Abstract
BackgroundLung 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.ObjectiveOxidative 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.MethodsMacrophages 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.ResultsOxidant 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.ConclusionsAZM 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.
Highlights
Lung allografts contain large amounts of iron (Fe), which inside lung macrophages may promote oxidative lysosomal membrane permeabilization (LMP), cell death and inflammation
Prevention of obliterative bronchiolitis in lung transplants by AZM is partly due to this action
The macrophages from lung transplant recipients with AZM displayed a slight decrease of Acridine orange (AO) green fluorescence (−6 ± 6) upon oxidant challenge, which was significantly less than the increase of AO green fluorescence observed in the macrophages from the healthy subjects (p < 0.01) (Figure 1A)
Summary
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. Lung macrophages function as large recipients of iron (Fe) [1,2,3,4,5]. Following the enzymatic digestion of degradable Fe-containing material (executed by lysosomal enzymes working at acidic pH), liberated Fe becomes re-utilized in different cellular processes that and the leakage of lysosomal Fe and hydrolytic enzymes in to the cytosol, may result in cell death [3,4,5,6,10,11,12]. AZM is a weak base and lysosomotropic, i.e., AZM is protonated, trapped and concentrated up to > 1000-fold inside the acidic lysosomes [24,25,26]
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