Iron-binding drugs targeted to lysosomes: a potential strategy to treat inflammatory lung disorders.
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 alpha-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.
Persson
H Lennart
HL
Division of Pulmonary Medicine, Faculty of Health Sciences, University of Linköping, SE-581 85 Linköping, Sweden. Lenpe@inr.liu.se
Richardson
Des R
DR
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D015507:Drugs, Investigational / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D008171:Lung Diseases / Q000201:enzymology / Q000473:pathology*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015507:Drugs, Investigational; D007502:Iron Chelating Agents; D007501:Iron