Endothelial cell heme oxygenase and ferritin induction by heme proteins: a possible mechanism limiting shock damage.
Acutely, hemin sensitizes endothelial cells to oxidants but chronically protects the endothelium through the induction of ferritin. By releasing its heme, methemoglobin can sensitize endothelial cells in a fashion similar to free hemin. Furthermore, prolonged incubation with the endothelium allows methemoglobin to induce heme oxygenase and ferritin and concomitantly to modulate oxidant-mediated cytotoxicity. Methemoglobin but not hemoglobin, metmyoglobin or cytochrome c induces heme oxygenase and ferritin. Heme needs to be released from methemoglobin, since sodium cyanide, haptoglobin, and hemopexin inhibit the induction of these proteins. Neutrophils can oxidize hemoglobin to methemoglobin, which can subsequently induce both heme oxygenase and ferritin. We speculate that in shock with disseminated intravascular coagulation, marginated PMNs oxidize hemoglobin to heme-releasing methemoglobin. If critical defenses such as haptoglobin and hemopexin are overwhelmed, heme enters the endothelin cells, sensitizing them to oxidant damage. Endothelial cell adaptation via heme-induced heme oxygenase and ferritin production might limit ultimate progression to pulmonary and other vascular leak syndromes.
Balla
J
J
Department of Medicine, University of Minnesota, Minneapolis 55455.
Jacob
H S
HS
Balla
G
G
Nath
K
K
Vercellotti
G M
GM
D000818:Animals; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000293:injuries / Q000378:metabolism*; D005293:Ferritins / Q000096:biosynthesis*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D006420:Hemeproteins / Q000378:metabolism; D008706:Methemoglobin / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012128:Respiratory Distress Syndrome / Q000209:etiology; D013552:Swine
D006420:Hemeproteins; D017382:Reactive Oxygen Species; D005293:Ferritins; D008706:Methemoglobin; D006419:Heme Oxygenase (Decyclizing)