October 6, 2009

Antioxidants in the treatment of IPF (idiopathic pulmonary fibrosis)

The disturbance of pulmonary antioxidant/oxidant balance leading to oxidative stress is thought to be one of the major factors contributing to the development of IPF ( Kinnula and Myllärniemi, 2008; Walters et al., 2008). In patients with IPF there is an excessive production of so-called reactive oxygen species (ROS): superoxide anion (O2-), hydrogen peroxide (H2O2), peroxynitrite and hydroxyl radicals (OH-). ROS damage proteins, lipids and other cellular macromolecules, activate profibrotic cytokines, and consequently enhance fibrosis. Production of ROS is increased in animals with bleomycin-induced fibrosis and ROS are required for the development of bleomycin-induced fibrosis in mice (Manoury et al., 2005). In animals fibrosis can be prevented or reduced by antioxidants (Kilinç et al, 1993). Taken together these data support the notion that antioxidant therapy may have a beneficial effect in the treatment of IPF.
Many antioxidants occur naturally in the body and/or are regularly present in the human diet. Glutathione, vitamins E and C, polyphenols and uric acid belong to this group. Numerous antioxidant polyphenols are present in plants, vegetables and fruits. Indeed, curcumin (Biswas et al., 2005) and resveratrol (Sener et al., 2007) ameliorate bleomycin-induced pulmonary fibrosis in rats. Glutathione is a major antioxidant in lungs. In addition to its antioxidant activity, glutathione suppresses the proliferation of human lung fibroblasts (Cantin et al., 1990) and regulates the fibrogenic effects of transforming growth factor beta (TGFβ) (Ono et al., 2009). Since glutathione does nor readily penetrate the cell membrane, and has bronchoconstrictor activity, most experimental studies were performed with its thiol precursor, N-acetyl cysteine (NAC). Other thiols or prodrugs known to be metabolized to thiols, such as erdosteine, have also been shown to prevent bleomycin-induced fibrosis in laboratory animals (Day, 2008). Animal studies strongly suggest that NAC and other antioxidants should be useful in the therapy of patients with IPF.

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Day, B.J. (2008). Antioxidants as potential therapeutics for lung fibrosis. Antioxid. Redox Signal. 10:355-371 .

Kilinç, C. Ozean, O,. Karaoz, E., Sunguroglu, K., Kuluay, T., an Karaca, L. (1993). Viamin E reduces bleomycin-induced fibrosis in mice: biochemical and morphological studies. J. Basic. Clin. Physiol. Pharmacol. 4: 249-269.

Kinnula V.L. and Myllärniemi, M. (2008). Oxidant-antioxidant imbalance as a potential contributor to the progression of human pulmonary fibrosis. Antioxid. Redox. Signal. 10: 727- 738.

Manouri, B., Nenan, S., Leclerc, O., Guenon, I., Boichot, E., Planquois, J-M., Bertrand, C.P., and Lagente, V. (2005). The absence of reactive oxygen species production protects mice against bleomycin-induced pulmonary fibrosis. Respir. Res. 6:11-23.

Ono, A, Utsugi, M., Masubuchi, K., Ishizuka, T., Kawata, T., Shimizu, Y., Hisada, T., Hamuro, J., Mori, M., Dobashi, K. (2009). Glutathione redox regulates TGFβ –induced fibrogenic effects through Smad3 activation. FEBS Lett 583: 357-362.

Sener, G., Topaloglu, N., Sehirtli, A.O., Ercan, F. and Gedik, N. (2007). Resveratrol alleviates bleomycin-induced lung injury in rats. Pulm. Pharmacol. Ther. 20:642-649.

Walters, D.M., Cho, H-Y and Kleeberger, S.R. (2008). Oxidative stress and antioxidants in the pathogenesis of pulmonary fibrosis: a potential role for Nrf2. Antioxid. Redox Signal. 10:321-332.