UMLS:C0022116 - FACTA Search

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Query: UMLS:C0022116 (ischemia)
91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Estrogen is known to stimulate endothelial nitric oxide production and attenuate endothelial dysfunction after ischemia and reperfusion. However, estrogen therapy increases the risk of breast and endometrial cancer. The present study was designed to determine whether idoxifene, a selective estrogen receptor modulator without adverse effects on reproductive organs, may stimulate nitric oxide release and protect endothelial function. In U-46619 precontracted superior mesenteric arterial (SMA) segments isolated from ovariectomized rats, idoxifene and 17 beta-estradiol resulted in a comparable dose-dependent vasorelaxation (maximal relaxation: 75.3 +/- 4.9 and 71 +/- 4.7%, respectively). Treatment of the rings with N(omega)-nitro-L-arginine methyl ester completely blocked idoxifene- and 17 beta-estradiol-induced vasorelaxation. In vitro incubation of SMA rings with TNF alpha significantly reduced vasorelaxation to an endothelium-dependent vasodilator, acetylcholine (maximal relaxation: 73 +/- 3.7 versus 95 +/- 2.9% pre-TNF alpha, P <.01). Idoxifene, but surprisingly not 17 beta-estradiol, prevented TNF alpha-induced endothelial dysfunction (maximal relaxation: 86 +/- 2.6% in idoxifene-treated rings and 77 +/- 5.1% in 17beta-estrogen-treated rings). In vivo ischemia and reperfusion resulted in significant endothelial dysfunction as evidenced by decreased vasorelaxation to acetylcholine (maximal relaxation: 48 +/- 5.5 versus 92 +/- 3.9% in normal SMA rings), but a normal relaxation response to an endothelium-independent vasodilator, acidified NaNO(2) (95 +/- 3.2%). Treatment with idoxifene at either 1 or 2 mg/kg/day, or 17beta-estrogen at 1 mg/kg/day for 4 days significantly preserved endothelial function (P <.01 versus vehicle). Taken together, these results demonstrate that idoxifene is an endothelium-dependent vasodilator and exerts significant endothelial protective effects against TNF alpha- and ischemia-reperfusion-induced endothelial injury. These results suggest that selective estrogen receptor modulators have therapeutic potential in diseases where endothelial dysfunction plays an important role.
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PMID:Nitric oxide stimulatory and endothelial protective effects of idoxifene, a selective estrogen receptor modulator, in the splanchnic artery of the ovariectomized rat. 1104 19

Low rates of coronary heart disease was found in Greenland Eskimos and Japanese who are exposed to a diet rich in fish oil. Suggested mechanisms for this cardio-protective effect focused on the effects of n-3 fatty acids on eicosanoid metabolism, inflammation, beta oxidation, endothelial dysfunction, cytokine growth factors, and gene expression of adhesion molecules; But, none of these mechanisms could adequately explain the beneficial actions of n-3 fatty acids. One attractive suggestion is a direct cardiac effect of n-3 fatty acids on arrhythmogenesis. N-3 fatty acids can modify Na+ channels by directly binding to the channel proteins and thus, prevent ischemia-induced ventricular fibrillation and sudden cardiac death. Though this is an attractive explanation, there could be other actions as well. N-3 fatty acids can inhibit the synthesis and release of pro-inflammatory cytokines such as tumor necrosis factoralpha (TNFalpha) and interleukin-1 (IL-1) and IL-2 that are released during the early course of ischemic heart disease. These cytokines decrease myocardial contractility and induce myocardial damage, enhance the production of free radicals, which can also suppress myocardial function. Further, n-3 fatty acids can increase parasympathetic tone leading to an increase in heart rate variability and thus, protect the myocardium against ventricular arrhythmias. Increased parasympathetic tone and acetylcholine, the principle vagal neurotransmitter, significantly attenuate the release of TNF, IL-1beta, IL-6 and IL-18. Exercise enhances parasympathetic tone, and the production of anti-inflammatory cytokine IL-10 which may explain the beneficial action of exercise in the prevention of cardiovascular diseases and diabetes mellitus. TNFalpha has neurotoxic actions, where as n-3 fatty acids are potent neuroprotectors and brain is rich in these fatty acids. Based on this, it is suggested that the principle mechanism of cardioprotective and neuroprotective action(s) of n-3 fatty acids can be due to the suppression of TNFalpha and IL synthesis and release, modulation of hypothalamic-pituitary-adrenal anti-inflammatory responses, and an increase in acetylcholine release, the vagal neurotransmitter. Thus, there appears to be a close interaction between the central nervous system, endocrine organs, cytokines, exercise, and dietary n-3 fatty acids. This may explain why these fatty acids could be of benefit in the management of conditions such as septicemia and septic shock, Alzheimer's disease, Parkinson's disease, inflammatory bowel diseases, diabetes mellitus, essential hypertension and atherosclerosis.
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PMID:Beneficial effect(s) of n-3 fatty acids in cardiovascular diseases: but, why and how? 1113 72

We hypothesized that ischemia/reperfusion (I/R) injury of the liver during normotensive gram-negative bacteremic sepsis alters the kinetics of circulating endotoxin, tumor necrosis factor-alpha (TNF-alpha), and coinduced mediators, thereby exacerbating sepsis-induced lung inflammation. Liver and lung dysfunction were studied after hematogenous infection of Sprague-Dawley rats with 10(9) Escherichia coli serotype O55:B5 (EC) and 90 min of secondary hepatic ischemia in EC + I/R and saline-infused (normal saline NS) x I/R rats, followed by brief (1 h) or longer reperfusion (24 h). TNF- alpha:leukotriene interactions in this model were examined using the 5-lipoxygenase-activating protein inhibitor MK-886. Compared with sham-operated EC + Sham animals, peak serum endotoxin, TNF-alpha, alanine aminotransferase, interleukin-6 (IL-6), and hepatic neutrophil (PMN) influx were higher in EC + I/R rats through 24 h (p < 0.05) despite comparable arterial pressure. Lung PMN influx and wet/dry weight ratios were likewise enhanced in EC + I/R versus EC + Sham or NS + I/R rats. MK-886 attenuated TNF-alpha concentrations and ischemic liver injury but not mortality. Thus, focal hepatic I/R augments circulating endotoxin, TNF-alpha, and postbacteremic lung inflammation early after normotensive E. coli bacteremic sepsis.
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PMID:Liver-lung interactions following Escherichia coli bacteremic sepsis and secondary hepatic ischemia/reperfusion injury. 1128 80

It is postulated that inadequate remodeling of the uterine spiral arteries in preeclampsia leads to focal ischemia and generation of inflammatory cytokines, such as tumor necrosis factor (TNF alpha) and interleukins (ILs), by the placenta. Our objective was to compare TNF alpha, IL-1 alpha, IL-1 beta, and IL-6 levels in placentas from patients with preeclampsia and normal term pregnancies. Because the placenta is a large heterogeneous organ, we analyzed multiple sites per placenta. On the average, there was a 3-fold variation in cytokine protein levels across the eight sites analyzed for each placenta. However, there were no significant overall differences among the normal term, preeclamptic, and preterm placentas from women without preeclampsia. There were also no significant differences in TNF alpha messenger ribonucleic acid between the normal term and preeclamptic placentas, although TNF alpha messenger ribonucleic acid levels were lower in placentas from preterm patients without diagnosis of preeclampsia than in the normal term placentas. In vitro, hypoxia stimulated the production of TNF alpha, IL-1 alpha and IL-1 beta, but not that of IL-6, by placental villous explants from both groups of patients, and this was not exaggerated in preeclampsia. Finally, although peripheral and uterine venous levels of TNF alpha were elevated in preeclamptic women compared with normal term patients, the ratio of uterine to peripheral venous TNF alpha levels was not significantly different from 1.0 for either patient group. Taken together, these results suggest that sources other than the placenta contribute to the elevated concentrations of TNF alpha and IL-6 found in the circulation of preeclamptic women.
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PMID:Expression of inflammatory cytokines in placentas from women with preeclampsia. 1139 47

The response of tumor necrosis factor alpha (TNF alpha), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), interleukin-1 receptor antagonist (IL-1ra), macrophage colony stimulating factor (MCSF), white blood cell (WBC), platelet (Plt), lactic acid (LAC) to cardiopulmnary bypass (CPB) were studied until 48 hours after aortic declamping in 11 patients who underwent elective CABG (n = 4), mitral valve plasty or replacement with modified maze procedure (n = 5), and both procedures (n = 2). The highest levels of the cytokines IL-6, IL-8, IL-10, and IL-1ra were observed after the removal of the cross clamp. These cytokines just after the aortic declamping are likely to be occurred not only by an interaction of the blood components with the artificial surfaces, but also by ischemia-reperfusion injury upon discontinuation of the aortic clamping. MCSF increased gradually in the late post-CPB phase and reached a peak at 48 hr after aortic declamping. MCSF may play an important role in regulating hematopoiesis on the postoperative days 1 and 2 in patients. In conclusion, the therapy based on the kinetics of these cytokines would be useful for patients undergoing CPB.
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PMID:[Serum cytokine levels response to cardiac surgery with cardiopulmonary bypass]. 1145 22

Stroke is the third most common cause of death in the Western world. The mechanisms of brain damage in the affected areas are largely unknown. Hence, rational treatment strategies are limited. Previous experimental evidence suggested that cerebral lesions were less prominent in CD95 (APO-1/Fas)-deficient (lpr) than in wild-type mice. Additional results strongly suggested that the CD95-ligand (CD95L) was a major cause of neuronal autocrine suicide in the penumbra. These data and the assumption that death-receptor systems might determine stroke-related damage in the brain prompted us to examine these systems in in vitro and in vivo models of ischemia. We showed that hybrids of TNF-deficient and gld mice were strongly resistant towards stroke-induced damage. To determine the mechanism of action of TNF and CD95L, we separately investigated their influence on primary ischemic death and secondary inflammatory injury. Inhibition of both TNF and CD95L in vitro prevented death of primary neurons induced by oxygen-glucose deprivation and reperfusion. The recruitment of inflammatory cells to the ischemic hemisphere was abrogated in the absence of both TNF and CD95L. Significantly, mice injected with a mixture of neutralizing anti-TNF and anti-CD95L antibodies 30 min after induction of stroke showed a marked decrease in both infarct volumes and mortality. Accordingly, the locomotor performance of these animals was not significantly impaired in comparison to sham-operated animals. These data reveal that inhibition of TNF and CD95L blocks stroke-related damage at two levels, the primary ischemic and the secondary inflammatory injury. These results offer new approaches in stroke treatment.
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PMID:Therapeutic neutralization of CD95-ligand and TNF attenuates brain damage in stroke. 1146 9

Excitotoxic cell death due to glutamate release is important in the secondary injury following CNS trauma or ischemia. Proinflammatory cytokines also play a role. Both glutamate and tumor necrosis factor-alpha (TNF(alpha)) are released immediately after spinal cord injury. Neurophysiological studies show that TNF(alpha) can potentiate the effects of glutamatergic afferent input to produce hyperactivation of brain-stem sensory neurons. Therefore, we hypothesized that TNF(alpha) might act cooperatively with glutamate to affect cell death in the spinal cord as well. Nanoinjections of either TNF(alpha) (60 pg) or kainate (KA; 32 ng) alone into the thoracic gray resulted in almost no tissue damage or cell death 90 min after injection. However, the combination of TNF(alpha) plus KA at these same doses produced a large area of tissue necrosis and neuronal cell death, an effect which was blocked by the AMPA receptor antagonist CNQX (17 ng). These results suggest that secondary injury may involve potentiation of AMPA receptor-mediated excitatory cell death by TNF(alpha).
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PMID:Tumor necrosis factor-alpha induces cFOS and strongly potentiates glutamate-mediated cell death in the rat spinal cord. 1149 24

The objective of the present study was to determine whether hypoxia/reoxygenation in the absence or presence of intestinal bacteria would affect the integrity of the gut mucosal epithelium (as evidenced by histologic changes) and increase the local production of cytokines (interleukin 6 [IL-6] and tumor necrosis factor [TNF]). Rat ileal mucosal membranes were harvested and their electrophysiologic properties and barrier function were measured ex vivo in the Ussing chamber system. Membranes were exposed to normoxia, normoxia + Escherichia coli, hypoxia for 40 min followed by normoxia, or hypoxia for 40 min + E. coli followed by normoxia for 3 h. IL-6 and TNF levels were measured using cytokine-dependent cellular assays. Morphological changes and the degree of DNA fragmentation were used as quantitative markers of gut mucosal injury. Mucosal integrity was maintained in the normoxia group. The addition of bacteria increased the IL-6 response and reduced mucosal integrity. During the hypoxic period, a transient decline in resistance (R) occurred and cytokine production was reduced. In the hypoxic ileal membranes not exposed to E coli, reoxygenation reversed the change in R and increased IL-6 production. The combination of hypoxia/reoxygenation plus E. coli bacterial challenge resulted in the greatest extent of gut mucosal injury and increase in TNF production. The results of this study support the hypothesis that the combination of increased intestinal bacterial levels superimposed on an ischemia/reperfusion injury increases the magnitude of gut mucosal injury and the production and subsequent release of proinflammatory cytokines.
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PMID:Hypoxia combined with Escherichia coli produces irreversible gut mucosal injury characterized by increased intestinal cytokine production and DNA degradation. 1153 Oct 20

TNF alpha administration mimics ischemic preconditioning and neutralizing antibodies to TNF alpha and IL-1 beta abolish exercise-induced preconditioning. However, the pharmacology of TNF alpha's cardioprotective effects and associated downstream signaling events has not been delineated. We evaluated the temporal and dose specific requirements of TNF alpha to function as a preconditioning mimetic. Furthermore we postulated that the preconditioning effect of TNF alpha might be orchestrated via sphingolipid signaling. The cardioprotective effect of TNF alpha and the role of sphingolipid signaling were assessed using a classical preconditioning protocol in the isolated perfused rat heart with the measurement of infarct size and contractile function modulation in response to index ischemia and reperfusion. Recombinant TNF alpha at an optimal dose of 0.5 ng/ml mimicked ischemic preconditioning by reducing infarct size by 60%v non-preconditioned ischemia-reperfusion controls (P<0.01). The infarct sparing effect of TNF alpha required a wash-out period prior to the index ischemic-reperfusion. Moreover, the classic ischemic preconditioning antagonist such as 5-hydroxydecanoate abolished TNF alpha preconditioning. An inhibitor of the sphingolipid signaling pathway, N-oleoylethanolamine (NOE, 1 microm) attenuated ischemic and TNF alpha preconditioning. Likewise, cell-permeable C(2)-ceramide and sphingosine 1-phosphate (sphingolipid signaling intermediates) both reproduced the preconditioning cardioprotective phenotype. Finally, TNF alpha and ceramide conferred preconditioning-like cardioprotection against post-ischemic contractile dysfunction and this cardioprotective effect was attenuated by NOE. In contrast, NOE did not reverse ischemic preconditioning enhanced post-ischemic contractile function. In conclusion, TNF alpha activates preconditioning-like tolerance against infarction and contractile dysfunction. This cardioprotection is mediated, in part, via activation of novel sphingolipid signaling intermediates.
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PMID:Identification of a novel role for sphingolipid signaling in TNF alpha and ischemic preconditioning mediated cardioprotection. 1205 55

Prostacyclin is an important endothelial mediator involved in the interaction of neutrophils (PMN) with the vessel wall. Many studies have shown the beneficial effects of prostacyclin in ischemia and reperfusion. However, no previous study has investigated the direct effects of the prostacyclin analogs iloprost (ILO) and alprostadil (PGE(1)) on the endothelial part of the adhesion process. Human umbilical vein endothelial cells (HUVECs) were grown to confluence, stimulated with 300 U/ml TNF-alpha and treated with increasing concentrations of ILO and PGE(1). The cells were washed to remove TNF and the inhibitors and adhesion of fluorescence-green labeled PMN was determined microscopically. ICAM-1, VCAM-1 and E-selectin expression were measured by a cell-surface ELISA. The chemoattractant activity of the endothelial cell releasate was tested in a Boyden chamber.ILO and PGE(1) reduced PMN-adhesion in a concentration-dependent manner (ILO: -54 +/- 9 % at 0.5 microM, PGE1: -46 +/- 10 % at 10 microM). However, the surface expression of ICAM-1, VCAM-1 and E-selectin remained unaltered. When the supernatant of iloprost/PGE(1)-treated cells was transferred onto cells that were activated, but not treated with ILO or PGE(1), the reduction of PMN adhesion remains sustained. These data indicate that the inhibitory effect of ILO/ PGE(1) treatment is achieved by a reduced chemoattractant potential. PAF-antagonists were able to block neutrophil adhesion and mimicked the effect of ILO, while exogenous PAF diminished the inhibitory effect of ILO concentration-dependently. This study demonstrates the beneficial effects of ILO and PGE(1) on inflammatorily activated endothelial cells. These prostacyclin analogs inhibit PMN-adhesion despite maximal adhesion molecule expression by regulating the balance of - yet to be determined - endothelial-derived mediators.
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PMID:Prostacyclin inhibits adhesion of polymorphonuclear leukocytes to human vascular endothelial cells due to adhesion molecule independent regulatory mechanisms. 1249 64

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