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Published ahead of print on February 2, 2006, doi:10.1164/rccm.200506-947OC

Am. J. Respir. Crit. Care Med., Volume 173, Number 9, May 2006, 1016-1022

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Submitted on June 20, 2005
Accepted on February 2, 2006

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

Mami Inayama1, Yasuhiko Nishioka1, Momoyo Azuma1, Susumu Muto2, Yoshinori Aono1, Hideki Makino1, Kenji Tani1, Hisanori Uehara3, Keisuke Izumi3, Akiko Itai2, and Saburo Sone1*

1 Department of Internal Medicine and Molecular Therapeutics, The University of Tokushima Graduate School, Tokushima, Japan, 2 Institute of Medicinal Molecular Design, Inc., Tokyo, Japan, 3 Department of Molecular and Environmental Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan

* To whom correspondence should be addressed. E-mail: yasuhiko{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, 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, while IMD-0354 alone did not cause any morphological change in the lung. When mice were evaluated 28 days after bleomycin administration, IMD-0354 dose-dependently reduced the collagen content and fibrotic scores as shown by histological 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 nuclear factor-kappa B, but not activator protein-1, in the lungs treated with bleomycin. The production of inflammatory cytokines, tumor necrosis factor-{alpha} and interleukin-1{beta}, 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 nuclear factor-kappa B.
Key words: nuclear factor kappa B, tumor necrosis factor-{alpha}, interleukin-1{beta}




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