Heme-mediated reactive oxygen species toxicity to retinal pigment epithelial cells is reduced by hemopexin

Hunt, Richard C.; Handy, Indhira; Smith, Ann

doi:10.1002/(sici)1097-4652(199607)168:1<81::aid-jcp10>3.0.co;2-s

Cited by 42 publications

(20 citation statements)

References 23 publications

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“…The importance of heme in inflammatory processes in vivo is further emphasized by the rapid increased expression of hemoglobin and heme scavengers, haptoglobin and hemopexin, respectively, in response to inflammation. [53][54][55][56] Hemopexin selectively delivers heme to cells expressing hemopexin receptors as present on cells in the liver and spleen. Observed differential effects of heme on the various organs may be partly related to a differential heme uptake by the various organs.…”

Section: Discussionmentioning

confidence: 99%

Heme is a potent inducer of inflammation in mice and is counteracted by heme oxygenase

Wagener

Eggert

Boerman

et al. 2001

Blood

384

324

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Various pathologic conditions, such as hemorrhage, hemolysis and cell injury, are characterized by the release of large amounts of heme. Recently, it was demonstrated that heme oxygenase (HO), the heme-degrading enzyme, and heme are able to modulate adhesion molecule expression in vitro. In the present study, the effects of heme and HO on inflammation in mice were analyzed by monitoring the biodistribution of radiolabeled liposomes and leukocytes in conjunction with immunohistochemistry. Small liposomes accumulate in inflamed tissues by diffusion because of locally enhanced vascular permeability, whereas leukocytes actively migrate into inflammatory areas through specific adhesive interactions with the endothelium and chemotaxis. Exposure to heme resulted in a dramatic increase in liposome accumulation in the pancreas, but also intestines, liver, and spleen exhibited significantly increased vascular permeability. Similarly, intravenously administered heme caused an enhanced influx of radiolabeled leukocytes into these organs. Immunohistochemical analysis showed differential up-regulation of the adhesion molecules ICAM-1, P-selectin, and fibronectin in liver and pancreas in heme-treated animals. Heme-induced adhesive properties were accompanied by a massive influx of granulocytes into these inflamed tissues, suggesting an important contribution to the pathogenesis of inflammatory processes. Moreover, inhibition of HO activity exacerbated hemeinduced granulocyte infiltration. Here it is demonstrated for the first time that heme induces increased vascular permeability, adhesion molecule expression, and leukocyte recruitment in vivo, whereas HO antagonizes heme-induced inflammation possibly through the down-modulation of adhesion molecules. IntroductionThe inflammatory response consists of a complex cascade of orchestrated signals resulting in increased permeability of blood vessels, changes in blood flow, and migration of leukocytes from blood to affected tissues. 1 Vascular permeability results from the partial retraction of endothelial cells of small venules in the vicinity of inflammation, leaving small intercellular gaps (approximately 0.1-0.4 m). This so-called vascular leakage results in slower blood flow by allowing the passage of water, salts, and small proteins from the plasma into the damaged area, whereas blood cells are retained within the vessels. 1 In normal circumstances the endothelial layer is nonadhesive for leukocytes. However, during inflammation, activated endothelial cells increase the surface expression of specific adhesion molecules, such as intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), endothelial leukocyte adhesion molecule (E-selectin), and P-selectin. 2 This increased cell surface adhesion enables circulating activated leukocytes to specifically interact with their ligands on the endothelium. 2 Although the inflammatory response of the host is considered essential in the protection against pathogens, activated leukocytes and endothelial cells ma...

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Section: Discussionmentioning

confidence: 99%

Heme is a potent inducer of inflammation in mice and is counteracted by heme oxygenase

Wagener

Eggert

Boerman

et al. 2001

Blood

384

324

View full text Add to dashboard Cite

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“…Furthermore, the binding of heme-HPX to the cells induces HO-1, MT-1, and ferritin. Finally, HPX inhibits heme toxic effects on retinal epithelial cells (Hunt et al, 1996a(Hunt et al, , 1996b.…”

Section: Hemopexin-mediated Protection Against Extracellular Hemementioning

confidence: 99%

Hemopexin: Structure, Function, and Regulation

Tolosano

Altruda

2002

DNA and Cell Biology

367

280

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Hemopexin (HPX) is the plasma protein with the highest binding affinity to heme among known proteins. It is mainly expressed in liver, and belongs to acute phase reactants, the synthesis of which is induced after inflammation. Heme is potentially highly toxic because of its ability to intercalate into lipid membrane and to produce hydroxyl radicals. The binding strength between heme and HPX, and the presence of a specific heme-HPX receptor able to catabolize the complex and to induce intracellular antioxidant activities, suggest that hemopexin is the major vehicle for the transportation of heme in the plasma, thus preventing heme-mediated oxidative stress and heme-bound iron loss. In this review, we discuss the experimental data that support this view and show that the most important physiological role of HPX is to act as an antioxidant after blood heme overload, rather than to participate in iron metabolism. Particular attention is also put on the structure of the protein and on its regulation during the acute phase reaction.

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“…Thus, free heme is covalently bound by hemopexin with high affinity (kD < 1 pmol/L) [4], and the hemehemopexin complex is transported to the liver where it is internalized by hepatocytes via receptor-mediated endocytosis [5][6][7]. Except from plasma hemopexin synthesized by hepatocytes, the molecule is also expressed in neurons of human brain [8], in ganglia of the neural retina [8], and hemopexin can also be induced in response to injury in peripheral nerves [9,10].…”

mentioning

confidence: 99%