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Published ahead of print on October 25, 2007, doi:10.1164/rccm.200702-264OC

Am. J. Respir. Crit. Care Med., Volume 177, Number 2, January 2008, 219-226

A more recent version of this article appeared on January 15, 2008
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Submitted on February 16, 2007
Accepted on October 25, 2007

Gene Transfer of Extracellular Superoxide Dismutase Ameliorates Pulmonary Hypertension in Rats

Fumihiko Kamezaki1, Hiromi Tasaki1*, Kazuhito Yamashita1, Masato Tsutsui2, Shinichiro Koide1, Sei Nakata1, Akihide Tanimoto3, Masahiro Okazaki1, Yasuyuki Sasaguri3, Tetsuo Adachi4, and Yutaka Otsuji1

1 Second Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyusyu, Japan, 2 Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, Kitakyusyu, Japan, 3 Department of Pathology, School of Medicine, University of Occupational and Environmental Health, Kitakyusyu, Japan, 4 Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, Gifu, Japan

* To whom correspondence should be addressed. E-mail: h-tasaki{at}med.uoeh-u.ac.jp.

RATIONALE: Pulmonary hypertension (PH) is a life- hreatening disease, characterized by vascular remodeling and vasoconstriction. Recent evidence suggests that oxidative stress may contribute to the pathogenesis and/or development of PH. OBJECTIVE: In the present study, we examined whether intratracheal gene transfer of human extracellular superoxide dismutase (ECSOD) could ameliorate monocrotaline (MCT)-induced PH in rats. METHODS: MCT-injected rats were intratracheally administered vehicle (MCT group), an adenovirus encoding {beta}-galactosidase (Ad{beta}gal group), or human ECSOD (AdECSOD group). RESULTS: By intratracheal gene transfer, ECSOD was successfully expressed in lung tissue, bronchoalveolar lavage, and plasma. Twenty-eight days after the MCT injection, right ventricular systolic pressure and the weight ratio of the right ventricle to the left ventricle plus septum were significantly lower in the AdECSOD group (42.50±1.46mm Hg and 0.453±0.029, respectively) than in the MCT group (59.89±1.61 mm Hg and 0.636±0.022, respectively) or the Ad{beta}gal group (61.50±2.61 mm Hg and 0.653±0.038, respectively). Moreover, vascular remodeling and proliferation of vascular smooth muscle cells in pulmonary arteries were markedly suppressed in the AdECSOD group. Importantly, 8-isoprostane in lung tissue was also significantly reduced in the AdECSOD group. CONCLUSIONS: ECSOD overexpression to the lung ameliorated the MCT-induced PH in rats. We suggest that ECSOD may act as the antioxidant in PH and that increased oxidative stress may be important in the pathogenesis of the MCT-induced PH.
Key words: monocrotaline, oxidative stress, intratracheal gene transfer, epithelial cell




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