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Query: UMLS:C0042384 (vasculitis)
 20,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Iron-derived reactive oxygen species play an important role in the pathogenesis of various vascular disorders including vasculitis, atherosclerosis, and capillary leak syndromes such as the adult respiratory distress syndrome (ARDS). We have suggested that acute incorporation of the heme moiety of hemoglobin released from red blood cells into endothelium could provide catalytically active iron to the vasculature. Adaptation to chronic heme stress involves the induction of heme oxygenase and ferritin; the latter provides cytoprotection against free radicals in vitro. The present studies examine the bioavailability of heme, derived from hemoglobin, to induce heme oxygenase and ferritin in rat lungs in vivo. Intravenous injection of methemoglobin, but not oxyhemoglobin, increases total lung heme oxygenase mRNA approximately fivefold after 16 h. Accompanying this mRNA induction, expression of total lung heme oxygenase enzyme activity is also markedly enhanced. In situ hybridization for heme oxygenase reveals mRNA accumulation in the lung microvascular endothelium, implying incorporation of heme into endothelial cells. Similarly, methemoglobin significantly increases the ferritin protein content of rat lungs and in parallel, ferritin light-chain mRNA increases approximately 1.6-fold, whereas heavy-chain mRNA is upregulated by approximately 1.9-fold. Immunoreactive ferritin is present in lung microvascular endothelium after methemoglobin treatment, suggesting incorporation of heme iron into pulmonary vasculature. Subcutaneous injection of Sn-protoporphyrin IX, a competitive inhibitor of heme oxygenase, does not affect methemoglobin-induced ferritin synthesis in lungs. We speculate that methemoglobin, which might be generated by activated leukocytes in ARDS associated with disseminated interavascular coagulation, can provide heme iron to lung microvascular endothelium to induce heme oxygenase and ferritin.
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PMID:Endothelial cell heme oxygenase and ferritin induction in rat lung by hemoglobin in vivo. 786 52

Iron-derived reactive oxygen species are implicated in the pathogenesis of various vascular disorders including atherosclerosis, vasculitis, and reperfusion injury. The present studies examine whether heme, when liganded to physiologically relevant proteins as in hemoglobin, can provide potentially damaging iron to intact endothelium. We demonstrate that reduced ferrohemoglobin, while relatively innocuous to cultured endothelial cells, when oxidized to ferrihemoglobin (methemoglobin), greatly amplifies oxidant (H2O2)-mediated endothelial-cell injury. Drawing upon our previous observation that free heme similarly primes endothelium for oxidant damage, we posited that methemoglobin, but not ferrohemoglobin, releases its hemes that can then be incorporated into endothelial cells. In support, cultured endothelial cells exposed to methemoglobin--in contrast to exposure to ferrohemoglobin, cytochrome c, or metmyoglobin--rapidly increased their heme oxygenase mRNA and enzyme activity, thereby supporting heme uptake; ferritin production was also markedly increased after such exposure, thus attesting to eventual incorporation of Fe. These cellular methemoglobin effects were inhibited by the heme-scavenging protein hemopexin and by haptoglobin or cyanide, agents that strengthen the liganding between heme and globin. If the endothelium is exposed to methemoglobin for a more prolonged period (16 hr), it accumulates large amounts of ferritin; concomitantly, and presumably associated with iron sequestration by this protein, the endothelium converts from hypersusceptible to hyperresistant to oxidative damage. We conclude that when oxidation of hemoglobin facilitates release of its heme groups, catalytically active iron is provided to neighboring tissue environments. The effect of this relinquished heme on the vasculature is determined both by extracellular factors--i.e., plasma proteins, such as haptoglobin and hemopexin--as well as intracellular factors, including heme oxygenase and ferritin. Acutely, if both extra- and intracellular defenses are overwhelmed, cellular toxicity arises; chronically, when ferritin is induced, resistance to oxidative injury may supervene.
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PMID:Endothelial-cell heme uptake from heme proteins: induction of sensitization and desensitization to oxidant damage. 841 93

Iron-derived reactive oxygen species (ROS) are implicated in the pathogenesis of numerous vascular disorders including atherosclerosis, microangiopathic haemolytic anaemia, vasculitis and reperfusion injury. One abundant source of redox-active iron is haem, which is inherently dangerous when released from intracellular haem proteins. The present review concerns the likely involvement of haem in vascular endothelial cell damage and the strategies used by endothelium to minimize such damage. Exposure of endothelial cells to haem greatly potentiates cell killing mediated by polymorphonuclear leukocytes and other sources of ROS. Free haem also promotes the conversion of low-density lipoprotein to cytotoxic oxidized products. If only because of its abundance, haemoglobin probably represents the most important potential source of haem within the vascular endothelium; free haemoglobin in plasma, when oxidized, can transfer haem to endothelium, thereby enhancing cellular susceptibility to oxidant-mediated injury. As a defence against such toxicity, upon exposure to free haem, endothelial cells up-regulate haem oxygenase-1 and ferritin. Haem oxygenase is a haem-degrading enzyme that opens the porphyrin ring, producing biliverdin, carbon monoxide and a most dangerous product-free redox-active iron. The latter can be controlled effectively by sequestration within ferritin, a multimeric protein with a very high capacity for storing iron. These homeostatic adjustments have been shown to be effective in the protection of endothelium against the damaging effects of exogenous haem and oxidants. The central importance of this protective system was highlighted recently by the discovery of a child diagnosed with haem oxygenase-1 deficiency, who exhibited extensive endothelial damage.
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PMID:Haem, haem oxygenase and ferritin in vascular endothelial cell injury. 1281 58

Rickettsiae, a diverse group of obligately intracellular gram-negative bacteria, include etiologic agents of the spotted fever and typhus groups of diseases. Rocky Mountain spotted fever and boutonneuse fever, due to Rickettsia rickettsii and R. conorii, respectively, are characterized by widespread infection of the vascular endothelium, microvascular injury, and vasculitis. Cultured human endothelial cells (EC) are highly susceptible to infection and respond by altering the expression of adhesion molecules, regulatory cytokines, and the antioxidant enzyme heme oxygenase (HO). In the vasculature, HO regulates the cyclooxygenase (COX) enzymes, among which the inducible isozyme COX-2 facilitates the synthesis of prostaglandins (PGs). Using in vitro and ex vivo models of infection, we demonstrate here that R. rickettsii infection of human EC causes robust induction of COX-2 mRNA and protein expression but has no apparent effect on the constitutive COX-1 isoform. Cells infected with viable rickettsiae consistently displayed significantly increased secretion of 6-keto-PGF(1alpha) and PGE(2). R. rickettsii-induced COX-2 was sensitive to inhibitors of de novo transcription and the pyridinylimidazole-based compound SB 203580, suggesting that this transcriptional host cell response involves signaling through p38 mitogen-activated protein kinase. PG production by infected cells was abrogated by NS 398 (a selective COX-2 inhibitor) and indomethacin (a pan-COX inhibitor). Immunohistochemical staining of sections of infected umbilical cords and corresponding uninfected controls revealed comparatively more intense and abundant staining for COX-2 in infected endothelia. Induction of the endothelial COX-2 system and the resultant enhanced release of vasoactive PGs may contribute to the regulation of inflammatory responses and vascular permeability changes during spotted fever rickettsioses.
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PMID:Infection of human endothelial cells with spotted Fever group rickettsiae stimulates cyclooxygenase 2 expression and release of vasoactive prostaglandins. 1692 98