Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Various beneficial effects of calcium channel blockers on cell and organ function following endotoxic shock, organ ischemia, and reperfusion have been reported; however, it is not known whether these agents have any salutary or deleterious effects on immune responses after low-flow conditions. Therefore, the aim of this study was to determine (a) the effect of hemorrhage on lymphocyte IL-2, IL-3, IL-6, and IFN-gamma synthesis, and (b) whether diltiazem has any salutary or adverse effects on these parameters when administered following hemorrhage and resuscitation. To study this, C3H/HeN mice were bled to a mean blood pressure of 35 mm Hg, maintained at that level for 60 min, and resuscitated with shed blood plus twice that volume of Ringer's lactate. Immediately following resuscitation mice received either diltiazem (2400, 800, or 400 micrograms/kg body wt), or an equivalent volume of saline. The mice were sacrificed 24 hr later, splenic lymphocytes were obtained, and their capacity to produce lymphokines was assessed. The results indicated that in the vehicle-treated animals, hemorrhage significantly decreased (P less than 0.05) IL-2, IL-3, IL-6, and IFN-gamma synthesis by 82 +/- 19%, 64 +/- 28%, 71 +/- 11%, and 86 +/- 14%, respectively. However, diltiazem (400 but not 2400 micrograms/kg) treatment after hemorrhage restored lymphocyte capacity to produce IL-2, IL-3, IL-6, and IFN-gamma (P less than 0.05). Additional groups of animals were subjected to sepsis by cecal ligation and puncture 3 days following hemorrhage.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Diltiazem restores IL-2, IL-3, IL-6, and IFN-gamma synthesis and decreases host susceptibility to sepsis following hemorrhage. 190 99

A period of cold and warm ischemia is obligatory when performing lung transplantation. Subtle ischemia-reperfusion injury induced in the course of transplantation can pass undetected or cause a short phase of reversible lung dysfunction. We hypothesized that ischemia-reperfusion injury may result in the local release of cytokines that have the capability to mediate acute lung injury early following transplantation. To test this hypothesis, 10 mongrel dogs were subjected to left lung allotransplantation. As performed in the clinical setting, donor lungs were preserved with Eurocollins solution and stored at 4 degrees C for 4 hr, which was followed by 1 hr of warm ischemia. Recipients received standard immunosuppression of cyclosporine, azathioprine, and low dose steroids. Bronchoalveolar lavage (BAL) and open lung biopsies were performed before operation and at approximately 1 hr, 4 hr, 24 hr, and 1 week after transplantation. A significant increase in BAL IL-2 levels was observed 4 hr after surgery (0 hr: 349 +/- 138 pg/ml; 4 hr: 757 +/- 284 pg/ml) (mean +/- SEM) (P < 0.05) which subsequently decreased 24 hr (320 +/- 168 pg/ml) after transplantation. BAL TNF-alpha levels were significantly increased 1 hr after transplantation (P < 0.05) (0 hr: 3.4 +/- 0.65 pg/ml; 1 hr: 13.3 +/- 8.0 pg/ml) returning to baseline after 24 hr (5.8 +/- 2.8 pg/ml). BAL IFN-gamma levels also significantly increased 1 and 4 hr after transplantation (0 hr: 7.2 +/- 2.1 pg/ml; 1 hr: 68.2 +/- 49.2 pg/ml; 4 hr: 301 +/- 131 pg/ml) (P < 0.05). This decreased back to baseline after 24 hr and 1 week (5.2 +/- 1.2 pg/ml and 9.7 +/- 7.9 pg/ml, respectively). There were no changes detected in plasma levels of cytokines. Histology showed evidence of grade 1-2 rejection after 1 week. We conclude that subjection of a lung allograft to standard periods of cold-warm ischemia will result in a temporary early elevation of IL-2, TNF-alpha, and IFN-gamma detectable only in the bronchoalveolar compartment. Such local increase in cytokines in the lung allograft may play an important role in the development of early allograft dysfunction.
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PMID:The early release of interleukin-2, tumor necrosis factor-alpha and interferon-gamma after ischemia reperfusion injury in the lung allograft. 799 55

The myocardial ischemia and reperfusion injury is caused by the re-introduction of coronary circulation in ischemic myocardial tissues. A number of experiments demonstrate that immunological response such as adherence of neutrophils to endothelial cells play a critical role in reperfusion injury. In this paper, the effect of global ischemia and reperfusion on the expression of cytokine genes by myocardial tissues as well as cell adhesion molecules by neutrophils were studied by using Langendorff model. Cardiac dysfunction and immunological response in 25 min global ischemia at 37.5 degrees C followed by 60 min reperfusion were studied in isolated rat heart perfused with blood supplied from support rat (Langendorff model). Cardiac functions were measured with a left intraventricular balloon. The mean post-experimental reduction of the left ventricular end-systolic pressure were 87.5 +/- 1.6% of pre-experimental level in the control perfusion group and 55.5 +/- 5.8% in the reperfusion group. Immunofluorescence flow cytometry showed that ischemia and reperfusion injury did not affect the expression of adhesion molecules on neutrophils which were isolated from perfused blood samples. Cytokine gene expression was analyzed by direct analysis of mRNA obtained from the blood-perfused, isolated rat heart. The level of expression of the cytokine genes was assessed using semiquantitative reverse transcriptase-polymerase chain reaction (semiquantitative RT-PCR). IL-6, IL-8, IFN-gamma, TNF-alpha were expressed in normal heart tissue at low level and were upregulated following ischemia and reperfusion. IL-1 beta, MCP-1 and IL-1 receptor antagonist were not expressed at detectable level in normal heart but were induced following global ischemia. IL-1 alpha was not expressed at detectable level in normal heart but was induced following reperfusion of the ischemic heart. Histological examination of myocardial tissue from the reperfusion group revealed no evidence of myocardial necrosis. Only a mild interstitial edema as well as weak focal hemorrhage was detected after reperfusion of ischemic hearts. These results suggest that there is a process which causes early stage of post-ischemic myocardial dysfunction without involving myocardial necrosis nor infiltration of inflammatory cells.
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PMID:[Cardiac dysfunction and endogenous cytokines in global ischemia and reperfusion injury]. 811 7

The roles of neutrophil Mac-1 (CD11b/18) adhesion molecule, TNF-alpha and IFN-gamma in hepatic warm ischemia-reperfusion injury (IRI) were investigated with a newly established mouse model. Blood supply to the left lateral and the median lobe of the liver was interrupted with an atraumatic clip for 50 minutes. From 1 hour to 24 hours after reperfusion, TNF-alpha in the ischemic liver tissue was detected. IFN-gamma was not detected in ischemic liver tissue and blood. Pretreatment with anti-mouse Mac-1 monoclonal antibody (mAb) diminished the plasma GPT level, area of necrosis, and number of myeloperoxidase positive cells in ischemic liver lobe at 24 hours after reperfusion. Pretreatment with anti-mouse TNF-alpha or anti-mouse IFN-gamma mAb did not affected any parameters. From these results, Mac-1 was considered to play an important role in a hepatic warm IRI. However, TNF-alpha and IFN-gamma were not considered to play a pivotal role in the pathogenesis of the injury and in the regulation of the neutrophils adhesion via Mac-1.
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PMID:[Roles of Mac-1, endogenous TNF-alpha, and IFN-gamma in pathogenesis of hepatic warm ischemia-reperfusion injury]. 854 78

Transplantation-related pathogenic factors such as ischemia or allograft-directed inflammation are associated with oxidative changes that might lead to cellular oxidative stress. The aim of this study was to investigate the impact of oxidative stress on: (1) CMV replication in cultured human endothelial cells and (2) the stimulation of endothelial cells by proinfiammatory cytokines. Both pathomechanisms are known to contribute to graft rejection crises in vivo. Oxidative stress was induced in endothelial cell cultures with 10-200 microM buthionine sulfoximine. Western blotting showed a significant increase in the production of CMV-specific immediate early and late proteins in buthionine sulfoximine-treated cultures. Immunocytochemical staining suggested that this effect was caused by increased numbers of CMV antigen expressing cells (66% immediate early; 78%, late). Quantitative polymerase chain reaction for CMV-specific DNA and virus titration revealed that enhanced viral replication levels correlated with increased virion production. As a measure for the endothelial cell activation status, the surface expression of HLA-ABC and HLA-DR and adhesion molecules (ICAM-1, ELAM-1, VCAM-1) was quantified by fluorometric methods. Whereas oxidative stress alone did not modulate any surface molecule expression, the IFN-gamma-mediated expression of HLA-ABC and HLA-DR and the IL-1-mediated expression of ICAM-1, but not of ELAM-1 and VCAM-1 (IL-1 + TNF-alpha), was amplified. Interestingly, the amplification of HLA molecule expression was even higher in CMV-infected endothelial cells. This study provides evidence that oxidative stress contributes to the regulation of CMV replication, virus shedding, and the activation of endothelial cells by proinflammatory cytokines as it is observed in transplant recipients.
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PMID:Impact of oxidative stress on human cytomegalovirus replication and on cytokine-mediated stimulation of endothelial cells. 868 57

End organ ischemia, fragmentation of elastic membranes, and aneurysm formation in patients with giant cell vasculitis results from an inflammation destroying the mural layers of large and medium sized arteries. Although the inflammatory infiltrate extends through all layers of the affected blood vessel, the most pronounced changes involve the intima and the internal elastic lamina. Analysis of the functional profile of tissue infiltrating CD68+ cells demonstrates that different subsets of macrophages can be distinguished. TGFbeta1-expressing CD68+ cells coproduce IL-1beta and IL-6, are negative for inducible nitric oxide synthase (iNOS), and exhibit a strong preference for localization in the adventitia. The adventitial homing of TGFbeta1+ CD68+ cells places them in the vicinity of IFN-gamma secreting CD4+ T cells which also accumulate in the exterior layer of the artery. Conversely, iNOS expressing CD68+ cells are negative for TGFbeta and are almost exclusively found in the intimal layer of the inflamed artery. The intimal-medial junction is the preferred site for 72-kD collagenase expressing CD68+ cells. Thus, TGFbeta1-producing macrophages colocalize with activated CD4+ T cells and home to an area of inflammation which is distant from the site of tissue damage but critical in regulating cellular influx, suggesting that TGFbeta1 functions as a proinflammatory mediator in this disease. iNOS- and 72-kD collagenase-producing macrophages accumulate at the center of pathology implying a role of these products in tissue destruction. These data indicate that the microenvironment controls the topographical arrangement as well as the functional commitment of macrophages.
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PMID:Correlation of the topographical arrangement and the functional pattern of tissue-infiltrating macrophages in giant cell arteritis. 883 14

Events in the early post-transplant period have been correlated with increased renal allograft loss. Immunologic reactions and ischemic injury have been implicated in this process. While the immunologic aspects of allograft injury have been studied extensively, ischemic effects remain less well understood. To study the effects of ischemia in rats with different genetic backgrounds without the introduction of an alloimmune response, a clamp was placed on the vascular pedicle of the left kidney for 60 min. The short-term effects (1 wk) of ischemia were studied in groups of PVG (RT1c), LEW (RT1), DA (RT1a) and WR (RT1u) rats, Immunoperoxidase staining demonstrated limited infiltration of monocytes, macrophages, and T-cells accompanied by upregulation of low levels of MHC class II antigens on tubular epithelial cells, peritubular capillaries, and interstitial cells in kidneys of PVG and WF rats. Kidneys of LEW and DA rats had greater influxes of monocytes, macrophages, and T cells in addition to higher amounts of MHC class II antigens upregulation on tubular epithelium and interstitial cells. The long-term effects of ischemia were studied in kidneys of WF rats. These kidneys had a progressive increase in infiltrating T cells, monocytes, macrophages and MHC class II expression on the tubular epithelium and the interstitial cells at 14, 30, and 90 d after the ischemic insult. The differences in MHC class II expression between ischemic kidneys of PVG and LEW rats were not associated with differences in production of mRNA for IL-2, IFN-gamma, and TNF-alpha. In summary, transient renal ischemia in the absence of an allogeneic immune response triggers a progression of inflammatory responses, including leukocyte infiltration, cytokine production and MHC class II antigen upregulation which appears to be strain-dependent.
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PMID:Immunohistochemical manifestations of unilateral kidney ischemia. 899 59

Brain prostanoid levels are normally low but can increase after ischemia and during inflammatory and infectious diseases. High prostanoid levels can affect brain function in several ways. In particular, prostaglandin E2 (PGE2) might exert both immunodepressive and proinflammatory actions. The present short review focuses on the regulation of prostanoid synthesis in microglial cultures and on the possible role of PGE2 in the down-regulation of microglial activation induced by lipopolysaccharide (LPS). Our studies were carried out using purified mouse or rat microglial cultures. LPS induced a dose-dependent expression of the inducible isoform of cyclooxygenase (COX-2), both in neonatal and adult microglial cultures. In the latter, the inducibility of COX-2 increased with time in culture, paralleling the acquisition of a more 'activated' microglial phenotype, and appeared to account for the time-dependent increase in the PGE2/TXB2 production ratio. The LPS-induced COX-2 expression and prostanoid production were down-regulated by potentially neurotoxic agents, such as nitric oxide (NO), the proinflammatory cytokine IFN-gamma (which acted both directly and indirectly, through its NO-inducing activity) and the HIV regulatory protein tat. On the other hand, COX-2 expression was up-regulated by the macrophage-deactivating cytokine TGF-beta 1, by exogenous PGE2 itself, which acted through EP2 receptors linked to cyclic AMP generation, and by non steroidal anti-inflammatory drugs. Interestingly, PGE2 utilized the same EP2 receptor-mediated signal transduction mechanism to down-regulate the expression of the inducible NO synthase and the production of NO. Largely, but not exclusively, through its effect on cyclic AMP, PGE2 can also: i) depress the expression of major histocompatibility complex class II antigens and of the costimulatory molecule B7-2; ii) down-regulate TNF and up-regulate IL-10 microglial production; iii) inhibit microglial IL-12 secretion. These observations, together with literature data on in vivo models of central nervous system (CNS) diseases, suggest a neuroprotective role of PGE2 in pathological conditions.
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PMID:Regulation of prostanoid synthesis in microglial cells and effects of prostaglandin E2 on microglial functions. 989 49

Molecular studies of giant cell arteritis indicate that T cells are recruited to the wall of medium-sized and large arteries, are activated locally, produce IL-2 and IFN-gamma, and regulate the activity of tissue-infiltrating macrophages. Downstream effects of T cell activation include the production of proinflammatory cytokines, metalloproteinases, and growth factors. Growth factors are instrumental in the process of intimal hyperplasia, leading to luminal occlusion and tissue ischemia. The amounts of IL-2, IFN-gamma, and the growth factor PDGF in the vascular lesions varies among patients and are correlated with differences in patterns of clinical manifestations. Giant cell arteritis complicated by cranial ischemia, such as anterior optic neuropathy or stroke, is characterized by high levels of IFN-gamma and PDGF. If the IFN-gamma-PDGF loop is less developed, fever and wasting can dominate the disease. Dominant production of IL-2 is associated with polymyalgia rheumatica. The finding of different inflammatory pathways translating into different clinical phenotypes may reflect differences in the contribution of the arterial wall. Alternative hypotheses include a role of multiple disease-inducing antigens with different tissue distributions or tropisms.
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PMID:Giant cell arteritis--a molecular approach to the multiple facets of the syndrome. 992 95

Adenosine is a potent endogenous anti-inflammatory agent released by cells in metabolically unfavorable conditions, such as hypoxia or ischemia. Adenosine modulates different functional activities in macrophages. Some of these activities are believed to be induced through the uptake of adenosine into the macrophages, while others are due to the interaction with specific cell surface receptors. In murine bone marrow-derived macrophages, the use of different radioligands for adenosine receptors suggests the presence of A2B and A3 adenosine receptor subtypes. The presence of A2B receptors was confirmed by flow cytometry using specific Abs. The A2B receptor is functional in murine macrophages, as indicated by the fact that agonists of A2B receptors, but not agonists for A1, A2A, or A3, lead to an increase in cAMP levels. IFN-gamma up-regulates the surface protein and gene expression of the A2B adenosine receptor by induction of de novo synthesis. The up-regulation of A2B receptors correlates with an increase in cAMP production in macrophages treated with adenosine receptor agonist. The stimulation of A2B receptors by adenosine or its analogues inhibits the IFN-gamma-induced expression of MHC class II genes and also the IFN-gamma-induced expression of nitric oxide synthase and of proinflammatory cytokines. Therefore, the up-regulation of the A2B adenosine receptor expression induced by IFN-gamma could be a feedback mechanism for macrophage deactivation.
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PMID:IFN-gamma up-regulates the A2B adenosine receptor expression in macrophages: a mechanism of macrophage deactivation. 1009 21


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