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Heme uptake by endothelium synergizes polymorphonuclear granulocyte-mediated damage
G Balla1, G Vercellotti, J W Eaton
1Department of Medicine, University of Minnesota, Minneapolis 55455.
Transactions of the Association of American Physicians
|January 1, 1990
Summary
Free heme effectively delivers iron into cells, increasing their susceptibility to oxidant damage. This heme-induced cell injury may contribute to various clinical conditions, highlighting potential therapeutic targets.
Area of Science:
- Biochemistry
- Cell Biology
- Toxicology
Background:
- Transition metals, especially iron, exacerbate oxidant damage to cellular organelles.
- Assessing iron's role in intact cell damage is challenging due to difficulties in experimentally increasing intracellular iron levels.
Purpose of the Study:
- To investigate heme as an effective iron delivery vehicle into intact cells.
- To determine if heme-loaded endothelial cells exhibit increased sensitivity to oxidant-mediated cytotoxicity.
- To explore potential therapeutic interventions for heme-induced vascular damage.
Main Methods:
- Endothelial cells were loaded with free heme in vitro.
- Cells were exposed to various oxidants (hydrogen peroxide, hypoxanthine/xanthine oxidase, phorbol-stimulated PMN).
- Lipid peroxidation levels and cytotoxicity were assessed.
- The effects of hemopexin and the iron chelator U74500A were evaluated.
Main Results:
- Endothelial cells rapidly incorporated free heme, leading to sensitization to oxidant-induced cytotoxicity.
- Heme-aggravated cytotoxicity correlated with increased lipid peroxidation in cell membranes.
- Hemopexin provided protection against PMN-mediated damage when added simultaneously.
- The iron chelator U74500A mitigated heme-augmented damage from hydrogen peroxide and PMN.
Conclusions:
- Heme serves as an efficient iron delivery system, sensitizing endothelial cells to oxidant injury.
- Lipid peroxidation appears to be a key mechanism in heme-aggravated endothelial damage.
- Compounds like U74500A show therapeutic potential for conditions involving heme-induced vascular damage.