Intratracheal instillation of ethyl pyruvate nanoparticles prevents the development of shunt-flow-induced pulmonary arterial hypertension in a rat model

Abstract

Purpose:To investigate whether inhalation of ethyl pyruvate (EP) encapsulated with poly(ethylene glycol)-block-lactide/glycolide copolymer nanoparticles (EP-NPs) can prevent the development of shunt-flow-induced hyperkinetic pulmonary arterial hypertension (PAH) in a rat model. Materials and methods: Rats were separated into five groups: blank (ie, no treatment after shunt flow), normal control (ie, no shunt flow or treatment), EP-NP instillation, EP-only instillation, and vehicle. The animals received intratracheal instillation of EP-NPs or other treatments immediately after a shunt flow, and treatment continued weekly until the end of the experiment. Hemodynamic data were recorded, pulmonary arterial remodeling was assessed, and levels of inflammatory mediators and ET1 expression in the lung and serum were analyzed. In addition, retention of EP in the lungs of rats in the EP-NP and EP-only groups was measured using highperformance liquid chromatography. Results: After 12 weeks, hemodynamic abnormalities and pulmonary arterial remodeling were improved in the EP-NP instillation group, compared with the blank, EP-only, and vehicle groups (P,0.05). In addition, the EP-NP group showed significantly decreased levels of HMGB1, IL-6, TNFα, reactive oxygen species, and ET1 in the lung during PAH development (P,0.05). Furthermore, EP-NP instillation was associated with reduced serum levels of inflammatory factors and ET1. High-performance liquid-chromatography measurement indicated that EP retention was greater in the lungs of the EP-NP group than in the EP-only group. Conclusion: EP-NP instillation attenuated inflammation and prevented pulmonary arterial remodeling during the development of PAH induced by shunt flow. In the future, EP-NP delivery into the lung might provide a novel approach for preventing PAH.

Nanotherapeutics for Treatment of Pulmonary Arterial Hypertension

“… Liu et al (2016) also examined the potential of ROS scavenging nanotherapeutics for the treatment of PAH. In their study, ethyl pyruvate, a derivative of pyruvic acid and an inhibitor of nuclear protein HMGB1, which in turn activates pro-inflammatory cytokines, was incorporated within poly(ethylene glycol)- block -lactide/glycolide (PEG-LG) NPs and examined their efficacy in a hyperkinetic model of PAH induced by shunt flow.…”

Ethyl Pyruvate Alleviates Pulmonary Hypertension through the Suppression of Pulmonary Artery Smooth Muscle Cell Proliferation via the High Mobility Group Protein B1/Receptor for Advanced Glycation End-Products Axis

“…In the treatment of pulmonary hypertension, we previously reported that EP can prevent and reverse pulmonary vascular remodeling; however, the precise molecular mechanism requires further clarification. 12,13) High mobility group protein B1 (HMGB1) exists as a nucleoprotein in almost all eukaryotic cells. It was originally discovered in the calf thymus, and it was so named because of its rapid migration via polyacrylamide gel electrophoresis.…”

“…In the treatment of pulmonary hypertension, we previously reported that EP can prevent and reverse pulmonary vascular remodeling; however, the precise molecular mechanism requires further clarification. 12 , 13) …”