Prevention of oxidant-induced cell death by intralysosomal iron binding
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
The lung is particularly prone to oxidative stress by its exposure to ambient oxygen and inhaled environmental oxidants. Abnormal assimilation and accumulation of iron are found in many lung disorders, which in redox-active form will exacerbate oxidative tissue damage. It may be that the most important cellular pool of redox -active iron exists within lysosomes. As a result, these organelles are very vulnerable to oxidative stress and may burst due to peroxidative membrane destabilization. Support for the importance of intralysosomal iron in cellular oxidant damage includes the observation that the iron chelator, desferrioxamine, which almost exclusively localizes within the lysosomal compartment, will protect cells against oxidati ve challenge. Iron chelators targeted to the lysosomes may therefore be a particularly efficient therapeutic strategy for cells under conditions of substantial oxidative stress.
The present study, employing cultures of human respiratory epithelial cells and murine macrophage-like cells, explores the protective effects by iron binding agents upon H202 and gamma radiation-induced lysosomal damage and cell death. Using these in vitro models, the present study shows: (1) that chelation of intralysosomal iron efficiently prevents lysosomal rupture and ensuing cell death induced by either H202 or gamma radiation; (2) that cell permeable lysosomotropic iron-chelators are much more efficient than those being internalized by endocytosis; (3) that intralysosomal iron is the most important cellular pool of redox-active iron for chelation therapy; (4) that ironcatalyzed peroxidative lysosomal destabilization is a decisive and early event in the apoptotic machinery.
Although apoferritin and desferrioxarnine suppress the reactivity of lysosomal iron, their efficacy is considerably restrained by their uptake by fluid-phase endocytosis. Apoferritin is digested intralysosomally which further decreases its iron sequestering potential, while desferrioxamine by its intralysosomal retention may disturbe normal cellular functions and cause iron-starvation. Amongst cell permeable iron-binding agents we tested a-lipoic acid, alipoamide, and a synthetic amine derivative of α-lipoarnide, α-lipoic acid-plus (5-[1,2] dithiolan-3-yl-pentanoic acid (2-dimethylamino-ethyl) amide). The large difference in the protective potential of these cell permeant iron-chelators derives from their being localized in different cellular compartments, which lends further support that lysososomes contain the most important pool of chelatable redox-active iron. Indeed, a-lipoic acid-plus by its lysosomotropism was by all means the most efficient iron chelator. On a molar basis α-lipoic acid-plus was 4,000 to 5,000 times more effective than desferrioxamine to prevent lysosomal rupture and cell death induced by H202 or gamma radiation.
We conclude that iron chelating therapy targeted to the lysosomes is an efficient strategy to protect oxidatively stressed cells in vitro. A corresponding efficacy of such treatment in vivo, and in iron dependent pulmonary disorders in particular, needs to be explored.
Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2003. , 60 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 812
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-27537Local ID: 12194ISBN: 91-7373-502-7OAI: oai:DiVA.org:liu-27537DiVA: diva2:248089
2003-10-23, Victoriasalen, Universitetssjukhuset, Linköping, 13:15 (Swedish)
Hultcrantz, Rolf, Professor
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