiro Ichikawa, Akira Koarai, Satoru Yanagisawa, Takashi Kikuchi, Yoshiaki Minakata, Kazuto Matsunaga, Masanori Nakanishi, Tsunahiko Hirano, Keiichiro Akamatsu, Kanako Furukawa, Masakazu Ichinose

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23 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)L764-L774
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Issue number8
Publication statusPublished - 2012 Apr 15


  • Chronic obstructive pulmonary disease
  • Fibroblast
  • Phosphodiesterase inhibitor
  • Proteinase
  • Reactive nitrogen species


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