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)

Recent studies suggest that graft microvascular endothelia may play an important role in the regulation of rejection. Alloantigen-dependent changes in microvascular endothelial phenotype may be associated with differences in infiltrate function in allografts vs. isografts, as reflected in alloantigen-specific CTL accumulation and cytokine production. To correlate cytokine production with differences in microvascular endothelial phenotype during allograft inflammation, we used PCR to identify cytokine mRNAs isolated from pooled cardiac isografts and allografts on days 1, 3, and 5 after transplantation. Graft microvascular endothelia express an inflamed phenotype associated with wound healing and the repair of tissue damage due to mechanical trauma, ischemia, and/or reperfusion injury--i.e., high levels of ICAM-1 expression and MECA-32 mAb reactivity. By day 1 in both isografts and allografts, mRNAs for the cytokines IL1 alpha, IL6, TNF, LT, and TGF beta are upregulated or induced. By the third day in cardiac allografts, an antigen-dependent endothelial phenotype is expressed, characterized by the presence of cell surface VCAM-1. Concomitantly, mRNAs for the lymphokines IL2 and IFN gamma are detected, followed by IL4 mRNA by day 5. The expression of VCAM-1 by allograft endothelia may influence the inflammatory process, by physically recruiting specific T cell subpopulations into the response and/or by delivering additional signals to the infiltrating cells. Eventually, these and other regulatory events occurring at these early times initiate a process that later results in alloreactive tissue destruction.
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PMID:Alloantigen-dependent endothelial phenotype and lymphokine mRNA expression in rejecting murine cardiac allografts. 847 68

Granulocytes play a significant role in vascular diseases. The mechanisms of neutrophil-mediated vascular injury include their increased endothelial adhesion and activation with release of inflammatory mediators. Pentoxifylline (PTX) has a well-demonstrated ability to act on the activated neutrophils. It increases chemotaxis and decreases their adherence to endothelial cells, oxidative burst, and enzyme release. In this preliminary study, we investigated the effects of PTX on ischemia-induced changes in polymorphonuclear neutrophils (PMN) activation and cytokine release. A double-blind, randomized, placebo-controlled trial was carried out in 14 patients (age range 46-86 years) suffering from critical ischemia, as defined by the European Consensus Document, or subacute ischemia due to occlusive arterial disease of the lower limb. Femoral and antecubital venous blood samples on the side of the ischemic leg were obtained from patients immediately before (TO) and after infusion (T24) of PTX or placebo. PMN activation was evaluated by study of cell migration, beta 2 integrin expression (CD11b/ CD18), oxidative burst, and elastase release. Inflammation proteins were analyzed, such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), interleukin-6 (IL-6), C-reactive protein (CRP), and fibrinogen. Before treatment, our results demonstrate an important activation in both femoral and antecubital venous blood. PMN activation markers, cytokine release, and other inflammation proteins were significantly increased compared with normal subjects. In the experimental group there was no significant difference between femoral and antecubital venous blood. Six patients received PTX infusion and seven patients were in the placebo group. The effect of PTX was evaluated after 24 h of treatment (1,200 mg). In the PTX group the following variables were improved compared with the placebo group: CD11b expression on PMNs, elastase released from PMNs, fibrinogen, CRP, TNF-alpha, and IL6 in plasma. These preliminary results should be interpreted with caution because of the small sample size. Further trials may contribute to more complete understanding.
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PMID:Leukocyte activation study during occlusive arterial disease of the lower limb: effect of pentoxifylline infusion. 869 73

The etiology of Parkinson's disease is not known. Nevertheless a significant body of biochemical data from human brain autopsy studies and those from animal models point to an on going process of oxidative stress in the substantia nigra which could initiate dopaminergic neurodegeneration. It is not known whether oxidative stress is a primary or secondary event. Nevertheless, oxidative stress as induced by neurotoxins 6-hydroxydopamine and MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) has been used in animal models to investigate the process of neurodegeneration with intend to develop antioxidant neuroprotective drugs. It is apparent that in these animal models radical scavengers, iron chelators, dopamine agonists, nitric oxide synthase inhibitors and certain calcium channel antagonists do induce neuroprotection against such toxins if given prior to the insult. Furthermore, recent work from human and animal studies has provided also evidence for an inflammatory process. This expresses itself by proliferation of activated microglia in the substantia nigra, activation and translocation of transcription factors, NF kappa-beta and elevation of cytotoxic cytokines TNF alpha, IL1-beta, and IL6. Both radical scavengers and iron chelators prevent LPS (lipopolysaccharide) and iron induced activation of NF kappa-B. If an inflammatory response is involved in Parkinson's disease it would be logical to consider antioxidants and the newly developed non-steroid anti-inflammatory drugs such as COX2 (cyclo-oxygenase) inhibitors as a form of treatment. However to date there has been little or no success in the clinical treatment of neurodegenerative diseases per se (Parkinson's disease, ischemia etc.), where neurons die, while in animal models the same drugs produce neuroprotection. This may indicate that either the animal models employed are not reflective of the events in neurodegenerative diseases or that because neuronal death involves a cascade of events, a single neuroprotective drug would not be effective. Thus, consideration should be given to multi-neuroprotective drug therapy in Parkinson's disease, similar to the approach taken in AIDS and cancer therapy.
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PMID:Neuroprotective strategies in Parkinson's disease using the models of 6-hydroxydopamine and MPTP. 1086 45

Excessive production of nitric oxide (NO) in the central nervous system (CNS) mediated by activation of microglia has been implicated in neurotoxicity after stresses such as ischemia. Baicalein, a polyphenolic flavonoid antioxidant, is known to have anti-inflammatory, anticarcinogenic, and neuroprotective effects. In the present study, we report the inhibitory effect of baicalein on endotoxin/cytokine-induced NO production and inducible nitric oxide synthase (iNOS) gene expression in microglia. Baicalein abolished the endotoxin/cytokine-induced expression of iNOS protein, iNOS mRNA, and iNOS promoter activity in a parallel concentration-dependent manner. The suppression of iNOS expression was not mediated through the down-regulation of tumor necrosis factor-alpha (TNF-alpha) by baicalein because TNF-alpha failed to enhance endotoxin/cytokine-induced NO production in microglia. From the electrophoretic mobility shift assay (EMSA), we found that baicalein exerted a distinct inhibitory effect on the DNA binding activity of transcription factors, and this was significantly greater in nuclear factor IL-6 (NF-IL6) than in nuclear factor kappa B (NF-kappaB) and activated protein 1 (AP-1). Although extracellular signal-regulated kinase (ERK) is critical to iNOS expression, endotoxin/cytokine-stimulated phosphorylation of ERK1/2 was not significantly inhibited by baicalein. These results indicate that NF-IL6 inactivation could be the major determinant for the suppression of NO production by baicalein in microglia. Furthermore, it suggests that the inhibitory effect of baicalein on microglia activation and neurotoxic factor production is responsible for its neuroprotective action.
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PMID:Inhibition of inducible nitric oxide synthase expression by baicalein in endotoxin/cytokine-stimulated microglia. 1510 49

Iloprost, a stable prostacyclin analogue, regulates expression of genes that are involved in inflammation and in cell growth and inhibits the in vitro production of cytokines. We evaluated the effect of an in vivo weekly iloprost treatment on TNF-alpha and IL6 monocyte production (evaluated by ELISA), on monocyte apoptosis (Annexin V/uptake of propidium iodide by flow cytometry) and on peripheral blood mononuclear cell (PBMC) TNF-alpha receptors (TNF-RI and TNF-RII) mRNA expression (RT-PCR) in 14 atherosclerotic critical limb ischemia patients. PBMC were stimulated with LPS for 24h. TNF-alpha production was significantly reduced by iloprost whereas IL6 production was not affected. Iloprost did not accelerate monocyte apoptosis. TNF-RI mRNA expression was not modified by iloprost, whereas TNF-RII mRNA expression was significantly reduced. Our data show that iloprost may have anti-inflammatory effects in addition to the well-known vasodilatatory and anti-aggregant ones.
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PMID:Iloprost treatment reduces TNF-alpha production and TNF-RII expression in critical limb ischemia patients without affecting IL6. 1609 91

Peroxisome proliferator-activated receptor (PPAR)-gamma is a ligand-activated transcription factor of nuclear hormone receptor superfamily. Thiazolidinedione rosiglitazone is a potent agonist of PPARgamma which was shown to induce neuroprotection in animal models of focal ischemia and spinal cord injury. We currently evaluated the therapeutic potential of rosiglitazone (6 mg/kg at 5 min, 6 h and 24 h; i.p.) following controlled cortical impact (CCI)-induced traumatic brain injury (TBI) in adult mice. CCI injury increased the cortical PPARgamma mRNA levels which were further elevated by rosiglitazone treatment. In addition, rosiglitazone treatment significantly decreased the cortical lesion volume measured at 7 days compared to vehicle treatment (by 56+/-7%; p<0.05; n=6/group). Following TBI, the spared cortex of the rosiglitazone group showed significantly less numbers of GSI-B4(+) activated microglia/macrophages and ICAM1(+) capillaries, and curtailed induction of pro-inflammatory genes IL6, MCP1 and ICAM1 compared to vehicle group. Rosiglitazone-treated mice also showed significantly less number of TUNEL(+) apoptotic neurons and curtailed induction of caspase-3 and Bax, compared to vehicle control. In addition, rosiglitazone significantly enhanced the post-TBI expression of the neuroprotective chaperones HSP27, HSP70 and HSP32/HO1, and the anti-oxidant enzymes catalase, Cu/Zn-SOD and Mn-SOD, compared to vehicle. Treatment with GW9662 (a specific PPARgamma antagonist) prevented all the above PPARgamma-mediated actions. Thus, PPARgamma activation confers neuroprotection after TBI by anti-inflammatory, anti-apoptotic and anti-oxidative mechanisms.
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PMID:PPARgamma agonist rosiglitazone is neuroprotective after traumatic brain injury via anti-inflammatory and anti-oxidative mechanisms. 1894 87

Inflammatory cell migration characteristic of ischemic damages has a dual role providing the tissue with factors needed for tissue injury recovery simultaneously causing deleterious development depending on the quality and the quantity of infiltrated cells. Extracellular superoxide dismutase (SOD3) has been shown to have an anti-inflammatory role in ischemic injuries where it increases the recovery process by activating mitogen signal transduction and increasing cell proliferation. However, SOD3 derived effects on inflammatory cytokine and adhesion molecule expression, which would explain reduced inflammation in vascular lesions, has not been properly characterized. In the present work the effect of SOD3 on the inflammatory cell extravasation was studied in vivo in rat hind limb ischemia and mouse peritonitis models by identifying the migrated cells and analyzing SOD3-derived response on inflammatory cytokine and adhesion molecule expression. SOD3 overexpression significantly reduced TNFalpha, IL1alpha, IL6, MIP2, and MCP-1 cytokine and VCAM, ICAM, P-selectin, and E-selectin adhesion molecule expressions in injured tissues. Consequently the mononuclear cell, especially CD68+ monocyte and CD3+ T cell infiltration were significantly decreased whereas granulocyte migration was less affected. According to our data SOD3 has a selective anti-inflammatory role in ischemic damages preventing the migration of reactive oxygen producing monocyte/macrophages, which in excessive amounts could potentially further intensify the tissue injuries therefore suggesting potential for SOD3 in treatment of inflammatory disorders.
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PMID:SOD3 reduces inflammatory cell migration by regulating adhesion molecule and cytokine expression. 1949 15

Our aim was to study the association of donor genetic features with long-term graft function as well as the impact of donor age, gender compatibility, cold ischemia time (CIT), and delayed graft function (DGF). We observed the outcomes of 125 kidney recipients for a minimum of 12 months (mean, 30.9 +/- 13.0 months). Grafts were obtained from 89 donors who underwent profiling for AHSG 1/2, MMP9 -1562C/T, IL6 -174G/C, IL1beta 3954C/T, MTHFR 677C/T, MTHFR 1298A/C, NOS3 -786C/T, and PAI1 4G/5G single-nucleotide polymorphisms (SNPs) using sequence-specific probe (SSP) polymerase chain reaction (PCR) and MPO -463G/A and CRP -390C/T/A with restriction fragment length polymorphism (RFLP) analysis. NOS3 IVa/b VNTR polymorphism was genotyped by gel electrophoresis of the respective PCR-generated DNA fragment. The presence of the aa eNOS genotype was connected with worse graft function. The aa genotype was also linked to acute rejection episodes. The lowest values of glomerular filtration rate (GFR) were displayed by recipients of grafts from donors with homozygotic PAI1 gene 5G polymorphism, linking paradoxically with lower PAI-1 synthesis suggesting that the intensity of proteolysis led to increased alloantigen specificity stimulating alloresponses. Graft function depended significantly on donor age with an influence of gender matching. GFR showed a significant dependence on DGF. Genetic features of the donor influenced long-term graft function. Variant eNOS gene polymorphism, which produced decreased eNOS activity, was linked to worse remote graft function. A similar negative impact was observed in the case of donor PAI1 polymorphism, with the functional consequence of lower gene product synthesis.
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PMID:Impact of donor-dependent genetic factors on long-term renal graft function. 1985 55

We analyzed the connections between recipient genetic features and 12-month graft function. The gene polymorphisms of myeloperoxidase (MPO), interleukin (IL)-1beta, IL-6, C-reactive protein (CRP), fetuin A, and homocysteine and their gene product concentrations were correlated with 12-month kidney transplant function. The 125 kidney recipients had at least 12 months of follow-up (average, 30.9 +/- 13.0 months). IL6-174G/C, IL1beta 3954C/T, MTHFR 677C/T, MTHFR 1298A/C, AHSG 1/2 SNPs were determined using SSP-polymerase chain reaction (PCR) and MPO-463G/A and CRP- 390C/T/A with RLFP analysis. Enzyme-linked immunosorbent assay (ELISA) was applied to estimate MPO, fetuin A, IL-6, and IL-1beta; FPIA was applied for L-homocysteine concentrations. The highest CRP values were linked to the presence of the TT genotype. We observed a positive correlation of CRP concentrations and GFR. Lower fetuin A concentrations were linked to the 256Ser allele, and higher levels to better graft function. Worse graft function was inversely associated with serum homocysteine concentrations. Two polymorphisms (CRP and fetuin A) showed functional consequences in recipients. None of the examined genetic determinations influenced long-term graft function. Higher values, although still within the normal range of CRP concentrations on the day of transplantation and 3 months thereafter, were related to greater values of eGFR at 12 months, suggesting that the higher intensity of the inflammatory reaction may be a manifestation of more effective healing of an ischemia reperfusion injury. Both homocysteine and fetuin A showed long-term prognostic importance.
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PMID:Recipient genetic determinants of inflammatory process and nonstandard atherosclerosis risk factors affect kidney graft function early posttransplantation. 1985 76

Background. Inflammation plays an important part in the healing process. Little is known about the extent local inflammatory trauma response interacts with the central circulation and inflammation produced by central organs. The aim of the present study was to examine whether high cut-off microdialysis catheters offer potential to in real time assess interstitial cytokines variations in conjunction to markers of metabolism distal to a blunt vascular contusion. Methods. In a standardised contusion trauma model, microdialysis catheters (high MW (100kDa)) were inserted in the gracilis muscle distal to the trauma for the local assessment of IL-6, IL-8, TNF-alpha, total protein and the metabolic mediators (glycerol, puruvate and lactate). The contra lateral uninjured leg served as control of the centrally mediated inflammation propagated to the extremities. Results. The trauma led to a significant and quantitatively large (8-10 fold) increase in inflammatory cytokines (IL6 and 8) as measured both in the injured and control legs. There was only a minor, and not significant increase in concentrations of cytokines in the injured leg compared to the control leg.. There were no signs of ischemia in either leg. Conclusion. The new finding in this study is that both central, and local, inflammatory responses as well as metabolic mediators may be assessed continuously in skeletal muscle tissue distal to a major injury in an animal model. The findings suggest that the large trauma elicits a generalised inflammatory response to trauma rather than propagating a local one distal to the trauma.
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PMID:Continuous assessment of concentrations of cytokines in experimental injuries of the extremity. 2005 79


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