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Leaky lysosomes in lung transplant macrophages: azithromycin prevents oxidative damage
Linköping University, Department of Medical and Health Sciences, Pulmonary Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medical and Health Sciences, Pulmonary Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
Division of Medicine, Hospital of Västervik, Västervik, Sweden.
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2012 (English)In: Respiratory research (Online), ISSN 1465-9921, E-ISSN 1465-993X, Vol. 13, no 83Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
BioMed Central, 2012. Vol. 13, no 83
Keyword [en]
Apoptosis; Bronchiolitis; Ferritin; Fibrosis; Inflammation; Iron; Macrophage
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-87232DOI: 10.1186/1465-9921-13-83ISI: 000311745500001OAI: oai:DiVA.org:liu-87232DiVA: diva2:587349
Available from: 2013-01-14 Created: 2013-01-14 Last updated: 2017-12-06Bibliographically approved

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Persson, LennartVainikka, Linda

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