UMLS:C0022116 - FACTA Search

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

We have analyzed chemokine mRNA expression in graft tissue of C3H/HEJ mice receiving allogeneic (C57BL/6) or xenogeneic [Lewis (LEW) rat donors] kidney grafts and correlated this with graft survival. Since donor-specific portal vein (pv) immunization is known to increase allo- and xenograft survival, in some cases recipients also received pretransplant pv or intravenous (iv) immunization; other animals received the antioxidant N-acetylcysteine (NAc) to examine the role of ischemia/reperfusion injury in the changes observed. Graft tissue and lymph nodes draining the respective grafts were obtained at various times posttransplantation and used for quantitative polymerase chain reaction analysis of mRNAs for different chemokines. In addition, lymphocytes were restimulated in culture with donor antigen and supernatants assayed for different cytokines. We observed that early increases in mRNA for MCP-1 preceded a polarization to type 2 cytokine production. Infusion of NAc twice daily for 4 days following transplantation further altered chemokine mRNA expression (increased MCP-1 and RANTES; decreased CINC); led to more enhanced type 2 cytokine production relative to control animals; and further increased xenograft survival. By use of heteroantibodies to different chemokines, anti-MCP-1 alone, but not antibodies to MIP-1alpha or RANTES, abolished this early polarization in cytokine production, implying a causal link between MCP-1 production and polarization in cytokine production. We conclude that manipulation of chemokine production early after transplantation might indirectly modify graft outcome by modifying cytokine production.
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PMID:Alterations in chemokine mRNA expression in animals receiving portal vein immunization and renal allo- or xenotransplantation precede altered cytokine production. 1052 5

Hepatic ischemia/reperfusion (I/R) results in a neutrophil-dependent lung and liver injury. The process of neutrophil recruitment and activation in this injury is at least partially dependent on the presence of the ELR+ CXC chemokines. Other investigations have shown that ELR- CXC chemokines can block ELR+ CXC chemokine neutrophil recruitment and activation in vitro. To begin to investigate the role of the balance between these 2 types of molecules in vivo in neutrophil recruitment and activation following hepatic I/R, we used our rat model of lobar hepatic I/R and pretreated animals with pharmacologic doses of gamma-interferon (gamma-IFN). gamma-IFN is known to upregulate some of the ELR- CXC chemokines, including gamma-IFN-inducible protein (IP-10) and monokine-induced by gamma-IFN (MIG), as well as down-regulate ELR+ CXC chemokine production. Following hepatic I/R or sham laparotomy, hepatic and pulmonary levels of the ELR- chemokines, IP-10 and MIG, and the ELR+ chemokines, rat cytokine-induced neutrophil chemoattractant (KC), macrophage inflammatory protein-2 (MIP-2), and epithelial neutrophil activating protein (ENA-78) were determined by ELISA, and lung and liver injury were assessed. In response to gamma-IFN, hepatic and pulmonary levels of the ELR- chemokines were increased and the levels of the ELR+ chemokines were decreased. Immunohistochemical staining confirmed the hepatocyte as the source of these molecules, as well as the changes in chemokine levels in response to gamma-IFN. There was an associated significant decrease in liver and lung injury, although there was no significant decrease in neutrophil influx in either tissue. This suggests that the alteration in the balance of ELR+ to ELR- CXC chemokines results in a decrease in tissue injury through a mechanism other than through an alteration in tissue neutrophil levels.
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PMID:The ratio of ELR+ to ELR- CXC chemokines affects the lung and liver injury following hepatic ischemia/ reperfusion in the rat. 1065 68

An allograft is often considered an immunologically inert playing field on which host leukocytes assemble and wreak havoc. However, we demonstrate that graft-specific physiologic responses to early injury initiate and promulgate destruction of vascularized grafts. Serial analysis of allografts showed that intragraft expression of the three chemokine ligands for the CXC chemo-kine receptor CXCR3 was induced in the order of interferon (IFN)-gamma-inducible protein of 10 kD (IP-10, or CXCL10), IFN-inducible T cell alpha-chemoattractant (I-TAC; CXCL11), and then monokine induced by IFN-gamma (Mig, CXCL9). Initial IP-10 production was localized to endothelial cells, and only IP-10 was induced by isografting. Anti-IP-10 monoclonal antibodies prolonged allograft survival, but surprisingly, IP-10-deficient (IP-10(-/-)) mice acutely rejected allografts. However, though allografts from IP-10(+/+) mice were rejected by day 7, hearts from IP-10(-/-) mice survived long term. Compared with IP-10(+/+) donors, use of IP-10(-/-) donors reduced intragraft expression of cytokines, chemokines and their receptors, and associated leukocyte infiltration and graft injury. Hence, tissue-specific generation of a single chemokine in response to initial ischemia/reperfusion can initiate progressive graft infiltration and amplification of multiple effector pathways, and targeting of this proximal chemokine can prevent acute rejection. These data emphasize the pivotal role of donor-derived IP-10 in initiating alloresponses, with implications for tissue engineering to decrease immunogenicity, and demonstrate that chemokine redundancy may not be operative in vivo.
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PMID:Donor-derived IP-10 initiates development of acute allograft rejection. 1130 58

The mechanisms by which nitric oxide (NO) exerts its protective effect in the ischemia/reperfusion (I/R) injury of the kidney have not been fully determined. The hypothesis of this study was based on the assumption that I/R upregulates some chemokines (MIP-2 and MIP-1alpha) as well as certain protein kinases (MAPK p44/42), and therefore we aimed in this work at recognizing if an exogenous NO donor would downregulate these effects in rat ischemic kidneys at the same time that it would offer functional protection as measured by serum creatinine. Sprague-Dawley rats were subjected to renal warm ischemia (75 min) and contralateral nephrectomy. Animals were divided into 3 groups (n = 8 per group): sham, ischemic control, and ischemic group treated with sodium nitroprusside (NaNP 5 mg/kg) given 15 min prior to reperfusion. Serum creatinine (SCr), serum chemokines (MIP-2 and MIP-1alpha), kidney tissue MAPK p44/42, kidney neutrophil infiltration determined by myeloperoxidase (MPO), and light histology were evaluated 4 h after reperfusion began. There were significant improvements in SCr and better histopathological features in the I/R-NaNP group compared with the I/R group. Similarly, the I/R-NaNP kidneys exhibited a downregulating effect of serum chemokines (MIP-2 and MIP-1alpha) and kidney tissue MAPK p44/42 that was not observed in the I/R group alone. The MPO levels were lower in the I/R-NaNP group compared with the I/R untreated group. We can conclude from these experiments that I/R of the rat kidney upregulated the production of MIP-2 and MIP-1alpha chemokines and the activation of MAPKp44/42. It also had a detrimental effect on the function and structure of the ischemic kidney. Exogenous NO had a temporal protective effect in organ function and histology and exerted a downregulating response in the production of MIP-2 and MIP-1alpha chemokines and the activation of MAPK p44/42 following I/R.
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PMID:Exogenous nitric oxide downregulates MIP-2 and MIP-1alpha chemokines and MAPK p44/42 after ischemia and reperfusion of the rat kidney. 1239 33

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

It has been proposed that mitogen-activated protein kinase (MAPK) pathways may play a role in the regulation of pro-inflammatory cytokines, such as interlukine-1, during cerebral ischemia. Our previous study showed that extracellular-signal-regulated kinases 1 and 2 (ERK 1/2) were activated during focal cerebral ischemia in mice [J. Cereb. Blood Flow Metab. 20 (2000) 1320]. However, the effect of ERK 1/2 activation in focal cerebral ischemia is still unclear. In this study we reported that in vivo phospho-ERK 1/2 expression increased following 30 min of middle cerebral artery occlusion (MCAO) in the mouse brain in both the ischemic core and perifocal regions. Western blot analysis and immunohistochemistry demonstrated that pro-treatment with 1,4-diamino-2,3-dicyano-1,4-bis butadiene (U0126) [J. Biol. Chem. 273 (1998) 18623] could significantly inhibit mouse brain phospho-MEK 1/2 and phospho-ERK 1/2 expression after 1-2 h of MCAO (p<0.05). Compared to the control group of mice, brain infarct volume was significantly decreased after 24 h of MCAO in the U0126-treated mice (27+/-6 vs. 46+/-9 mm(2), p<0.05). Inhibition of the MEK/ERK 1/2 pathway also prevented downstream kinase Elk-1 phosphorylation, and further reduced cytokine IL-1beta mRNA, but not TNFalpha, IL-1alpha, or chemokine MIP-1alpha mRNA expression. Our data demonstrates that in vivo the close linking of MEK 1/2, ERK 1/2, Elk-1, and IL-1 mRNA expression in the cerebral ischemia animals suggests that ERK 1/2 pathway activation is important in pro-inflammatory cytokine IL-1beta signaling, which induces an inflammatory response and exacerbates ischemic brain injury. Inhibiting the ERK 1/2 pathway may therefore provide a novel approach for the reduction of ischemia-induced IL-1beta overexpression.
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PMID:Inhibition of MEK/ERK 1/2 pathway reduces pro-inflammatory cytokine interleukin-1 expression in focal cerebral ischemia. 1467 Jun 31

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

Tissue damage after ischemia and reperfusion (I/R) is largely caused by the sequelae of neutrophil infiltration. This inflammatory process can be initiated as the result of stroke, coronary ischemia, trauma, and other related conditions. The infiltration of neutrophils is facilitated by the expression of adhesion molecules on the surface of endothelial cells. Particularly important are the selectin family of adhesion molecules at the onset of neutrophil-mediated injury. The aim of this study was to determine the role of selectin inhibition in the modulation of chemokine expression and Akt/MAPK signaling after liver I/R. In addition, we evaluated the optimal dose and time of administration of a small molecule selectin inhibitor, TBC-1269. Mice subjected to 90 min of partial (70-80%) hepatic ischemia followed by 3 h of reperfusion were divided into 15 groups (n = 4/group); sham, ischemic control, and 10, 20, and 40 mg/kg dose groups for the antiselectin molecule were studied at 3 times of drug administration: 1 h before reperfusion (but after ischemia), at the time of reperfusion, and at 15 min after reperfusion. The parameters measured after 3 h of reperfusion included liver function tests (ALT and AST), histopathology, and tissue myeloperoxidase (MPO). Chemokine expression (MIP-1alpha, MIP-1beta, MIP-2 and KC), Akt, MAPK (p44/p42), and RSK expressions were also measured in liver tissue by enzyme-linked immunosorbent assay (ELISA) and Western blot analysis, respectively. It was demonstrated that the small molecule multi-selectin inhibitor (TBC-1269) offered the most significant protection for the ischemic liver when given at 40 mg/kg at the time ofreperfusion. AST significantly differed between the control group and the group receiving 40 mg/kg at the time of reperfusion (p = .01). MPO levels in the liver tissue of the ischemic controls were significantly increased when compared to the levels of this enzyme in the TBC-1269 group at 40 mg/kg. Histological examination reflected the same results, with a significant difference (p = .02) between these same two groups. The chemokine profile also showed that the same treatment group had a downregulation of MIP-lalpha, MIP-1beta, MIP-2, and KC, as well as a lower expression of Akt, MAPK(p44/42), and RSK when compared to the control group. Thus, we demonstrated that the small molecule selectin inhibitor, TBC-1269, offered significant functional and structural protection of the ischemic liver when given at 40 mg/kg at the time of reperfusion. Lower doses and different times of administration did not show as prominent a drug effect. This selectin inhibition modulated the expression of Akt, MAPK (p44/42), and RSK, as well as MIP-1alpha, MIP-1beta, MIP-2, and KC chemokines. These alterations in cellular signaling and chemokine expression represent potential mechanisms or pathways of inflammatory response in I/R.
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PMID:Selectin inhibition modulates Akt/MAPK signaling and chemokine expression after liver ischemia-reperfusion. 1576 97

Many studies have shown that pigment epithelium-derived factor (PEDF) has neurotrophic effects on retinal cells and hippocampal, spinal cord, and cerebellar granule cell neurons, but much less work has examined the effects of PEDF on glia. In this study, we show that PEDF changes microglial morphology within 1 h of exposure, to a more deactivated form, while having no effect on the expression of such activation markers as OX-42 and ED-1. In contrast, urea activates acid phosphatase, and PEDF blocks that activation. PEDF also activates NFkappaB, accompanied by the induction of mRNAs and proteins for the chemokines macrophage inflammatory protein-1alpha (MIP-1alpha, MIP-2, and MIP-3alpha. All the chemokines stimulate acid phosphatase activity, and high doses of MIP-2 and MIP-3alpha), alter the morphology of the microglia at 1 h after treatment. These results suggest that the use of PEDF for clinical treatments, such as for retinal neovascularization, brain injury, or ischemia, should be undertaken with caution because of the possibility of induction of inflammation caused by microglial or other immune cell migration in response to the chemokines induced by PEDF.
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PMID:Pigment epithelium-derived factor induces the production of chemokines by rat microglia. 1581 38

Inflammation contributes to perinatal brain injury and can be induced by hypoxia-ischemia (HI) or exposure to infection (fetal inflammatory response). The anti-inflammatory cytokine interleukin-10 (IL10) has been shown to have neuroprotective effects following HI. To determine whether IL10 can reduce the inflammatory response to lipopolysaccharide (LPS) in microglial cell cultures, primary microglial (MG) and/or HAPI cells (new MG-like cell line) were treated with LPS (50 ng/ml) in the presence or absence of IL10 (20 ng/ml) for 0.5, 1, 4, and 8 h. TNFalpha, MIP-1alpha, and RANTES were assayed by ELISA. Chemokine receptors, CCR5, CXCR3, and CX3CR1 (fractalkine receptor) were assayed by semiquantitative RT-PCR. We found that in MG cell cultures TNFalpha, MIP-1alpha, and RANTES release after 8-h exposure to LPS was significantly higher compared to non-exposed MG cells (P < 0.001). In HAPI cell cultures similar stimulation of mRNA levels was found for TNFalpha, MIP-1alpha, CXCR3, and CX3CR1. IL10 inhibited TNFalpha, MIP-1alpha, and RANTES release of LPS-stimulated MG cells as well as TNFalpha, MIP-1alpha, and CXCR3 mRNA expression by HAPI cells after exposure to LPS (P < 0.05). In contrast to those inhibitory effects, there was no change in fractalkine, and a modest increase in CX3CR1 mRNA levels was found in the presence of IL10. We conclude that the inflammatory response induced in microglial cells by LPS can be markedly reduced by IL10. The increase in fractalkine receptor (CX3CR1) is also potentially protective. Our results suggest that treatment of damaging neuroinflammatory insults such hypoxia-ischemia, with IL10 may be protective for the immature brain.
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PMID:Interleukin-10 inhibits endotoxin-induced pro-inflammatory cytokines in microglial cell cultures. 1583 61

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