Anti-fibrotic effects of theophylline on lung fibroblasts

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Abstract

Theophylline has been used in the management of bronchial asthma and chronic obstructive pulmonary disease for over 50 years. It has not only a bronchodilating effect, but also an anti-inflammatory one conducive to the inhibition of airway remodeling, including subepithelial fibrosis. To date however, whether theophylline has a direct inhibitory effect on airway fibrosis has not been established. To clarify this question, we examined whether theophylline affected the function of lung fibroblasts. Theophylline suppressed TGF-β-induced type I collagen (COL1) mRNA expression in lung fibroblasts and also inhibited fibroblast proliferation stimulated by FBS and TGF-β-induced α-SMA protein. A cAMP analog also inhibited TGF-β-induced COL1 mRNA expression in lung fibroblasts. A PKA inhibitor reduced the inhibitory effect of theophylline on TGF-β-induced COL1 mRNA expression. These results indicate that theophylline exerts anti-fibrotic effects, at least partly, through the cAMP-PKA pathway.

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Materials and methods

Materials. Human Transforming growth factor-β1(TGF-β1), theophylline, dibutyryl cAMP (a cAMP analog), Rp-cAMPS triethylammonium salt (a specific PKA inhibitor, Rp-cAMP), and water-soluble dexamethasone were purchased from Sigma (St. Louis, MO). Isogen was purchased from Nippon Gene (Tokyo, Japan). The Cell Counting Kit-8 was from Dojindo Laboratories (Kumamoto, Japan).

Cell culture. Normal human lung fibroblast (NHLF) (Sanko Jyunyaku, Tokyo, Japan) and human lung fibroblast cell line (WI-38)

Theophylline inhibits TGF-β-induced COL1 mRNA expression in NHLF and WI-38 cells

TGF-β, one of the potent inducers of COL1, is involved in the pathogenesis of airway fibrosis in both asthma and COPD [12]. To investigate the inhibitory effect of theophylline on TGF-β-induced COL1 mRNA expression in human lung fibroblasts, NHLF and WI-38 cells were treated with TGF-β in the presence or absence of theophylline. The amount of COL1 mRNA expression was determined by the real-time PCR method. Theophylline decreased TGF-β-induced COL1 mRNA expression in NHLF cells (Fig. 1A) and

Discussion

Theophylline, clinically used in the management of airway diseases over the past 50 years, has been demonstrated to exert not only a bronchodilating effect, but also other pleiotropic benefits, including anti-inflammatory effects, improvement of respiratory muscle function, and enhancement of mucociliary clearance [3]. So far, however, the direct effect of theophylline on airway fibrosis, one of the features of airway remodeling, has not been assessed. Our examination of whether theophylline

Acknowledgments

We thank Yoko Habe for secretarial assistance. This work was supported by grants from the Japanese Ministry of Education, Culture, Sports, Science and Technology.

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