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Leaky lysosomes in lung transplant macrophages: azithromycin prevents oxidative damage
H Lennart Persson1, Linda K Vainikka, Maria Sege
1Division of Pulmonary Medicine, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden. Lennart.Persson@lio.se
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.
Insights
Azithromycin (AZM) protects lung transplant macrophages from oxidative damage by stabilizing lysosomes. This may help prevent obliterative bronchiolitis in lung transplant recipients.
Area of Science:
- Immunology
- Transplantation Biology
- Pharmacology
Background:
- Lung allografts accumulate iron, potentially causing oxidative stress and cell death in macrophages via lysosomal membrane permeabilization (LMP).
- The macrolide antibiotic azithromycin (AZM) concentrates in acidic lysosomes and may interact with iron.
Purpose of the Study:
- To assess oxidative lysosomal leakage in lung macrophages from transplant recipients with or without AZM treatment and healthy subjects.
- To evaluate AZM's protective efficiency against oxidants in murine macrophages.
Main Methods:
- Macrophages from lung transplant recipients and healthy donors, plus J774 cells, were oxidatively stressed after AZM or other treatments.
- Assessed lysosomal membrane permeabilization (LMP), cell death, iron (Fe), reduced glutathione (GSH), and H-ferritin levels.
Main Results:
- Macrophages from untreated transplant recipients showed more LMP and cell death with higher Fe levels.
- Despite higher Fe and lower GSH, AZM-treated macrophages resisted oxidant challenge.
- AZM demonstrated superior protection against oxidative LMP and cell death compared to other agents.
Conclusions:
- Azithromycin enhances the resistance of lung transplant macrophages and their lysosomes to oxidative stress.
- This protective mechanism may contribute to the prevention of obliterative bronchiolitis post-lung transplantation.
