title: Leaky lysosomes in lung transplant macrophages: azithromycin prevents oxidative damage.
abstract: BACKGROUND
  Lung allografts contain large amounts of iron (Fe), which inside lung macrophages may promote oxidative lysosomal membrane permeabilization (LMP), cell death and inflammation. The macrolide antibiotic azithromycin (AZM) accumulates 1000-fold inside the acidic lysosomes and may interfere with the lysosomal pool of Fe.
  
  
  OBJECTIVE
  Oxidative lysosomal leakage was assessed in lung macrophages from lung transplant recipients without or with AZM treatment and from healthy subjects. The efficiency of AZM to protect lysosomes and cells against oxidants was further assessed employing murine J774 macrophages.
  
  
  METHODS
  Macrophages harvested from 8 transplant recipients (5 without and 3 with ongoing AZM treatment) and 7 healthy subjects, and J774 cells pre-treated with AZM, a high-molecular-weight derivative of the Fe chelator desferrioxamine or ammonium chloride were oxidatively stressed. LMP, cell death, Fe, reduced glutathione (GSH) and H-ferritin were assessed.
  
  
  RESULTS
  Oxidant challenged macrophages from transplants recipients without AZM exhibited significantly more LMP and cell death than macrophages from healthy subjects. Those macrophages contained significantly more Fe, while GSH and H-ferritin did not differ significantly. Although macrophages from transplant recipients treated with AZM contained both significantly more Fe and less GSH, which would sensitize cells to oxidants, these macrophages resisted oxidant challenge well. The preventive effect of AZM on oxidative LMP and J774 cell death was 60 to 300 times greater than the other drugs tested.
  
  
  CONCLUSIONS
  AZM makes lung transplant macrophages and their lysososomes more resistant to oxidant challenge. Possibly, prevention of obliterative bronchiolitis in lung transplants by AZM is partly due to this action.
authors.affiliation: Division of Pulmonary Medicine, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden. Lennart.Persson@lio.se
authors.forename: H Lennart
authors.initials: HL
authors.lastname: Persson
authors.forename: Linda K
authors.initials: LK
authors.lastname: Vainikka
authors.forename: Maria
authors.initials: M
authors.lastname: Sege
authors.forename: Urban
authors.initials: U
authors.lastname: Wennerström
authors.forename: Sören
authors.initials: S
authors.lastname: Dam-Larsen
authors.forename: Jenny
authors.initials: J
authors.lastname: Persson
mesh_terms: D000328:Adult; D000975:Antioxidants / Q000494:pharmacology; D017963:Azithromycin / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007501:Iron / Q000378:metabolism*; D016040:Lung Transplantation / Q000473:pathology*; D008247:Lysosomes / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects
chemical_list: D000975:Antioxidants; D016877:Oxidants; D017963:Azithromycin; D007501:Iron