Iron-binding drugs targeted to lysosomes: a potential strategy to treat inflammatory lung disorders

Abstract

In many inflammatory lung disorders, an abnormal assimilation of redox-active iron will exacerbate oxidative tissue damage. It may be that the most important cellular pool of redox-active iron exists within lysosomes, making these organelles vulnerable to oxidative stress. In experiments employing respiratory epithelial cells and macrophages, the chelation of intra-lysosomal iron efficiently prevented lysosomal rupture and the ensuing cell death induced by hydrogen peroxide, ionising radiation or silica particles. Furthermore, cell-permeable iron-binding agents (weak bases) that accumulate within lysosomes due to proton trapping were much more efficient for cytoprotection than the chelator, desferrioxamine. On a molar basis, the weak base α-lipoic acid plus was 5000 times more effective than desferrioxamine at preventing lysosomal rupture and apoptotic cell death in cell cultures exposed to hydrogen peroxide. Thus, iron-chelating therapy that targets the lysosome might be a future treatment strategy for inflammatory pulmonary diseases.

Keywords::

• apoptosis
• desferrioxamine
• lipoic acid
• oxidative stress
• silica
• WR-1065