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

There is a large body of evidence that the liver microcirculation has to be considered as a major target in hepatic ischemia/reperfusion injury. The nature of microvascular injury, which precedes manifestation of hepatic parenchymal tissue damage, includes both hypoxia due to lack of microvascular perfusion (i.e. no-reflow), and a reperfusion-associated inflammatory response, which includes the activation and dysfunction of leukocytes and Kupffer cells (the reflow paradox). No-reflow in sinusoids is thought to be caused by endothelial cell swelling and intravascular hemoconcentration, and involves also a deterioration of the balance between ET and NO. The reflow paradox is associated with: (i) the release and action of proinflammatory cytokines (TNF-alpha, IL-1) and oxygen radicals; (ii) the up-regulation of endothelial and leukocytic adhesion molecules (selectins, beta-integrins, ICAM-1); and (iii) the interaction of leukocytes with the endothelial lining of the hepatic microvasculature.
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PMID:Role of microcirculation in hepatic ischemia/reperfusion injury. 1043 6

The objective of the present study was to determine whether long-term arterial hypertension renders the microvasculature more vulnerable to the deleterious inflammatory responses elicited by ischemia and reperfusion (I/R). Intravital fluorescence microscopy was used to monitor leukocyte adherence and emigration, platelet-leukocyte aggregation, and albumin extravasation in mesenteric postcapillary venules of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) after 10 minutes of ischemia and subsequent reperfusion. Significant and comparable increases in leukocyte adherence/emigration and the formation of platelet aggregates were elicited by I/R in both WKY and SHR. Albumin extravasation was enhanced after I/R in SHR, but not in WKY. Monoclonal antibodies directed against the adhesion glycoproteins CD18, P-selectin, or ICAM-1 showed similar patterns of protection against the I/R-induced inflammatory responses in WKY and SHR. The enhanced albumin extravasation noted in postischemic venules of SHR was prevented by immunoneutralization of either CD18 on leukocytes or ICAM-1 on endothelial cells. These results suggest that, whereas long-term arterial hypertension does not significantly modify the leukocyte and platelet recruitment normally elicited in venules by I/R, it does result in an exaggerated albumin leakage response, which is mediated by an interaction between beta(2) (CD18) integrins on leukocytes and ICAM-1 on endothelial cells.
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PMID:Microvascular responses to ischemia/reperfusion in normotensive and hypertensive rats. 1045 43

We used IL-6 knock-out (KO) mice to evaluate a possible role for IL-6 in the pathogenesis of splanchnic artery occlusion shock (SAO). SAO shock was induced by clamping both the superior mesenteric artery and the celiac trunk, followed by release of the clamp. There was a marked increase in the peroxynitrite formation in the plasma of the SAO-shocked IL-6 wild-type (WT) mice after reperfusion. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine in the necrotic ileum in shocked IL-6 WT mice. SAO-shocked WT mice developed a significant increase of tissue myeloperoxidase (MPO) and malondialdehyde (MDA) activity and marked histological injury to the distal ileum. SAO shock was also associated with a significant mortality (0% survival). Reperfused ileum tissue sections from SAO-shocked WT mice showed positive staining for P-selectin. Little specific staining was observed in sham-WT mice. Staining of ileum tissue obtained from sham-operated WT mice with anti-ICAM-1 antibody showed weak but diffuse staining, demonstrating that ICAM-1 is constitutively expressed. However, after SAO shock the staining intensity increased substantially in the ileum section from WT mice. Intensity and degree of P-selectin and ICAM-1 were markedly reduced in tissue section from SAO-shocked IL-6 KO mice. SAO-shocked IL-6 KO mice also show significant reduction of neutrophil infiltration into the reperfused intestine, as evidenced by reduced MPO activity, improved histological status of the reperfused tissues, reduced peroxynitrite formation, reduced MDA levels, and improved survival. In vivo treatment with anti-IL-6 significantly prevents the inflammatory process. Our results clearly demonstrate that IL-6 plays an important role in ischemia and reperfusion injury and allows the hypothesis that inhibition of IL-6 may represent a novel and possible strategy. Part of this effect may be due to inhibition of the expression of adhesion molecules and subsequent reduction of neutrophil-mediated cellular injury.
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PMID:IL-6 knock-out mice exhibit resistance to splanchnic artery occlusion shock. 1049 18

Following ischemia-reperfusion (I/R), platelet adhesion is thought to represent the initial event leading to remodeling and reocclusion of the vasculature. The mechanisms underlying platelet adhesion to the endothelium have not been completely established. Endothelial cells rendered ischemic acquire a procoagulant phenotype, characterized by fibrinogen accumulation. Therefore, we evaluated whether fibrinogen deposition during I/R mediates platelet adhesion. Using fluorescence microscopy, fibrinogen deposition and the accumulation of platelets were assessed in vivo in a model of intestinal I/R (1.5 hours/60 minutes). Fibrinogen accumulated in arterioles and venules early after the onset of reperfusion. The deposition of fibrinogen colocalized with large numbers of adherent platelets (520 +/- 65 and 347 +/- 81 platelets/mm(2) in arterioles and venules). Pretreatment with an antifibrinogen antibody attenuated platelet adhesion. Intracellular adhesion molecule (ICAM)-1 served as a major receptor for fibrinogen, since fibrinogen deposition and platelet adhesion to the endothelial cell surface were markedly decreased in ICAM-1-deficient mice. The platelet alpha(IIb)/beta(3) integrin plays a key role in fibrinogen-dependent platelet accumulation, because (1) platelet adhesion involved RGD-recognition sequences, and (2) platelets isolated from a patient with Glanzmann's disease showed decreased interaction with the postischemic endothelium. Since platelets are demonstrated here to induce tyrosine phosphorylation in endothelial cells, platelet recruitment might contribute to the development of an inflammatory reaction during I/R.
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PMID:Fibrinogen deposition at the postischemic vessel wall promotes platelet adhesion during ischemia-reperfusion in vivo. 1057 98

Leukocyte infiltration into the brain has been implicated in the development of ischemic brain damage. In this study, simulated in vitro ischemia/reperfusion and IL-1beta were found to up-regulate both the expression of intercellular adhesion molecule- (ICAM-1) in cultured human cerebromicrovascular endothelial cells (HCEC) and the adhesion of allogenic neutrophils to HCEC. Both HCEC and human fetal astrocytes (FHAS) also responded to IL-1beta and to in vitro ischemia/reperfusion by a pronounced up-regulation of IL-8 and MCP-1 mRNA and by increased release of IL-8 and MCP-1 in cell culture media. FHAS were found to release 30-times higher levels of MCP-1 than HCEC under both basal and ischemic conditions. However, 100 u/ml IL-1beta induced greater stimulation of both IL-8 and MCP-1 secretion in HCEC (50 and 20 times above controls, respectively) than in FHAS (three and two times above controls, respectively). IL-8 was the principal neutrophil chemoattractant released from IL-1beta-treated HCEC, since IL-8 antibody completely inhibited neutrophil chemotaxis enticed by HCEC media. However, the IL-8 antibody neutralized only 50% of IL-1beta-stimulated neutrophil chemoattractants released from FHAS, and 40%-60% of ischemia-stimulated chemotactic activity released by either HCEC or FHAS. These results suggest that simulated in vitro ischemia, in addition to IL-8 and MCP-1, stimulates secretion of other bioactive chemokines from HCEC and FHAS.
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PMID:Increased expression of bioactive chemokines in human cerebromicrovascular endothelial cells and astrocytes subjected to simulated ischemia in vitro. 1058 Jul 98

Leukocytes play a key role in the inflammatory processes such as ischemia-reperfusion of the coronary vasculature. Their interaction with the endothelium is closely regulated. The first step in the process is the rolling of leukocytes (eg, neutrophils) along the microvascular endothelium. This is regulated by the selectin family of cell adhesion molecules, primarily P-selectin. The next step in the inflammatory cascade is the firm adhesion of these neutrophils to the activated or dysfunctional endothelium. This process is governed by the beta2-integrins on the leukocytes (eg, CD11/CD18) and by ICAM-1 on the activated endothelium. CD11/CD18 is a beta2-integrin, and ICAM-1 is a member of the immunoglobulin superfamily of adhesion glycoproteins. By their interaction, neutrophils flatten out and adhere to the vascular endothelium. Many of these adhered neutrophils are then able to transmigrate across the endothelium to the site of the inflammation (ie, the focus of the ischemia-reperfusion). This transmigration is primarily stimulated by PECAM-1, another member of the immunoglobulin superfamily. These processes are discussed in this brief review.
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PMID:Role of the beta2-integrins and immunoglobulin superfamily members in myocardial ischemia-reperfusion. 1058 4

The aim of the present study was to investigate the protective effect of the pineal secretary product melatonin in a model of splanchnic artery occlusion shock (SAO). SAO shock was induced in rats by clamping both the superior mesenteric artery and the celiac trunk for 45 min, followed thereafter by release of the clamp (reperfusion). At 60 min after reperfusion, animals were sacrificed for tissue histological examination and biochemical studies. There was a marked increase in the oxidation of dihydrorhodamine 123 to rhodamine (a marker of peroxynitrite-induced oxidative processes) in the plasma of the SAO-shocked rats after reperfusion, but not during ischemia alone. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine, an index of nitrogen species such as peroxynitrite, in the necrotic ileum in shocked rats. SAO-shocked rats developed a significant increase of tissue myeloperoxidase and malondialdehyde activity, and marked histological injury to the distal ileum. SAO shock was also associated with a significant mortality (0% survival at 2 hr after reperfusion). Reperfused ileum tissue sections from SAO-shocked rats showed positive staining for P-selectin, which was mainly localized in the vascular endothelial cells. Ileum tissue sections obtained from SAO-shocked rats with anti-intercellular adhesion molecule (ICAM-1) antibody showed a diffuse staining. Melatonin (applied at 3 mg/kg, 5 min prior to reperfusion, followed by an infusion of 3 mg/kg per hr), significantly reduced ischemia reperfusion injury in the bowel as evaluated by histological examination. This prevented the infiltration of neutrophils into the reperfused intestine, is evidenced by reduced myeloperoxidase activity and reduced lipid peroxidation. This was evaluated by malondialdehyde activity which reduced the production of peroxynitrite during reperfusion, markedly reduced the intensity and degree of P-selectin and ICAM-1 in tissue section from SAO-shocked rats and improved their survival. Taken together, our results clearly demonstrate that melatonin treatment exerts a protective effect and part of this effect may be due to inhibition of the expression of adhesion molecule and peroxynitrite-related pathways and subsequent reduction of neutrophil-mediated cellular injury.
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PMID:Beneficial effects of melatonin in a rat model of splanchnic artery occlusion and reperfusion. 1062 2

Sulfatide binds to P- and L-selectin, which play important roles in the initiation of neutrophil-endothelial interactions. Sulfatide protects skin flaps from ischemia-reperfusion injury. The purpose of this study was to evaluate the augmented protection when anti-rat ICAM-1 and anti-rat LFA-1 antibodies are combined with sulfatide in the ischemia-reperfusion model of rat skin flaps. Sulfatide was administered intravenously just before elevation of the right abdominal epigastric flap, and monoclonal antibodies were injected 30 min before clamp release. The femoral artery and vein were clamped above and below the epigastric vessels for 11 h and then the clamp was released. The administration of both sulfatide and monoclonal antibodies significantly increased the flap surviving area (6.58 +/- 0.61 cm(2) versus the group with monoclonal antibodies alone, 4.43 +/- 0.32 cm(2), P = 0.01). In the untreated rats the area was 1.86 +/- 0.36 cm(2). Histological examination 24 h after reperfusion in the group treated with sulfatide and monoclonal antibodies showed only slight leukocyte invasion into the flap, and myeloperoxidase activity 24 h after reperfusion was significantly reduced. This study indicates that both sulfatide and monoclonal antibodies protect rat skin flaps from ischemia-reperfusion injury.
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PMID:Sulfatide and monoclonal antibodies prevent reperfusion injury in skin flaps. 1064 77

Brief episodes of ischemia can render an organ resistant to subsequent severe ischemia. This 'ischemic preconditioning' is ascribed to various mechanisms, including oxidative stress. We investigated whether preconditioning exists on an endothelial level. Human umbilical vein endothelial cells (HUVECs) were transiently confronted with oxidative stress (1 mM H(2)O(2), 5 min). Adhesion molecules ICAM-1 and E-selectin and release of cytokines IL-6 and IL-8 to subsequent stimulation with TNF-alpha (2.5 ng/ml, 4 h) were measured (flow cytometry and immunoassay), as were nuclear translocation of the transcription factor NFkappaB (Western blotting, confocal microscopy) and redox status of HUVECs (quantification of glutathione by HPLC). TNF-alpha elevated IL-6 in the cell supernatant from 8.8 +/- 1 to 41 +/- 3 pg/ml and IL-8 from 0.5 +/- 0. 03 to 3 +/- 0.2 ng/ml. ICAM-1 was increased threefold and E-selectin rose eightfold. Oxidative stress (decrease of glutathione by 50%) reduced post-TNF-alpha levels of IL-6 to 14 +/- 3 and IL-8 to 1 +/- 0.2; the rise of ICAM-1 was completely blocked and E-selectin was only doubled. The anti-inflammatory effects of preconditioning via oxidative stress were paralleled by reduction of the translocation of NFkappaB on stimulation with TNF-alpha, and antagonized by the intracellular radical scavenger N-acetylcysteine. 'Anti-inflammatory preconditioning' of endothelial cells by oxidative stress may account for the inhibitory effects of preconditioning on leukocyte adhesion in vivo.
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PMID:Endothelial preconditioning by transient oxidative stress reduces inflammatory responses of cultured endothelial cells to TNF-alpha. 1069 71

There is recent evidence that angiotensin-converting enzyme (ACE) inhibition reduces postischemic injury and angiotensin II receptor inhibition may have similar effects. We therefore further characterized the role of ACE- vs. AT1-receptor inhibition on cell injury and temporal association of leukocyte endothelial interaction in response to ischemia-reperfusion. A combined in vivo and in vitro study comparing the ACE inhibitor enalapril and the AT1-receptor antagonist losartan was performed. The extent and temporal correlation of cellular damage (propidium-iodide staining), microvascular perfusion failure and leukocyte-endothelial interaction (leukocyte adherence) were investigated by means of intravital microscopy, after the application of hemodynamically ineffective doses of enalapril and losartan (5 mg/kg). A hamster dorsal skinfold model with a 4-h tourniquet ischemia was used. In vitro, the effect of enalapril and losartan on polymorphonuclear cell (PMN) adherence, as well as adhesion molecule expression (ICAM-1, VCAM-1), on hypoxia- or IL-1beta-stimulated endothelial cells (HUVEC) was assessed using a PMN-adhesion assay and flow cytometry, respectively. Ischemia-reperfusion responses revealed a biphasic pattern, comprised of an early phase (30 min) of acute cellular damage and microvascular perfusion failure, followed by a late increase (240 min) in leukocyte adherence in vivo. Enalapril significantly reduced early cellular damage, microvascular perfusion failure, and leukocyte adherence in response to ischemia-reperfusion. Conversely, AT1 receptor inhibition with losartan proved to be ineffective at attenuating postischemic microcirculatory disorders (leukocyte-endothelial interactions, microvascular perfusion failure) and aggravated cellular injury. In vitro, enalapril reduced PMN adherence and ICAM-1 and VCAM-1 expression, while losartan was ineffective in the same respect. Following ischemia-reperfusion injury, ACE- versus AT1-receptor inhibition induce differential effects concerning the extent and temporal association of cell injury and leukocyte-endothelial interaction. The use of enalapril combines the beneficial effects of preventing cell and vascular injury immediately after reperfusion, with a delayed inhibition of the inflammatory response. Since the AT1-receptor inhibitor losartan did not mimic effects obtained with ACE inhibition, it is conceivable that the responses in ischemia-reperfusion are mediated by a non-angiotensin II-AT1 receptor-dependent mechanism.
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PMID:Differential effects of short-term ace- and AT1-receptor inhibition on postischemic injury and leukocyte adherence in vivo and in vitro. 1071 75


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