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• _5 value "Furthermore, the demonstrated vaso-occlusion and vascular inflammation present in several hemoglobinopathies are thought to be caused by increased adhesive interactions between the vascular endothelium and circulating blood cells (Moore et al., 1996; Hebbel, 1997; Solovey et al., 2001). In sickle cell disease, accumulation of heme, adhesion molecule expression, and an increased risk of renal failure have recently been demonstrated (Shiu et al., 2000; Nath et al., 2001a; Bonaventura et al., 2002; Frenette, 2002), strengthening the idea that heme-induced oxidative and inflammatory insults relate to its etiology (Wagener et al., 2001a). B. Consequences of Heme-Induced Oxidative Stress and Inflammation These recent observations may have widespread implications for the understanding of various inflammatory complications. It implicates, on the one hand, that at sites of injury, the released heme may be a physiological response that is necessary to recruit inflammatory cells, to initiate inflammatory processes, and to function as a first \"danger signal\". However, on the other hand, excess of free heme may cause oxidative and inflammatory injury. In that case, it is of utmost importance to shield the oxidative and inflammatory properties of free heme; e.g., prevention of the formation of methemoglobin, which easily releases its heme, may be helpful in the design of safe \"blood substitutes\". This adds to the hypothesis that heme-induced inflammation is involved in the pathology of diverse conditions, such as renal failure, atherosclerosis, complications after artificial blood transfusion, peritoneal endometriosis, and heart transplant failure (Jacob, 1994; Nath et al., 1995; Alayash, 2000; Sato et al., 2001; Van Langendonckt et al., 2002). Based on our findings, it seems important that packed red blood cells should be first washed before administration to a patient to prevent inflammatory complications during blood transfusions, since during storage a significant amount of erythrocytes will have been lysed, resulting in large amounts of free heme that may initiate inflammation. Alternatively, patients with increased vascular free heme, e.g., after intravascular hemolysis, may benefit from plasmapheresis or dialysis to dilute its potential damaging activities. Furthermore, appearance of functional relevant polymorphisms for haptoglobin, hemopexin, and HO could be important for people with increased risk of heme release or people with already compromised redox balance, such as diabetes patients, sports people, or people undergoing transplantation or surgery. In case these individuals have a compromised protection against heme and heme protein-mediated inflammation priming of HO-1 expression or administration of heme/hemoglobin scavengers may protect them from injury. For the hemoglobin scavenger, haptoglobin, there have been three major polymorphisms described that are associated with different prevalence of many inflammatory diseases, including infections, atherosclerosis, and autoimmune disorders (Langlois and Delanghe, 1996). Interestingly, these different polymorphisms possess also different hemoglobin-scavenging activity (Wuyts et al., 2000). Moreover, the carriers of the polymorphisms that are severely impaired in hemoglobin binding show to be more susceptible to cardiovascular diseases, such as atherosclerosis (Braeckman et al., 1999). This may possibly be explained by our findings of heme-mediated oxidative and inflammatory effects, such as foam cell formation, adhesion molecule expression, and leukocyte recruitment (Wagener et al., 2001b, 2003b). Interestingly, both polymorphisms in haptoglobin and HO-1 are considered risk factors for restenosis after percutaneous transluminal angioplasty (Exner et al., 2001; Roguin et al., 2001). C. The Role of Heme Oxygenase in Inflammation In 1916, Suzuki postulated the idea that prior exposure to toxins induces resistance to second..." provenance.
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