title: Intratracheal instillation of ethyl pyruvate nanoparticles prevents the development of shunt-flow-induced pulmonary arterial hypertension in a rat model.
abstract: OBJECTIVE
  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.
  
  
  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 high-performance 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cardiovascular Surgery Department, Qilu Hospital of Shandong University.
authors.forename: Kai
authors.initials: K
authors.lastname: Liu
authors.affiliation: Cardiovascular Surgery Department, Qilu Hospital of Shandong University.
authors.forename: Xiquan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Cardiovascular Surgery Department, Qilu Hospital of Shandong University.
authors.forename: Guangqing
authors.initials: G
authors.lastname: Cao
authors.affiliation: Pharmacy College of Shandong University, Jinan, People's Republic of China.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Cardiovascular Surgery Department, Qilu Hospital of Shandong University.
authors.forename: Chuanzhen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Cardiovascular Surgery Department, Qilu Hospital of Shandong University.
authors.forename: Hourong
authors.initials: H
authors.lastname: Sun
authors.affiliation: Cardiovascular Surgery Department, Qilu Hospital of Shandong University.
authors.forename: Xinyan
authors.initials: X
authors.lastname: Pang
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000517:prevention & control*; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D020011:Protective Agents / Q000008:administration & dosage / Q000737:chemistry; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology; D011773:Pyruvates / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D066253:Vascular Remodeling / Q000187:drug effects / Q000502:physiology
chemical_list: D019332:Endothelin-1; D015850:Interleukin-6; D011091:Polyesters; D020011:Protective Agents; D011773:Pyruvates; D014409:Tumor Necrosis Factor-alpha; C000589473:polyethylene glycol-poly(lactide-co-glycolide); C046522:ethyl pyruvate; D011092:Polyethylene Glycols
keywords: ethyl pyruvate; high-mobility group box 1; pulmonary artery hypertension