Injection of iron compounds followed by induction of the stress response causes tissue injury and apoptosis

To determine whether iron-laden tissue subsequently stimulated to produce t he stress ("heat shock") response-sustained injury, hindlimbs of male ND4 m ice were injected with iron salts, hemin, or hemoglobin. The stress respons e was induced with sodium arsenite or with heat. Ulcers appeared at the inj ection site. Tissues were analyzed by three distinct techniques-electron mi croscopy, TUNEL stain, and agarose gel electrophoresis of low molecular wei ght DNA-which collectively suggest that the tissue injury is, at least in p art, the consequence of accelerated apoptosis. The data suggest that the to xicity of free iron is amplified by induction of the stress (heat shock) re sponse to signal a programmed response. This model and mechanism may have i mplications in pathological processes ranging from the cutaneous wounds of venous stasis disease to the tissue failure of multiple organ dysfunction.