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Blood, 15 March 2004, Vol. 103, No. 6, pp. 2196-2204.
Prepublished online as a Blood First Edition Paper on November 6, 2003; DOI 10.1182/blood-2003-06-1980.
Submitted June 18, 2003
Accepted November 3, 2003
Activated protein C inhibits bronchial hyperresponsiveness and Th2 cytokine expression in the mouse
Hisamichi Yuda, Yukihiko Adachi, Osamu Taguchi, Esteban C Gabazza*, Osamu Hataji, Hajime Fujimoto, Shigenori Tamaki, Kimiaki Nishikubo, Kenji Fukudome, Corina N D'Alessandro-Gabazza, Junko Maruyama, Masahiko Izumizaki, Michiko Iwase, Ikuo Homma, Ryo Inoue, Haruhiko Kamada, Tatsuya Hayashi, Michael Kasper, Peter J Barnes, and Koji Suzuki
Third Department of Internal Medicine, Mie University School of Medicine, Mie, Japan; Department of Molecular Pathobiology, Mie University School of Medicine, Mie, Japan
Second Department of Physiology, Mie University School of Medicine, Mie, Japan
Department of Immunology, Saga Medical School, Saga, Japan
Second Department of Physiology, Showa University School of Medicine, Tokyo, Japan
Institute of Anatomy, Technical University of Dresden, Dresden, Germany
National Heart and Lung Institute, Imperial College School of Medicine, London, United Kingdom
* Corresponding author; email: gabazza{at}clin.medic.mie-u.ac.jp.
Asthma is one of the most common diseases and is characterized by airway obstruction, airway inflammation and increased airway responsiveness. Glucocorticoids are very effective in treatment, but their long-term use is associated with several side effects, so that new anti-inflammatory drugs are in development. Activated protein C (APC) is a serine protease with potent anti-inflammatory effects. This study evaluated the effect of inhaled APC on airway inflammation and hyperresponsiveness in a murine asthma model. Asthma was induced in BALB/c mice by exposure to chicken egg ovalbumin (OVA) and the effect of inhaled APC was assessed by administering prior to OVA exposure. Inhalation of APC significantly inhibited the expression of Th2 cytokines, IgE, eosinophilic inflammation and hyperresponsiveness. APC also significantly suppressed the expression of Th2 cytokines and IgE from lymphocytes isolated from OVA-sensitized/challenged animals. In addition, binding of STAT6 and NF- B oligonucleotides to lung nuclear proteins was significantly reduced in mice treated with inhaled APC. In brief, the exogenous supplementation of APC inhibits the immunological and inflammatory responses induced by Th2 cytokines in a mouse model of asthma and may represent a novel anti-inflammatory treatment.
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