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(Hypertension. 2009;53:877.)
© 2009 American Heart Association, Inc.

Original Articles

Nanoparticle-Mediated Delivery of Nuclear Factor B Decoy Into Lungs Ameliorates Monocrotaline-Induced Pulmonary Arterial Hypertension

Satoshi Kimura; Kensuke Egashira; Ling Chen; Kaku Nakano; Eiko Iwata; Miho Miyagawa; Hiroyuki Tsujimoto; Kaori Hara; Ryuichi Morishita; Katsuo Sueishi; Ryuji Tominaga; Kenji Sunagawa

From the Departments of Surgery (S.K., R.T.), Cardiovascular Medicine (K.E., L.C., K.N., E.I., M.M., K. Sunagawa), and Pathology (K. Sueishi), Graduate School of Medical Science, Kyushu University, Fukuoka; Hosokawa Powder Technology Research Institute (H.T., K.H.), Osaka; and Division of Clinical Gene Therapy (R.M.), Osaka University Medical School, Osaka, Japan.

Correspondence to Kensuke Egashira, Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail egashira{at}cardiol.med.kyushu-u.ac

Pulmonary arterial hypertension (PAH) is an intractable disease of the small pulmonary artery that involves multiple inflammatory factors. We hypothesized that a redox-sensitive transcription factor, nuclear factor B (NF-B), which regulates important inflammatory cytokines, plays a pivotal role in PAH. We investigated the activity of NF-B in explanted lungs from patients with PAH and in a rat model of PAH. We also examined a nanotechnology-based therapeutic intervention in the rat model. Immunohistochemistry results indicated that the activity of NF-B increased in small pulmonary arterial lesions and alveolar macrophages in lungs from patients with PAH compared with lungs from control patients. In a rat model of monocrotaline-induced PAH, single intratracheal instillation of polymeric nanoparticles (NPs) resulted in delivery of NPs into lungs for 14 days postinstillation. The NP-mediated NF-B decoy delivery into lungs prevented monocrotaline-induced NF-B activation. Blockade of NF-B by NP-mediated delivery of the NF-B decoy attenuated inflammation and proliferation and, thus, attenuated the development of PAH and pulmonary arterial remodeling induced by monocrotaline. Treatment with the NF-B decoy NP 3 weeks after monocrotaline injection improved the survival rate as compared with vehicle administration. In conclusion, these data suggest that NF-B plays a primary role in the pathogenesis of PAH and, thus, represent a new target for therapeutic intervention in PAH. This nanotechnology platform may be developed as a novel molecular approach for treatment of PAH in the future.

Key Words: pulmonary hypertension • lung • inflammation • leukocytes

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Nanoparticle-Mediated Drug Delivery and Pulmonary Hypertension

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				J. C. Bonner, J. W. Card, and D. C. Zeldin Nanoparticle-Mediated Drug Delivery and Pulmonary Hypertension Hypertension, May 1, 2009; 53(5): 751 - 753. [Full Text] [PDF]