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Endothelial cells, Fenton reaction, Histochemistry, Hydrogen peroxide, Hyperplastic smooth muscle, Iron, Neointima, Neutrophils, Smooth muscle, Superoxide


Background: To explore the hypothesis that tissue iron and reactive oxygen species, including superoxide (O2), mediate acute inflammatory and late hyperplastic responses to vascular injury, we studied experimental overdistension of normal carotid and femoral arteries in dogs. Experimental design: Arterial segments isolated in situ were distended with Ringer solution at 2 atmospheres pressure. In initial experiments the arteries were excised immediately after distension and immersed in diaminobenzidine solutions containing Mn++ ions to initiate histochemical reactions for O2. In other experiments distended arterial segments were reperfused with arterial blood in the presence or absence of the iron chelator, deferoxamine, or the low-cost superoxide dismutase mimic, manganese chloride, and examined microscopically at 3 hours, 7 days, or 30 days. The degree of acute inflammation or smooth muscle hyperplasia was determined by quantitative morphometry; free iron capable of redox cycling was determined histochemically. Results: (1) O2 was produced by injured endothelial cells; (2) free iron is present on the surfaces of endothelial cells in the distended arterial segments; (3) an acute subintimal inflammatory response occurs at 3 hours after distension injury, followed by proliferation of mural smooth muscle cells at 7 days, and neointima formation at 30 days; (4) single doses of either the low molecular weight superoxide dismutase mimic, manganese chloride, or the strong iron chelator, deferoxamine, administered during and immediately after arterial distension, prevent the early inflammatory and late hyperplastic responses to distension injury. Conclusions: Tissue iron and oxidants may participate importantly in the over-reaction to arterial injury that leads to restenosis.