Lane-Hamilton Syndrome Ferritin Protects Lung Macrophages Against Iron and Oxidation
2011 (English)In: CHEST, ISSN 0012-3692, Vol. 139, no 2, 361-367 p.Article in journal (Refereed) Published
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)-alpha 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-alpha (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-alpha 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.
Place, publisher, year, edition, pages
American College of Chest Physicians , 2011. Vol. 139, no 2, 361-367 p.
National CategoryEngineering and Technology
IdentifiersURN: urn:nbn:se:liu:diva-66311DOI: 10.1378/chest.10-0818ISI: 000287773100019OAI: oai:DiVA.org:liu-66311DiVA: diva2:403227