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)

Interleukin (IL-4) is a pluripotent cytokine that stimulates proliferation of activated T-cells and has antineoplastic activity against human renal tumors in animal systems. In phase I trials, IL-4 could be tolerated at doses up to 20 micrograms/kg, with dose-limiting toxicities consisting of fever, fluid retention, nasal congestion, and mucositis. We report the results of two separate Phase II trials of IL-4 in 30 patients with metastatic malignant melanoma and 19 patients with advanced renal cancer. IL-4 was administered intravenously every 8 h for 14 doses in two 5-day courses separated by a 9-day interval. The first 27 patients were treated at a dose of 800 micrograms/m2, but after three of these patients developed cardiac toxicities, the dose was decreased to 600 micrograms/m2. One complete response occurred in a patient with metastatic melanoma (duration > or = 30 months). No responses were seen among the patients with renal cancer. The most frequent side effects were fever, nausea, malaise, nasal congestion, and diarrhea. Reversible hepatic and renal dysfunction were also common. Hypotension was infrequent, but transient weight gain due to fluid retention was common. The major life-threatening toxicities were cardiac and gastrointestinal. Suspected cardiac ischemia was observed in two patients, pericarditis in one, and arrhythmias in two. Three patients had major upper gastrointestinal bleeding without evidence of local tumor. We conclude that IL-4, when given as a single agent on this schedule at maximum tolerated dose, does not possess meaningful activity in renal cancer or melanoma.
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PMID:Phase II studies of recombinant human interleukin-4 in advanced renal cancer and malignant melanoma. 813 48

We have shown that hypoxia (2% O2 approximately pO2 14 mmHg) as opposed to O2 atmospheric pressure (20.9% O2 approximately pO2 140 mmHg) can deeply affect the production of cytokines in human peripheral mononuclear cells (PBMC) in the presence or absence of a specific T-cell activator such as phytohemagglutinin (PHA). In hypoxia, interleukin (IL)-2, IL-4, and interferon (IFN)-gamma production increased by 110, 70, and 50% over that of controls, respectively, in PHA-stimulated PBMC (P < 0.05). Moreover, in hypoxia, IL-6 production was significantly enhanced in both resting and PHA-stimulated PBMC by 36 and 37%, respectively (P < 0.05). However, in hypoxia, IL-10 production decreased in both resting and stimulated PBMC, being 80 and 67% of controls, respectively (P < 0.05). PBMC proliferation was not significantly affected by hypoxia, although PBMC susceptibility to PHA was about 80% of that of the control (P < 0.05) after 40 hr of treatment, whereas the cycle progression of hypoxic PBMC was delayed. From an evaluation of these results, hypoxia apparently modifies the production of cytokines by PBMC. These results have both theoretical and practical interest because local hypoxia is very common in several conditions, such as inflammation and local ischemia, and is a host-nonspecific defense against infection. Furthermore, these results suggest a differential pattern of cytokine production in vivo in hypoxic tissues.
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PMID:Hypoxia affects cytokine production and proliferative responses by human peripheral mononuclear cells. 936 46

Polymorphonuclear neutrophils (PMN) and monocytes play a role in vascular diseases. Animal experimental models, using deleukocytation or injection of anti-CD11b-anti-CD18 monoclonal antibodies (inhibition of leukocytic adhesion and of interaction with the endothelial cell) have confirmed this role in the ischemia-reperfusion syndrome and in myocardial infarction. In man, increased production of oxygen radicals, PMN release of elastase, increased monocyte formation of tissue factor (TF) and integrins have been noted in coronary artery disease, in chronic arteriopathy of the lower limbs and in association with vascular risk factors such as diabetes. Pharmacological alteration of leukocyte hyperactivity therefore seems to be justified. Pentoxifylline, used with good effect in arteriopathy of the lower limbs, affects numerous leukocytic functions: diminution in adherence and in PMN production of free radicals, diminution in the formation of TF and cytokines (TNF). Gingkolides reduce leukocytic interactions and platelet activation through an anti-PAF (Platelet Activation Factor) action. Aspirin may interfere with free radicals and inhibit TF formation. alpha-tocopherol blocks the activation, by free radicals, of the transcription factor NF k B. By altering the TNF and IL-1 cytokines, leukocytic activation can be controlled. Other cytokines (IL-4, IL-10) have an immunosuppressive action and reduce the formation of TF. The pharmacological targets are therefore multiple. Their use in vascular diseases is only at a very preliminary stage.
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PMID:[Modulators of leukocytic functions]. 960 25

Ischemia-reperfusion injury (IRI) is a major cause of renal dysfunction in both native kidneys and renal allografts. To broaden our understanding of the inflammatory mediators involved in IRI, we used multi-probe RNase protection assays to examine the expression of 26 different cytokine genes in a murine model of renal IRI. We observed that, in addition to up-regulation of IL-1beta and to a lesser extent TNF-alpha, IRI was associated with an intense and sustained up-regulation of three gp130-signaling cytokines, IL-6, IL-11, and leukemia inhibitory factor (LIF), as well as with up-regulation of the neutrophil chemotactic and activating mediator macrophage inflammatory protein (MIP)-2. Macrophage colony-stimulating factor (M-CSF) and monocyte chemoattractant protein (MCP)-1 were also moderately up-regulated after IRI, whereas mRNA levels of several other inflammatory mediators including IL-1alpha, IL-2, IL-4, interferon (IFN)-gamma, GM-CSF, and RANTES were minimally increased or remained undetectable. These findings identify MIP-2 as an attractive target for inhibition of leukocyte recruitment in renal IRI and also suggest a potentially novel role for gp130-mediated signals in IRI.
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PMID:Prominent and sustained up-regulation of gp130-signaling cytokines and the chemokine MIP-2 in murine renal ischemia-reperfusion injury. 1075 57

Brain ischemia is characterized by local inflammation reflected by accumulation of inflammatory cells and a multitude of mediators. Among them, cytokines and chemokines may influence the inflammatory cascade that follows cerebral ischemia. Here we report on brain hemispheric and systemic increase of pro-inflammatory IL-17 and IFN-gamma, the anti-inflammatory cytokines IL-4 and IL-10, and the chemokines IP-10, IL-8 and MIP-2, 1 h to 6 days after permanent middle cerebral artery occlusion (pMCAO). IL-17 and IFN-gamma mRNA levels were elevated in the ischemic hemispheres of pMCAO-operated rats compared with corresponding hemispheres of sham-operated rats. Levels were slightly elevated at 1 h, and peaked at 6 days after pMCAO. IL-8 and MIP-2 levels in the ischemic hemispheres peaked at 24 h, whereas IP-10 showed a biphasic profile with two peaks at 6 h and 6 days after pMCAO. IL-4 peaked in the ischemic hemispheres at 6 h, when IL-10 levels were lower than in sham-operated rats, and IL-10 levels peaked at 2 days after pMCAO. Systemically, the numbers of IL-17 and IFN-gamma mRNA expressing blood mononuclear cells were elevated already at 1 h after pMCAO, preceding the changes in the ischemic hemispheres. Altered levels of IL-17 and IFN-gamma after pMCAO may affect outcome of brain ischemia.
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PMID:IL-17 and IFN-gamma mRNA expression is increased in the brain and systemically after permanent middle cerebral artery occlusion in the rat. 1131 24

We examined the effects of early blockade of CD62 selectin-mediated adhesive interactions in steatotic rat liver models of ex vivo cold ischemia followed by reperfusion or transplantation by administration of P-selectin glycoprotein ligand-1 (rPSGL-Ig). In the model of cold ischemia/reperfusion, livers pretreated ex vivo with rPSGL-Ig at harvesting from obese Zucker rats showed significantly decreased portal resistance, increased bile production, and diminished hepatic endothelial neutrophil infiltration, as compared with untreated controls. Pretreatment of fatty livers with rPSGL-Ig prior to transplantation extended the survival of lean Zucker rat recipients from 40% to 90%. This effect correlated with significantly improved liver function, depressed neutrophil activity, and decreased histologic features of hepatocyte injury. Intragraft expression of CD62 P-selectin was similar in both recipient groups. rPSGL-Ig treatment decreased intragraft infiltration by CD3/CD25 cells, diminished expression of pro-inflammatory TNFalpha, IL-6, iNOS, IL-2 and IFN-gamma, without significantly affecting mRNA levels coding for anti-inflammatory IL-4. Thus, rPSGL-Ig blockade of CD62-mediated adhesive interactions protects against severe ischemia/reperfusion injury suffered otherwise by steatotic rat livers. These findings document the potential utility of rPSGL-Ig in increasing the transplant donor pool through modulation of marginal steatotic livers.
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PMID:P-selectin glycoprotein ligand-1 (rPSGL-Ig)-mediated blockade of CD62 selectin molecules protects rat steatotic liver grafts from ischemia/reperfusion injury. 1220 60

Today, the major problem in organ transplantation is not acute graft rejection but chronic graft deterioration. In addition to alloantigen-specific events, alloantigen independent factors like donor age, previous diseases, consequences of brain death, and perioperative events of ischemia/reperfusion injury have a major impact on long-term graft function. The induction of the stress protein heme oxygenase-1 (HO-1) protects cells from injury and apoptosis. Here, we tested the protective effects of HO-1 induction in a clinically relevant kidney transplant model. Induction of HO-1 expression following cobalt-protoporphyrin (CoPP) treatment in organ donors prolonged graft survival and long-term function remarkably following extended periods of ischemia. Positive effects were observed with both optimal and marginal grafts from old donor animals. Structural changes characteristic for chronic rejection, as well as graft infiltration by monocytes/macrophages and CD8+ T cells, were substantially reduced following HO-1 induction. Up-regulation of HO-1 expression before organ transplantation was also associated with reduced levels for tumor necrosis factor (TNF)-alpha mRNA, increased levels for interferon (IFN)-gamma, and bcl-x, and insignificant differences for CD25, interleukin (IL)-2, IL-4, IL-6, and IL-10 mRNA levels. The significant improvement of long-term graft function following induction of HO-1 expression in donor organs suggests that this strategy may be a novel clinical treatment option with particular relevance for transplantation of marginal organs.
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PMID:Inhibition of ischemia/reperfusion injury and chronic graft deterioration by a single-donor treatment with cobalt-protoporphyrin for the induction of heme oxygenase-1. 1235 73

Liver injury induced by ischemia/reperfusion (I/R) is the prime factor in delayed or loss graft function following transplantation. CD4+ T lymphocytes are key cellular mediators of antigen-independent inflammatory response triggered by I/R. We attempted to modulate rat liver I/R injury by targeted gene therapy with CD40Ig, which blocks the CD40-CD154 costimulation pathway. One hundred percent of Ad-CD40Ig-pretreated orthotopic liver transplants (OLTs) subjected to 24 h of cold (4 degrees C) ischemia survived > 14 days (vs 50% in untreated/Ad-beta-gal groups). Ad-CD40Ig treatment decreased sGOT levels and depressed neutrophil infiltration, compared with controls. These functional data correlated with histological Suzuki's grading of hepatic injury, which in untreated/Ad-beta-gal groups showed severe necrosis (> 60%) and moderate to severe sinusoidal congestion; the Ad-CD40Ig-pretreated group revealed minimal sinusoidal congestion/necrosis. Unlike in controls, OLT expression of mRNA coding for IL-2/IFN-gamma remained depressed, whereas that of IL-4/IL-13 reciprocally increased in the Ad-CD40Ig group. Ad-CD40Ig reduced frequency of TUNEL+ cells and pro-apoptotic Caspase-3, but enhanced antioxidant HO-1 and anti-apoptotic Bcl-2/Bcl-xl expression. Thus, prolonged blockade of CD40-CD154 by CD40Ig exerts potent cytoprotection against hepatic I/R injury. These results provide the rationale for a novel gene therapy approach to maximize the organ donor pool through the safer use of liver transplants exposed to prolonged cold ischemia.
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PMID:Gene therapy for liver transplantation using adenoviral vectors: CD40-CD154 blockade by gene transfer of CD40Ig protects rat livers from cold ischemia and reperfusion injury. 1474 76

Hepatic ischemia/reperfusion injury is a clinically important problem. While the mechanisms of the initial event and subsequent neutrophil-dependent injury are somewhat understood, little is known about the regulation of endogenous hepatoprotective effects on this injury. Interleukin 12 (IL-12) plays a role in the induction of this injury, but involvement of interleukin 18 (IL-18) has not been clarified. Using a murine model of partial hepatic ischemia and subsequent reperfusion, the aim of the current study was to determine whether IL-18 is up-regulated during hepatic ischemia/reperfusion and to determine the role of endogenous IL-18 in the development and regulation of inflammatory hepatic ischemia/reperfusion injury. Hepatic IL-18 expression was up-regulated from 1 to 8 hours after reperfusion. Hepatic ischemia/reperfusion induced nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1) activation, as defined by electrophoretic mobility shift assay, and caused significant increases in liver neutrophil recruitment, apoptosis, hepatocellular injury, and liver edema as defined by liver myeloperoxidase content, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end-labeling (TUNEL) staining, serum aminotransferase levels, and liver wet-to-dry weight ratios. In mice treated with neutralizing antibody to IL-18, ischemia/reperfusion-induced increases in CXC chemokine expression, activation of NF-kappaB and AP-1, and apoptosis were greatly reduced. Furthermore, under blockade of IL-18, anti-inflammatory cytokines such as IL-4 and IL-10 were greatly up-regulated. Signal transducer and activator of transcription 6 (STAT6) was significantly activated under blockade of IL-18. These conditions also caused significant reduction in liver neutrophil sequestration and liver injury. In conclusion, the data suggest that IL-18 is required for facilitating neutrophil-dependent hepatic ischemia/reperfusion injury through suppressing anti-inflammatory cytokine expression.
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PMID:Interleukin 18 causes hepatic ischemia/reperfusion injury by suppressing anti-inflammatory cytokine expression in mice. 1499 88

The immune system is a system of dynamic equilibrium, with inflammatory responses (mediated by T helper type 1 cells, interleukin [IL]-1beta, interferon-gamma, and tumor necrosis factor-alpha [TNF-alpha]) being balanced by anti-inflammatory responses (mediated by T regulatory type 1 cell, T helper type 3 cells, IL-4, IL-10, and transforming growth factor-beta). Therefore, neutralization of inappropriate inflammatory cytokines is a therapeutic strategy that has been attempted in many chronic inflammatory conditions, mostly targeting TNF-alpha, using either monoclonal antibodies or modified receptor proteins (etanercept). There is functional redundancy among the inflammatory cytokines. For example, in addition to TNF-alpha, both IL-1beta and IL-6 are elevated in patients with chronic heart failure (CHF); thus neutralizing the activity of TNF-alpha alone may be an inadequate approach in this patient group. Immune-modulation therapy (IMT) results in downregulation of proinflammatory cytokine levels and upregulation of anti-inflammatory cytokines. This alteration in the balance between proinflammatory and anti-inflammatory cytokines may be more appropriate than neutralizing the activity of a single cytokine in the treatment of conditions such as CHF. Several animal studies investigating the effect of IMT in inflammatory conditions including allergic contact hypersensitivity, ischemia reperfusion injury, and atherogenesis are reviewed.
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PMID:Biologic effects and basic science of a novel immune-modulation therapy. 1592 61


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