Heme proteins such as myoglobin or hemoglobin, when released into the extracellular space, can instigate tissue toxicity. Myoglobin is directly implicated in the pathogenesis of renal failure in rhabdomyolysis. In the glycerol model of this syndrome, we demonstrate that the kidney responds to such inordinate amounts of heme proteins by inducing the heme-degradative enzyme, heme oxygenase, as well as increasing the synthesis of ferritin, the major cellular repository for iron. Prior recruitment of this response with a single preinfusion of hemoglobin prevents kidney failure and drastically reduces mortality (from 100% to 14%). Conversely, ablating this response with a competitive inhibitor of heme oxygenase exacerbates kidney dysfunction. We provide the first in vivo evidence that induction of heme oxygenase coupled to ferritin synthesis is a rapid, protective antioxidant response. Our findings suggest a therapeutic strategy for populations at a high risk for rhabdomyolysis. (J. Clin. Invest. 1992. 90:267-270.)

Iron-derived reactive oxygen species are implicated in the pathogenesis of various vascular disorders including atherosclerosis, vasculitis, and reperfusion injury.

During hemodialysis, cardiopulmonary decompensation may appear in uremic patients, possibly caused by plugging of pulmonary vessels by leukocytes. In 34 patients we noted leukopenia (20% of initial levels) during hemodialysis that in 15 was associated with impaired pulmonary function. When we infused autologous plasma, incubated with dialyzer cellophane, into rabbits and sheep, sudden leukopenia and hypoxia occurred, with doubling of pulmonary-artery pressures and quintupling of pulmonary-lymph effluent. Histologic examination showed severe pulmonary-vessel-leukostasis and interstitial edema. The syndrome was prevented by preinactivation of complement but was reproduced by infusions of plasma in which complement was activated by zymosan. Thus, acute pulmonary dysfunction from complement-mediated leukostasis may play a major part in the acute cardiopulmonary complications of cellophane-membrane hemodialysis.

Oxidized low density lipoprotein (LDL), formed in vivo from presently unknown reactions, may play a role in atherogenesis. In vitro, transition metals such as iron and copper will facilitate LDL oxidation, but these metals are unlikely to exist in free form in normal body fluids. We have explored the possibility that LDL oxidation may be promoted by heme, a physiologically ubiquitous, hydrophobic, iron-containing compound. Indeed, during several-hour incubation, heme caused extensive oxidative modification of LDL; however, such modification requires only minutes in the presence of small amounts of HjO 2 or preformed lipid hydroperoxides within the LDL. Oxidative interactions between heme, LDL, and peroxides lead to degradation of the heme ring and consequent release of heme iron, which further accelerates heme degradation. Coupled (evidently iron-catalyzed) heme degradation and LDL oxidation are both effectively inhibited by hydrophobic antioxidants and iron chelators. That such hemin-induced LDL oxidation may be involved in atherogenesis is supported by the finding that LDL oxidized by hemin is extremely cytotoxic to cultured aortic endothelial cells. Overall, these investigations not only lend support to the idea that LDL oxidation by physiological substances such as heme may play a role in the process of atherogenesis but also may have broader implications, as similar oxidative reactions between heme and unsaturated fatty acids may occur consequent to hemorrhagic injury. (Arteriosclerosis and Thrombosis 1991;ll:1700-1711)

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