TY - JOUR
T1 - Nanoparticle-mediated delivery of nuclear factor KB decoy into lungs ameliorates monocrotaline-induced pulmonary arterial hypertension
AU - Kimura, Satoshi
AU - Egashira, Kensuke
AU - Chen, Ling
AU - Nakano, Kaku
AU - Iwata, Eiko
AU - Miyagawa, Miho
AU - Tsujimoto, Hiroyuki
AU - Hara, Kaori
AU - Morishita, Ryuichi
AU - Sueishi, Katsuo
AU - Tominaga, Ryuji
AU - Sunagawa, Kenji
N1 - Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.
PY - 2009/5/1
Y1 - 2009/5/1
N2 - 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 κB (NF-κB), which regulates important inflammatory cytokines, plays a pivotal role in PAH. We investigated the activity of NF-κB 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-κB 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-κB decoy delivery into lungs prevented monocrotaline-induced NF-κB activation. Blockade of NF-κB by NP-mediated delivery of the NF-κB decoy attenuated inflammation and proliferation and, thus, attenuated the development of PAH and pulmonary arterial remodeling induced by monocrotaline. Treatment with the NF-κB decoy NP 3 weeks after monocrotaline injection improved the survival rale as compared with vehicle administration. In conclusion, these data suggest that NF-κB 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.
AB - 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 κB (NF-κB), which regulates important inflammatory cytokines, plays a pivotal role in PAH. We investigated the activity of NF-κB 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-κB 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-κB decoy delivery into lungs prevented monocrotaline-induced NF-κB activation. Blockade of NF-κB by NP-mediated delivery of the NF-κB decoy attenuated inflammation and proliferation and, thus, attenuated the development of PAH and pulmonary arterial remodeling induced by monocrotaline. Treatment with the NF-κB decoy NP 3 weeks after monocrotaline injection improved the survival rale as compared with vehicle administration. In conclusion, these data suggest that NF-κB 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.
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U2 - 10.1161/HYPERTENSIONAHA.108.121418
DO - 10.1161/HYPERTENSIONAHA.108.121418
M3 - Article
C2 - 19307469
AN - SCOPUS:73549117035
VL - 53
SP - 877
EP - 883
JO - Hypertension
JF - Hypertension
SN - 0194-911X
IS - 5
ER -