Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Chemokine receptors play a crucial role in the recruitment of immune cells to sites of inflammation. Although chronic diseases of the brain are often accompanied by inflammatory events, there is presently no information about the occurrence and regulation of these receptors in the central nervous system (CNS). Moreover, one CC-chemokine receptor, CKR5, has recently been identified as coreceptor for HIV-1 entry into macrophages. HIV-1 target cells in brain are macrophage-related microglia, which suggests that they are infected by the same mechanism (He et al.,: Nature 385:645-649, 1997). Although rats are not susceptible to HIV-1 infection, they can be used to study chemokine receptor regulation in a variety of brain pathologies. After cloning CC-CKR5 and establishing reverse transcriptase polymerase chain reaction (RT-PCR) for its ligands macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and regulated on activation, normal T cell-expressed and secreted (RANTES), we studied expression of these four mRNAs in purified microglia and compared it with their expression in rat brain. Lipopolysaccharide (LPS)-treated microglia showed transiently increased mRNA levels of both CKR5 and its ligands. Similar data were obtained from brains of LPS-injected rats. In middle cerebral artery occluded (MCAO)-animals, RANTES mRNA was unaffected, whereas CKR5 mRNA showed a sustained rise until 96 hr after surgery. MIPs exogenously added to microglial cultures markedly reduced CKR5 mRNA expression, whereas RANTES did not. MIP mRNAs, in contrast to RANTES and CKR5 mRNAs, were undetectable in normal brain. RANTES appears to play a role distinct from MIPs in brain. In summary, upregulation of CC-chemokines and CKR5 in the CNS upon bacterial infection or in ischemia may impact on microglial activation stage and result in increased risk of HIV-1 infection.
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PMID:Cloning of rat HIV-1-chemokine coreceptor CKR5 from microglia and upregulation of its mRNA in ischemic and endotoxinemic rat brain. 967 Sep 89

The CXCR3 chemokine receptor, a member of the CXCR family, has been linked to a pathological role in autoimmune disease, inflammatory disease, allograft rejection, and ischemia. In the kidney, expression of the CXCR3 receptor and its ligands is up-regulated in states of glomerulonephritis and in allograft rejection, but little is known about the expression and functional role the CXCR3 receptor might play. Here, we study the function of the CXCR3 chemokine receptor in an immortalized human proximal tubular cell line (IHKE-1). Stimulation of the CXCR3 receptor by its selective agonist monokine induced by IFN-gamma leads via a Ca(2+)-dependent mechanism to an up-regulation of early growth response gene (EGR)-1. Overexpression of EGR-1 induces down-regulation of copper-zinc superoxide dismutase and manganese superoxide dismutase and stimulates the generation of reactive oxygen species (ROS) via the NADH/NADPH-oxidase system. EGR-1 overexpression or treatment with monokine induced by IFN-gamma resulted in a ROS-dependent inhibition of basolateral Na(+)/K(+)-ATPase activity, compromising sodium transport in these cells. Thus, activation of the CXCR3 receptor in proximal tubular cells might disturb natriuresis during inflammatory and ischemic kidney disease via EGR-1-mediated imbalance of ROS.
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PMID:Up-regulation of early growth response gene-1 via the CXCR3 receptor induces reactive oxygen species and inhibits Na+/K+-ATPase activity in an immortalized human proximal tubule cell line. 1251 59

Previous experiments demonstrated plasmid-, retroviral-, or adenoviral-mediated vIL-10 gene transfer could prolong allograft survival, but transgene expression was rapidly extinguished. Feline immunodeficiency virus (FIV) can integrate into genomic DNA of nondividing cells, resulting in indefinite transgene expression. We hypothesized FIV-mediated gene transfer could provide long-term gene expression, and improved allograft survival. FIV-vIL-10 and FIV-beta-gal were produced using the FELIX vector system. With vector transfer to syngeneic cardiac grafts, beta-galactosidase reporter gene expression was noted as early as day 5, was strongly expressed at days 10 and 20, and persisted for 50 days after transplantation. For allografts, FIV-vIL-10 gene transfer more than doubled mean survival from 10 +/- 1.6 to 22.3 +/- 3 days. When combined with other immunosuppressants, such as anti-CD40L mAb, FTY720, or anti-CD3 mAb, the mean survival times were prolonged to 27 +/- 4.6 days, 27.8 +/- 4.6 days, and 45.5 +/- 4.9 days, respectively. Multiple chemokine and chemokine receptor genes were induced by ischemia-reperfusion injury in syngeneic grafts, and in allogeneic grafts more genes were induced and to a greater degree. In allogeneic grafts transduced with FIV-IL-10, a number of the chemokine genes were suppressed. Therefore, FIV virus-mediated vIL-10 gene transfer prolongs allograft survival and, in combination with other agents, produces an additive effect.
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PMID:Feline immunodeficiency virus-mediated viral interleukin-10 gene transfer prolongs non-vascularized cardiac allograft survival. 1275 11

Although almost every known chemokine and chemokine receptor is expressed at some stage during development of allograft rejection, mechanistic studies indicate that the actual key effector mechanisms are rather few. Thus, in vivo studies have alleviated concerns regarding possible biological redundancy and the pleiotropic effects of these molecules, and have resulted in a focus on CXCR3, CCR5 and their respective ligands as key mediators of host alloresponses, especially in acute rejection. Data are also accruing regarding the importance of chemokine/chemokine receptor pathways in ischemia/reperfusion, chronic rejection and tolerance induction following co-stimulation blockade, providing new targets for immune monitoring and therapeutic intervention.
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PMID:Chemokines and their receptors as markers of allograft rejection and targets for immunosuppression. 1449 53

Transplantation of allogeneic grafts presents several challenges to the innate and adaptive immune systems including chemokine leukocyte recruitment, activation, and effector function. We defined the chemokines and receptors induced by the transplant procedure/ischemia injury, alloantigen and gene transfer vector administration in murine cardiac grafts. E1, E3 deleted AdRSVbetagal was transferred into grafts at the time of transplantation, grafts were harvested after 1-14 days, and a pathway-specific cDNA array was used to evaluate the levels of 67 chemokine and chemokine receptor genes. Transplantation resulted in ischemic injury and induction of a number of similar genes in both the syngeneic and allogeneic grafts, such as CXCL1 and CXCL5, which increased dramatically on day 1 and returned rapidly to baseline in the syngeneic grafts. Alloantigen stimulated the adaptive immune response and induced the presence of more inflammatory genes within the grafts, particularly at later time points. The adenovirus vector induced a broader panel of genes, among them potent inflammatory chemokines CXCL9 and CXCL10, that are induced earlier or more strongly compared with alloantigen stimulation alone. As alloantigen and adenovirus vectors both induce similar sets of genes, targeting these molecules may not only inhibit alloimmunity, but also enhance the utility of the gene transfer vector.
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PMID:Differential chemokine and chemokine receptor gene induction by ischemia, alloantigen, and gene transfer in cardiac grafts. 1451 Jun 95

Intrauterine infection produces an inflammatory response in the fetus characterized by increased inflammatory cytokines in the fetal brain and activation of brain microglial cells. Intrauterine infection can release bacterial cell wall products into the fetal circulation. Lipopolysaccharides (LPS) are derived from the cell walls of gram negative organisms. The degree of microglial cell activation may influence the extent of brain injury following an inflammatory stimulus. Chemokines, which are released by activated microglia, regulate the influx of inflammatory cells to the brain. Accordingly, therapeutic strategies that reduce the extent of chemokine expression in microglial cells may prove neuroprotective. Minocycline (MN), a semisynthetic tetracycline derivative, protects brain against global and focal ischemia in rodents and inhibits microglial cell activation. To determine if minocycline can reduce the production of chemokines and chemokine receptors in response to LPS, microglial-like BV-2 and HAPI cells were cultured in the presence or absence of 100 ng/ml of LPS. Enzyme-linked immunosorbent assay (ELISA) and semi-quantitative RT-PCR were used to examine changes in inflammatory chemokines (macrophage inflammatory protein-1 (MIP-1alpha), regulated upon activation, normal T cell expressed and secreted (RANTES), and inducible protein-10 (IP-10)) and chemokine receptor (C-C chemokine receptor 5 (CCR5) and C-X-C chemokine receptor 3 (CXCR3)) production, respectively. We found that in both cell lines chemokine release after 4-, 8-, and 16-h exposure to LPS was significantly higher compared to non-exposed cells for all the chemokines measured, P<0.001. Minocycline inhibited chemokine release of LPS-stimulated BV-2 cells. There was even greater inhibition (up to 50%) of mRNA expression after exposure to LPS (P<0.001). We conclude that endotoxin enhanced the expression of chemokines and chemokine receptors in microglial-like cell lines. Modulation of this expression was achieved with minocycline. Recognition of the mechanisms whereby minocycline exerts its anti-inflammatory effect on microglia may uncover specific targets for pharmacologic intervention.
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PMID:Differential expression of chemokines and chemokine receptors during microglial activation and inhibition. 1502 59

Transient renal ischemia induces both inflammatory and fibrotic processes and is a major cause of acute and chronic renal insufficiency. Study of ischemia-reperfusion injury in gene-targeted mice has identified multiple factors responsible for inflammation, whereas mechanisms underlying fibrosis remain poorly defined. Here we demonstrate by both gene inactivation and target protein blockade that a single chemokine receptor subtype, the fractalkine receptor CX3CR1, is able to reduce both inflammation and fibrosis after ischemia-reperfusion injury in the mouse, leading to partially preserved renal function after injury. The mechanism involves selective effects in the outer medulla, including reduced accumulation of macrophages and reduced expression of the macrophage and platelet-derived fibrogenic protein platelet-derived growth factor-B. CX3CR1 is the first chemokine receptor shown to contribute to fibrogenesis in renal ischemia-reperfusion injury.
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PMID:Chemokine receptor CX3CR1 regulates renal interstitial fibrosis after ischemia-reperfusion injury. 1687 40

Chemokines help to establish cerebral inflammation after ischemia, which comprises a major component of secondary brain injury. The CXCR4 chemokine receptor system induces neural stem cell migration, and hence has been implicated in brain repair. We show that CXCR1 and interleukin-8 also stimulate chemotaxis in murine neural stem cells from the MHP36 cell line. The presence of CXCR1 was confirmed by reverse transcriptase PCR and immunohistochemistry. Interleukin-8 evoked intracellular calcium currents, upregulated doublecortin (a protein expressed by migrating neuroblasts), and elicited positive chemotaxis in vitro. Therefore, effectors of the early innate immune response may also influence brain repair mechanisms.
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PMID:The MHP36 line of murine neural stem cells expresses functional CXCR1 chemokine receptors that initiate chemotaxis in vitro. 1728 63

Hypoxic-ischemic (HI) brain injury in the perinatal period causes significant morbidity. Minocycline (MN) is a tetracycline derivative that has reduced brain injury in various animal models of neurodegeneration, including perinatal ischemia. To determine whether MN can modulate the expression of chemokine receptors and interleukin-10 (IL10) in a model of neonatal brain injury, we produced an HI insult to the right cerebral hemisphere (ipsilateral) of the 7-day-old rat (PD7) by right common carotid artery ligation and 2.25 hr of hypoxia in 8% oxygen. MN (45 mg/kg, i.p.) or vehicle (PBS) was injected twice: 2 days and immediately before the HI insult. At 0, 1, 3, and 24 hr and 14 days after HI, total RNA from the ipsilateral and contralateral (exposed to hypoxia only) hemispheres was extracted, reverse transcribed, and amplified with gene-specific primers using a semiquantitative RT-PCR for macrophage inflammatory protein-1alpha), interferon-inducible protein (IP-10), C-C chemokine receptor 5 (CCR5; MIP-1alpha receptor), C-X-C chemokine receptor 3 (CXCR3; IP-10 receptor), and IL10. We found that, in the ipsilateral hemisphere, a significant (P < 0.05) increase in MIP-1alpha, IP-10, CCR5, and CXCR3 mRNA levels was observed. MN treatment decreased mRNA levels for CCR5 and CXCR3. In contrast, the levels of antiinflammatory cytokine IL10 were markedly decreased as a result of HI insult. Treatment with MN, however, had no effect on IL10. We conclude that MN decreased proinflammatory chemokine receptor expression but had little or no influence on the expression of antiinflammatory cytokine IL10. These effects confirm the antiinflammatory effect of MN in neonatal HI brain injury.
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PMID:Minocycline modulates chemokine receptors but not interleukin-10 mRNA expression in hypoxic-ischemic neonatal rat brain. 1754 54

Chemokines are a family of small, structurally related cytokines that regulate trafficking of different subsets of leukocytes, thus critically regulating inflammation. The chemokine system influences allograft biology at 3 main levels: 1) the process of ischemia-reperfusion injury, 2) the induction of transplant tolerance, and 3) the pathogenesis of acute rejection and chronic allograft nephropathy. Accordingly, following ischemia/reperfusion in a rat model, CXCR2 produced at the graft level attracts and activates granulocytes, which in turn promotes graft damage. Moreover, in some experimental models CCR4 recruits T regulatory cells and mediates transplant tolerance. Furthermore, the discovery of the involvement of CXCR3 in the induction of the alloresponse to transplant suggests that this chemokine receptor might represent an important target for treatment of both acute rejection and chronic allograft nephropathy. Indeed, CXCR3 ligands play a pivotal role in the initiation and amplification of host alloresponses and also alter vascular cell functions, which explains their critical role not only in the development of acute rejection, but also in the pathogenesis of chronic allograft nephropathy, where both immune- and nonimmune- mediated mechanisms are involved. Finally, we have recently demonstrated that the pretransplant serum level of the CXCR3 ligand IP-10/CXCL10 is a clinically useful parameter for the identification of subjects with a high risk of acute rejection, chronic allograft nephropathy, and graft failure. This simple test could contribute to the prevention of acute rejections and the individualization of immunosuppressive therapies.
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PMID:[Chemokines: possible therapeutic targets and useful clinical parameters in renal transplantation]. 1755 33


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