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Published ahead of print on February 2, 2006, doi:10.1164/rccm.200506-947OC
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American Journal of Respiratory and Critical Care Medicine Vol 173. pp. 1016-1022, (2006)
© 2006 American Thoracic Society
doi: 10.1164/rccm.200506-947OC

Original Article

A Novel I{kappa}B Kinase-beta Inhibitor Ameliorates Bleomycin-induced Pulmonary Fibrosis in Mice

Mami Inayama*, Yasuhiko Nishioka*, Momoyo Azuma, Susumu Muto, Yoshinori Aono, Hideki Makino, Kenji Tani, Hisanori Uehara, Keisuke Izumi, Akiko Itai and Saburo Sone

Departments of Internal Medicine and Molecular Therapeutics, and Molecular and Environmental Pathology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima; and Institute of Medicinal Molecular Design, Inc., Tokyo, Japan

Correspondence and requests for reprints should be addressed to Saburo Sone, M.D., Ph.D., Department of Internal Medicine and Molecular Therapeutics, Institute of Health Biosciences, the University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan. E-mail: ssone{at}clin.med.tokushima-u.ac.jp

Rationale: I{kappa}B kinase-beta is a critical regulator in the activation of nuclear factor-{kappa}B (NF-{kappa}B), a transcription factor related to the expression and regulation of proinflammatory cytokines.

Objective: To evaluate if inhibition of I{kappa}B kinase-beta ameliorates pneumonitis and pulmonary fibrosis.

Methods: We examined whether a novel I{kappa}B kinase-beta inhibitor, IMD-0354, attenuates bleomycin-induced pulmonary fibrosis in mice.

Measurements and Main Results: Administration of IMD-0354 significantly improved the loss of body weight and survival of mice treated with bleomycin, whereas IMD-0354 alone did not cause any morphologic change in the lung. When mice were evaluated 28 d after bleomycin administration, IMD-0354 dose-dependently reduced the collagen content and fibrotic scores as shown by histologic examination. The findings in the bronchoalveolar lavage demonstrated that the proportions of neutrophils and lymphocytes were decreased in mice treated with IMD-0354 on Day 7 and 14, respectively. IMD-0354 treatment was confirmed to inhibit the activation of NF-{kappa}B, but not activator protein-1, in the lungs treated with bleomycin. The production of inflammatory cytokines tumor necrosis factor-{alpha} and interleukin-1beta was reduced in the lungs of mice treated with IMD-0354.

Conclusions: These results suggest that IMD-0354 might be useful to ameliorate the inflammation in the lungs induced by fibrotic injury and the subsequent fibrogenesis via inhibiting the expression of profibrotic cytokines related to the activation of NF-{kappa}B.

Key Words: interleukin-1beta • nuclear factor-{kappa}B, tumor necrosis factor-{alpha}




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