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. 2016 Apr;67(4):290-8.
doi: 10.1097/FJC.0000000000000352.

Intratracheal Administration of Prostacyclin Analogue-incorporated Nanoparticles Ameliorates the Development of Monocrotaline and Sugen-Hypoxia-induced Pulmonary Arterial Hypertension

Satoshi Akagi  1 , Kazufumi Nakamura, Hiromi Matsubara, Megumi Kondo, Daiji Miura, Tetsuya Matoba, Kensuke Egashira, Hiroshi Ito
Affiliations

Intratracheal Administration of Prostacyclin Analogue-incorporated Nanoparticles Ameliorates the Development of Monocrotaline and Sugen-Hypoxia-induced Pulmonary Arterial Hypertension

Satoshi Akagi et al. J Cardiovasc Pharmacol. 2016 Apr.

Abstract

Nanoparticles (NPs) have been used as novel drug delivery systems. Drug-incorporated NPs for local delivery might optimize the efficacy and minimize the side effects of drugs. Intravenous prostacyclin improves long-term survival in patients with pulmonary arterial hypertension (PAH), but it causes serious side effects such as catheter-related infections. We investigated the efficacy and safety of intratracheal administration of a prostacyclin analogue, beraprost (BPS), incorporated NPs in Sugen-hypoxia-normoxia and monocrotaline rat models of PAH and in human PAH pulmonary arterial smooth muscle cells (PASMCs). After a single administration, BPS NPs significantly decreased right ventricular pressure, right ventricular hypertrophy, and pulmonary artery muscularization in the 2 rat models. BPS NPs significantly improved the survival rate in the monocrotaline rat model. No infiltration of inflammatory cells, hemorrhage, or fibrosis was found in the liver, kidney, spleen, and heart after the administration of BPS NPs. No liver or kidney dysfunction was found in the blood examinations. BPS and BPS NPs significantly inhibited the proliferation of human PAH PASMCs after 24 hours of treatment. BPS NPs significantly continued to inhibit the proliferation of human PAH PASMCs at 24 hours after the removal of BPS NPs. BPS NPs significantly induced apoptosis in PAH PASMCs compared to that in non-PAH PASMCs. Intratracheal administration of BPS NPs ameliorates pulmonary hypertension in PAH rat models by a sustained antiproliferative effect and a proapoptotic effect on PAH PASMCs.

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Conflict of interest statement

The authors report no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Effects of a single administration of BPS NPs in SuHx model rats. A, RVSP in the 3 experimental groups (n = 6). B, RV hypertrophy [ratio of RV/(LV + VS)] in the 3 experimental groups (n = 6). C, Percentage of fully muscularized small pulmonary arteries (PAs) in the 3 experimental groups (n = 6). *P < 0.05 versus control.
FIGURE 2
FIGURE 2
Effects of a single administration of BPS NPs in MCT model rats. A, RVSP in the 3 experimental groups (n = 6). B, RV hypertrophy [ratio of RV/(LV + S)] in the 3 experimental groups (n = 6). C, Percentage of fully muscularized small PAs in the 3 experimental groups (n = 6). *P < 0.05 versus control.
FIGURE 3
FIGURE 3
Effects of a single administration of BPS-NPs on survival rates. Survival rates analyzed by the Kaplan–Meier method in the PBS, FITC NP, and the BPS NP group are shown.
FIGURE 4
FIGURE 4
Incorporation of FITC NPs in pulmonary arteries. Representative images of the lung by immunostaining. A, Staining of α-smooth muscle actin (αSMA) in SuHx model rats and normal rats at day 1, 3, and 7. Green is FITC. Red is αSMA. Blue is 4′,6-diamidino-2-phenylindole (DAPI). Bar = 500 μm. B, Staining of CD31 in SuHx model rats and normal rats on day 1, 3, and 7. Green is FITC. Red is CD31. Blue is DAPI. Bar = 500 μm.
FIGURE 5
FIGURE 5
Deposition of FITC NPs in airways. A, Methods of intratracheal administration of NPs using a MicroSprayer. B, Schema of trachea and bronchi. We cut the trachea and bronchi at dotted line. Cross-sectional image of each number was shown in C. C, Cross-sectional image of trachea and bronchi. Red indicates αSMA. Blue indicates DAPI. Bar = 500 μm.
FIGURE 6
FIGURE 6
Micrograph of cross sections of the liver, kidney, spleen, and heart stained with hematoxylin and eosin.
FIGURE 7
FIGURE 7
Inhibitory effect of BPS NPs on the proliferation of human PASMCs. A, Non-PAH PASMCs. B, PAH PASMCs. Counts per minute (cpm) are expressed as a percentage of cpm of PASMCs treated with a diluent (control). *P < 0.05 versus PDGF. + → − = Twenty-four hours after removal of BPS or BPS-NPs.
FIGURE 8
FIGURE 8
Effect of BPS NPs on the apoptosis of human PASMCs in the TUNEL assay. A, Representative images reflecting findings of induction of apoptosis in PAH PASMCs. Bar = 50 μm. B, Mean data for TUNEL-positive nuclei 24 hours after treatment with BPS NPs in non-PAH PASMCs and PAH PASMCs.
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References

    1. Humbert M, Lau EM, Montani D, et al. Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation. 2014;130:2189–2208. - PubMed
    1. Moncada S, Gryglewski R, Bunting S, et al. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature. 1976;263:663–665. - PubMed
    1. Starling MB, Neutze JM, Elliott RL. Control of elevated pulmonary vascular resistance in neonatal swine with prostacyclin (pgi2). Prostaglandins Med. 1979;3:105–117. - PubMed
    1. Rubin LJ, Mendoza J, Hood M, et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Results of a randomized trial. Ann Intern Med. 1990;112:485–491. - PubMed
    1. Barst RJ, Rubin LJ, Long WA, et al. ; Primary Pulmonary Hypertension Study Group. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996;334:296–301. - PubMed

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