title: Nanoparticle facilitated inhalational delivery of erythropoietin receptor cDNA protects against hyperoxic lung injury.
abstract: Our goals were to develop and establish nanoparticle (NP)-facilitated inhalational gene delivery, and to validate its biomedical application by testing the hypothesis that targeted upregulation of pulmonary erythropoietin receptor (EpoR) expression protects against lung injury. Poly-lactic-co-glycolic acid (PLGA) NPs encapsulating various tracers were characterized and nebulizated into rat lungs. Widespread NP uptake and distribution within alveolar cells were visualized by magnetic resonance imaging, and fluorescent and electron microscopy. Inhalation of nebulized NPs bearing EpoR cDNA upregulated pulmonary EpoR expression and downstream signal transduction (ERK1/2 and STAT5 phosphorylation) in rats for up to 21 days, and attenuated hyperoxia-induced damage in lung tissue based on apoptosis, oxidative damage of DNA, protein and lipid, tissue edema, and alveolar morphology compared to vector-treated control animals. These results establish the feasibility and therapeutic efficacy of NP-facilitated cDNA delivery to the lung, and demonstrate that targeted pulmonary EpoR upregulation mitigates acute oxidative lung damage.
  
  
  BACKGROUND
  Acute lung injury often results in significant morbidity and mortality, and current therapeutic modalities have proven to be ineffective. In this article, the authors developed nanocarrier based gene therapy in an attempt to upregulate the expression of pulmonary erythropoietin receptor in an animal model. Inhalation delivery resulted in reduction of lung damage.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Ravikumar
authors.affiliation: Department of Bioengineering, University of Texas at Arlington, Arlington, TX, USA.
authors.forename: Jyothi U
authors.initials: JU
authors.lastname: Menon
authors.affiliation: Department of Bioengineering, University of Texas at Arlington, Arlington, TX, USA.
authors.forename: Primana
authors.initials: P
authors.lastname: Punnakitikashem
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Dipendra
authors.initials: D
authors.lastname: Gyawali
authors.affiliation: Department of Radiology and Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Osamu
authors.initials: O
authors.lastname: Togao
authors.affiliation: Department of Radiology and Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Masaya
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Jianning
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Ye
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Orson W
authors.initials: OW
authors.lastname: Moe
authors.affiliation: Department of Bioengineering, University of Texas at Arlington, Arlington, TX, USA. Electronic address: Knguyen@uta.edu.
authors.forename: Kytai T
authors.initials: KT
authors.lastname: Nguyen
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: Connie.Hsia@utsouthwestern.edu.
authors.forename: Connie C W
authors.initials: CCW
authors.lastname: Hsia
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D002460:Cell Line; D018076:DNA, Complementary / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D018014:Gene Transfer Techniques; D006801:Humans; D018496:Hyperoxia / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D019344:Lactic Acid / Q000737:chemistry*; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D055370:Lung Injury / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D017207:Rats, Sprague-Dawley; D017467:Receptors, Erythropoietin / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D018076:DNA, Complementary; D017467:Receptors, Erythropoietin; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid
keywords: Aerosol nebulization; Cytoprotection; Gene therapy; Hyperoxia; Oxidative stress damage; Poly-lactic-co-glycolic acid nanoparticles