title: Targeted endothelial delivery of nanosized catalase immunoconjugates protects lung grafts donated after cardiac death.
abstract: BACKGROUND
  Donor organ shortage represents a major problem in lung transplantation. Donation after cardiac death could help to expand the pool of organs, but the additional period of warm ischemia after cardiac arrest aggravates primary graft dysfunction. The pulmonary endothelium of the graft constitutes an important source and target of reactive oxygen species generated during ischemia and reperfusion. Targeted protection of graft pulmonary endothelial cells by the antioxidant enzyme catalase, conjugated with a platelet/endothelial cell adhesion molecule-1 (PECAM-1) antibody to nanosized particles (anti-PECAM/catalase conjugates), might improve outcome in lung transplantation using donors after cardiac death and prolonged hypothermic preservation.
  
  
  METHODS
  Left lung transplantation was performed in 18 pigs. Before cardiac arrest, donors received anti-PECAM/catalase, unconjugated component mixture or vehicle solution. After 90-min warm and 18-hr hypothermic ischemia, lungs were transplanted, and function was assessed during 6 hr after reperfusion. Samples of bronchoalveolar lavage fluid and lung tissue were taken thereafter. Six sham-operated animals served as controls.
  
  
  RESULTS
  During 6-hr reperfusion, anti-PECAM/catalase significantly ameliorated graft function, evidenced by major improvements of gas exchange and reduced intrapulmonary shunt fraction. Furthermore, lipid peroxidation, alveolar leakage, and edema formation were reduced in protected grafts. Similarly moderate lung pathology was seen after transplantation.
  
  
  CONCLUSIONS
  Augmentation of the antioxidant capacity of graft pulmonary endothelial cells with anti-PECAM/catalase nanoparticles represents a straightforward approach to enable a safe transplantation of prolonged preserved donation after cardiac death lungs. Anti-PECAM/catalase protection alleviated oxidative stress and allowed immediate reconstitution of normal gas exchange and pulmonary microcirculation, a prerequisite for improved graft and patient outcome.
authors.affiliation: Department of Surgery, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Germany. Gerhard.Preissler@med.uni-muenchen.de
authors.forename: Gerhard
authors.initials: G
authors.lastname: Preissler
authors.forename: Florian
authors.initials: F
authors.lastname: Loehe
authors.forename: Ines V
authors.initials: IV
authors.lastname: Huff
authors.forename: Ulrich
authors.initials: U
authors.lastname: Ebersberger
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Shuvaev
authors.forename: Iris
authors.initials: I
authors.lastname: Bittmann
authors.forename: Iris
authors.initials: I
authors.lastname: Hermanns
authors.forename: James C
authors.initials: JC
authors.lastname: Kirkpatrick
authors.forename: Karl
authors.initials: K
authors.lastname: Fischer
authors.forename: Martin E
authors.initials: ME
authors.lastname: Eichhorn
authors.forename: Hauke
authors.initials: H
authors.lastname: Winter
authors.forename: Karl W
authors.initials: KW
authors.lastname: Jauch
authors.forename: Steven M
authors.initials: SM
authors.lastname: Albelda
authors.forename: Vladimir R
authors.initials: VR
authors.lastname: Muzykantov
authors.forename: Rainer
authors.initials: R
authors.lastname: Wiewrodt
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D002374:Catalase / Q000008:administration & dosage*; D003643:Death; D016503:Drug Delivery Systems; D042783:Endothelial Cells / Q000276:immunology; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage*; D016040:Lung Transplantation / Q000379:methods* / Q000473:pathology / Q000502:physiology; D053758:Nanoparticles / Q000008:administration & dosage; D009926:Organ Preservation / Q000379:methods*; D018384:Oxidative Stress; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology; D011659:Pulmonary Gas Exchange; D034421:Sus scrofa; D014019:Tissue Donors
chemical_list: D000906:Antibodies; D018796:Immunoconjugates; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D002374:Catalase