Lane-Hamilton syndrome: ferritin protects lung macrophages against iron and oxidation.
BACKGROUND
Lysosomal disruption and consequent apoptosis have been implicated in lung diseases characterized by iron overload. Free reactive iron in lysosomes sensitizes cells to oxidative stress. Apoptosis is prevented by heavy-chain (H)-ferritin, which can incorporate lysosomal iron into ferritin molecules. Tumor necrosis factor (TNF)-α stimulates the synthesis of H-ferritin. Idiopathic pulmonary hemosiderosis presents with the accumulation of iron and the upregulation of ferritin synthesis. We therefore analyzed the lysosomal response to oxidants and the role of H-ferritin synthesis in lung macrophages (LMs) harvested from the first Swedish case, to our knowledge, of Lane-Hamilton syndrome.


METHODS
Iron-exposed murine macrophages were used as a reference. Both cell types were stimulated with TNF-α (or not), then iron was assessed cytochemically and by atomic absorption spectrophotometry. H-ferritin expression was analyzed by Western blot and reduced glutathione (GSH) by spectrofluorometry. Following exposure to hydrogen peroxide, lysosomal membrane integrity and DNA degradation were analyzed by flow cytometry, whereas morphologic signs of apoptosis and necrosis were assessed by light microscopy.


RESULTS
GSH levels were approximately equal in LMs and murine macrophages. Although LMs contained much more iron than murine macrophages, lysosomal iron was bound in a harmless unreactive state by ample amounts of ferritin and hemosiderin, its lysosomal degradation product. Therefore, lysosomes of LMs were more oxidant resistant, and these cells were more adept at surviving oxidative stress. In both cell types, TNF-α prevented oxidant-induced lysosomal damage and cell death by upregulating synthesis of H-ferritin and GSH.


CONCLUSIONS
Iron-overloaded LMs are equipped with an efficient armor of antioxidative mechanisms of which H-ferritin and hemosiderin seem to be particularly important.
Persson
H Lennart
HL
Division of Experimental Pathology, Linköping University, Linköping; Division of Pulmonary Medicine, Linköping University, Linköping. Electronic address: Lennart.Persson@lio.se.
Vainikka
Linda K
LK
Division of Experimental Pathology, Linköping University, Linköping.
Eriksson
Hanna B
HB
Division of Pulmonary Medicine, Linköping University, Linköping.
Wennerström
Urban
U
Division of Medicine, Hospital of Västervik, Västervik, Sweden.
D000328:Adult; D000818:Animals; D001052:Apoferritins / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis; D001379:Azathioprine / Q000627:therapeutic use; D015153:Blotting, Western; D003131:Combined Modality Therapy; D004249:DNA Damage; D003937:Diagnosis, Differential; D055050:Diet, Gluten-Free; D005260:Female; D005434:Flow Cytometry; D005938:Glucocorticoids / Q000627:therapeutic use; D005978:Glutathione / Q000378:metabolism; D006486:Hemosiderosis / Q000175:diagnosis / Q000378:metabolism* / Q000628:therapy; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008171:Lung Diseases / Q000175:diagnosis / Q000378:metabolism* / Q000628:therapy; D008247:Lysosomes / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000378:metabolism*; D008775:Methylprednisolone / Q000627:therapeutic use; D051379:Mice; D018384:Oxidative Stress; D011241:Prednisone / Q000627:therapeutic use; D013050:Spectrometry, Fluorescence; D013054:Spectrophotometry, Atomic; D013577:Syndrome; D014057:Tomography, X-Ray Computed
D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D001052:Apoferritins; D005978:Glutathione; D001379:Azathioprine; D011241:Prednisone; D008775:Methylprednisolone