endothelin-1 and ethyl-pyruvate

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.. 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 high-performance liquid chromatography.. 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.. 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.

Topics: Animals; Disease Models, Animal; Endothelin-1; Hypertension, Pulmonary; Interleukin-6; Lung; Male; Nanoparticles; Polyesters; Polyethylene Glycols; Protective Agents; Pulmonary Artery; Pyruvates; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha; Vascular Remodeling

Ethyl pyruvate (EP) is an anti-inflammatory and anti-oxidant agent associated with many diseases. In this study, we evaluated whether EP could attenuate monocrotaline-induced pulmonary arterial hypertension (PAH).. A PAH model was established by subcutaneously injecting a single dose of monocrotaline (60 mg/kg). And then a daily intraperitoneal injection of EP (50 mg/kg) was administered on day 1 to day 28 (preventive EP treatment) or day 15 to day 28 (therapeutic EP treatment). Hemodynamic changes were measured by catheterization, and the right ventricle hypertrophy index, the medial wall thickness, and the medial wall areas were also calculated. Enzyme-linked immunosorbent assay and immunohistochemical analysis were used to determine the serum levels and expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and endothelin-1 (ET-1) in the lung tissue.. Both preventive and therapeutic EP treatment significantly ameliorated hemodynamic changes and vascular remodeling indicators (all P < 0.05). The serum levels and expression of TNF-α, IL-6, and ET-1 in the lung tissue were also significantly decreased (all P < 0.05).. EP ameliorates monocrotaline-induced PAH and reverses pulmonary vascular remolding in rats by inhibiting the release of TNF-α and IL-6 and reducing the expression of ET-1.

Topics: Animals; Anti-Inflammatory Agents; Disease Models, Animal; Drug Administration Schedule; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Hypertension, Pulmonary; Injections, Intraperitoneal; Interleukin-6; Male; Monocrotaline; Pyruvates; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha