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Published ahead of print on June 7, 2007, doi:10.1164/rccm.200609-1292OC

Am. J. Respir. Crit. Care Med., Volume 176, Number 5, September 2007, 431-438

A more recent version of this article appeared on September 1, 2007
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Submitted on September 12, 2006
Accepted on June 6, 2007

Glycogen Synthase Kinase-3{beta} Inhibition Attenuates Asthma in Mice

Zhang Bao1, Shuhui Lim1, Wupeng Liao1, Yuzhi Lin1, Christoph Thiemermann2, Bernard P Leung3, and W. S. Fred Wong4*

1 Department of Pharmacology, National University of Singapore, Yong Loo Lin School of Medicine, Singapore, Singapore, 2 Center for Translational Medicine and Therapeutics, William Harvey Research Institute, London, United Kingdom, 3 Department of Physiology, National University of Singapore, Yong Loo Lin School of Medicine, Singapore, Singapore, 4 Department of Pharmacology, National University of Singapore, Yong Loo Lin School of Medicine, Singapore, Singapore; Immunology Program, Office of Life Sciences, National University of Singapore, Singapore, Singapore

* To whom correspondence should be addressed. E-mail: phcwongf{at}nus.edu.sg.

Rationale: Persistent activation of nuclear factor-{kappa}B has been associated with the development of asthma. Glycogen synthase kinase-3{beta} is known to regulate the activity of nuclear factor-{kappa}B. Objective: We hypothesized that inhibition of glycogen synthase kinase-3{beta} may have anti-inflammatory effects in allergic asthma. Methods: BALB/c mice sensitized and challenged with ovalbumin developed airway inflammation. Bronchoalveolar lavage fluid was assessed for total and differential cell counts, and for cytokine and chemokine levels. Lung tissues were examined for cell infiltration and mucus hypersecretion, and for the expression of inflammatory biomarkers. Serum IgE levels were determined by enzyme-linked immunosorbant assay. Airway hyperresponsiveness was monitored by direct airway resistance analysis. Measurements and Main Results: Intravenous administration of TDZD-8, a selective glycogen synthase kinase-3{beta} inhibitor, significantly inhibited ovalbumin-induced increases in total cell counts, eosinophil counts, and IL-5, IL-13 and eotaxin levels recovered in bronchoalveolar lavage fluid in a dose-dependent manner. TDZD-8 substantially reduced the serum levels of ovalbumin-specific IgE. Histological studies showed that TDZD-8 dramatically inhibited ovalbumin-induced lung tissue eosinophilia and airway mucus production. TDZD-8 also markedly suppressed ovalbumin-induced mRNA expression of ICAM-1, VCAM-1, Muc5ac, and three members of the chitinase family (acidic mammalian chitinase, Ym1 and Ym2). In addition, TDZD-8 significantly reduced ovalbumin-induced airway hyperresponsiveness to inhaled methacholine. Western blot analysis of whole lung lysates revealed that TDZD-8 markedly attenuated the phosphorylation of the nuclear factor-{kappa}B subunit p65 from ovalbumin-challenged mice. Conclusions: Our findings implicate that inhibition of glycogen synthase kinase-3{beta} may provide a novel means for the treatment of allergic airway inflammation.
Key words: bronchoalveolar lavage fluid, ovalbumin, nuclear factor-{kappa}B, eosinophilia, mucus hypersecretion




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