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)

The identification of bone marrow-derived endothelial progenitor cells has altered our understanding of new blood vessel growth and tissue regeneration. Previously, new blood vessel growth in the adult was thought to only occur through angiogenesis, the sprouting of new vessels from existing structures. However, it has become clear that circulating bone marrow-derived cells can form new blood vessels through a process of postnatal vasculogenesis, with endothelial progenitor cells selectively recruited to injured or ischemic tissue. How this process occurs has remained unclear. One common element in the different environments where vasculogenesis is believed to occur is the presence of a hypoxic stimulus. We have identified the chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 as critical mediators for the ischemia-specific recruitment of circulating progenitor cells. We have found that the endothelial expression of SDF-1 acts as a signal indicating the presence of tissue ischemia, and that its expression is directly regulated by hypoxia-inducible factor-1. Stromal cell-derived factor 1 is the only chemokine family member known to be regulated in this manner. Later events, including proliferation, patterning, and assembly of recruited progenitors into functional blood vessels, are also influenced by tissue oxygen tension and hypoxia. Interestingly, both SDF-1 and hypoxia are present in the bone marrow niche, suggesting that hypoxia may be a fundamental requirement for progenitor cell trafficking and function. As such, ischemic tissue may represent a conditional stem cell niche, with recruitment and retention of circulating progenitors regulated by hypoxia through differential expression of SDF-1.
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PMID:Homing to hypoxia: HIF-1 as a mediator of progenitor cell recruitment to injured tissue. 1588 71

Recent advances in clinical islet transplantation have allowed patients with type 1 diabetes to become insulin independent, but the procedure is limited since islets from two donors per recipient are typically required. This limitation arises because within a few days of the islets being embolized into the portal circulation, at least half of the transplanted beta-cells have undergone apoptotic cell death triggered by hypoxic and chemokine/cytokine-mediated stress. We hypothesized that the survival of beta-cells in the early post-transplant period would be enhanced if naturally occurring inhibitor of apoptosis proteins (IAPs) were transiently overexpressed in the grafts. In the present study, we used a growth-regulatable beta-cell line (betaTC-Tet) as a model for beta-cells within islets, and examined whether adenovirally delivered XIAP (X-linked IAP-a highly potent IAP) could enhance beta-cell survival. In vitro, XIAP-expressing betaTC-Tet cells were markedly resistant to apoptosis in an ischemia-reperfusion injury model system and following exposure to cytokines. When Ad-XIAP transduced betaTC-Tet cells were transplanted subcutaneously into immunodeficient mice, the grafts were able to reverse diabetes in 3 days, vs. 21 days for Ad-betaGal transduced cells. This approach may allow more efficient use of the limited existing supply of human islets.
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PMID:XIAP overexpression in islet beta-cells enhances engraftment and minimizes hypoxia-reperfusion injury. 1588 33

Inhibition of poly(ADP-ribosyl)ation in oxidative stress-related pathologies has recently emerged as a very effective anti-inflammatory intervention in animal models of arthritis, colitis, diabetes and shock. Recent data from three laboratories also support the role of poly(ADP-ribose) polymerase-1 (PARP-1) activation in asthma. Similarly to other inflammatory conditions, the protective effects of PARP inhibition and the PARP-1 knock out phenotype in asthma models have been attributed to inhibition of inflammatory signal transduction (mainly via NF-kappaB) and of oxidative stress-induced cell dysfunction and tissue injury. Here I discuss the complex role of poly(ADP-ribosyl)ation in the regulation of inflammatory cell migration, chemokine and cytokine production and expression of other inflammatory mediators (inducible nitric oxide synthase, matrix metalloproteinases) in asthma. The role of PARP-1 in other oxidative stress-related lung diseases such as asbestosis, silicosis, acute respiratory distress syndrome and ischemia-reperfusion injury is also reviewed.
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PMID:Poly(ADP-ribosyl)ation in asthma and other lung diseases. 1591 36

As a result of vascular injury, activated platelets will rapidly interact with circulating platelets, via membrane glycoprotein complex alphaIIbbeta3 (GPIIb-IIIa) and fibrinogen, to form a thrombus or a plug preventing fatal bleeding. In addition, platelets interacting with ruptured atherosclerotic plaques or with the surface of diseased vessels can aggregate and induce ischemia that prevents blood flow. However, increasing evidence has also shown that circulating platelets interact with leukocytes and endothelial cells, via specific adhesion molecules, in inflammation, vascular remodelling and thrombosis. The aim of this chapter is to present the importance of cell-cell interactions involving platelets and leukocytes in events related to inflammation, coagulation, vascular remodelling and thrombosis. A key adhesion molecule implicated in platelet interaction with leukocytes is P-selectin, also known as CD62P. It is present on activated platelets and endothelial cells, and its counterpart on leukocytes is known as P-selectin glycoprotein ligand-1 (PSGL-1). A critical co-factor leading to leukocyte activation in platelet-monocyte aggregate formation is the presence of a chemokine known as RANTES. It acts in concert with platelet P-selectin and PSGL-1 in monocyte stimulation.
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PMID:Platelet-leukocyte aggregates and derived microparticles in inflammation, vascular remodelling and thrombosis. 1614 74

Our previous studies showed that beta(2)-microglobulin knockout mice treated with anti-asialoGM1 (beta2MKO/alphaAsGM1 mice) are resistant to injury caused by cecal ligation and puncture (CLP). However, CLP-induced injury is complex. Potential mechanisms of injury include systemic infection, cecal ischemia, and translocation of bacterial toxins such as endotoxin and superantigens. Currently, it is unclear which of these mechanisms of injury contributes to mortality in wild-type mice and whether beta2MKO/alphaAsGM1 mice are resistant to any particular mechanisms of injury. In the present study, we hypothesized that systemic infection is the major cause of injury after CLP in wild-type mice and that beta2MKO/alphaAsGM1 mice are resistant to infection-induced injury. To test this hypothesis, wild-type and beta2MKO/alphaAsGM1 mice were treated with the broad-spectrum antibiotic imipenem immediately after CLP to decrease the impact of systemic infection in our model. Treatment of wild-type and beta2MKO/alphaAsGM1 mice with imipenem decreased bacterial counts by at least two orders of magnitude. However, all wild-type mice, whether treated with saline or imipenem, died by 42 h after CLP and had significant hypothermia, metabolic acidosis, and high plasma concentrations of the cytokines interleukin-6, macrophage inflammatory protein-2, and keratinocyte-derived chemokine. beta2MKO/alphaAsGM1 mice showed 40% long-term survival, which was increased to 90% by imipenem treatment. beta2MKO/alphaAsGM1 mice had less hypothermia, decreased metabolic acidosis, and lower cytokine concentrations at 18 h after CLP compared with wild-type mice. These results suggest that infection is not the major cause of mortality for wild-type mice in our model of CLP. Other mechanisms of injury such as cecal ischemia or translocation of microbial toxins may be more important. beta2MKO/alphaAsGM1 mice appear resistant to these early, non-infection-related causes of CLP-induced injury but showed delayed mortality associated with bacterial dissemination, which was ablated by treatment with imipenem.
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PMID:Differential effect of imipenem treatment on injury caused by cecal ligation and puncture in wild-type and NK cell-deficient beta(2)-microgloblin knockout mice. 1616 41

TLRs are conserved pattern recognition receptors that detect motifs of pathogens and host material released during injury. For unknown reasons, renal TLR2 mRNA is mainly expressed by tubular cells and is enhanced upon renal ischemia/reperfusion (I/R) injury. We evaluated the role of TLR2 in I/R injury using TLR2-/- and TLR2+/+ mice, TLR2 antisense oligonucleotides, and chimeric mice deficient in leukocyte or renal TLR2. Tubular cells needed TLR2 to produce significant cytokine and chemokine amounts upon ischemia in vitro. TLR2 played a proinflammatory and detrimental role in vivo after I/R injury, as reflected by a reduction in the amount of local cytokines and chemokines, leukocytes, and the level of renal injury and dysfunction in TLR2-/- mice compared with controls. Analysis of chimeric mice suggested that TLR2 expressed on renal parenchyma plays a crucial role in the induction of inflammation and injury. TLR2-antisense treatment protected mice from renal dysfunction, neutrophil influx, and tubular apoptosis after I/R injury compared with nonsense treatment. In summary, we identified renal-associated TLR2 as an important initiator of inflammatory responses leading to renal injury and dysfunction in I/R injury. These data imply that TLR2 blockade could provide a basis for therapeutic strategies to treat or prevent renal ischemic injury.
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PMID:Renal-associated TLR2 mediates ischemia/reperfusion injury in the kidney. 1616 81

The chemokine CCL2 is considered as one of the main effectors driving postischemic infiltration of monocytes into the brain parenchyma. New experimental data, however, suggest that CCL2 could also participate in blood-brain barrier (BBB) 'opening' during the transmigration of monocytes. The current study examines the role of CCL2 in regulating BBB permeability after ischemia in vitro. To address this issue, an in vitro BBB model (coculture of astrocytes and brain endothelial cells) was subjected to 5 h of oxygen glucose deprivation, followed by reoxgenation (in vitro ischemia/reperfusion (I/R)) for 0 to 48 h. During reperfusion, there was a biphasic enhancement of barrier permeability, with a 200-fold increase in barrier permeability to FITC-albumin at 6 h and a further period of disruption around 24 h. The latter coincided with increased secretion of CCL2 by both astrocytes and brain endothelial cells and increased levels of the CCL2 receptor, CCR2. Applying antisense oligonucleotide or neutralizing antibody to block CCL2 significantly decreased I/R-induced enhancement of BBB permeability (approximately twofold) and redistribution of tight-junction (TJ) proteins (occludin, zonula occluden-1, 2, claudin-5). Similarly, absence of CCR2 from endothelial cells caused stabilization of TJ complexes and decreased the permeability of brain endothelial barrier during in vitro I/R. These data suggest CCL2/CCR2 has an important role in regulating brain endothelial permeability and might be a potential novel therapeutic target for stroke.
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PMID:Effects of the chemokine CCL2 on blood-brain barrier permeability during ischemia-reperfusion injury. 1619 92

The current study explored the concept that adult and pediatric populations differ in their response to major injury. Male C57BL/6 mice of a "young adult" (8-12 weeks) or "mature adult" (12-13 months) age were subjected to partial hepatic ischemia and reperfusion. Mature adult mice displayed significantly more liver injury than young adult mice as assessed histologically and by serum levels of alanine aminotransferase. Interestingly, there was far less neutrophil accumulation in the livers of mature adult mice. However, liver-recruited neutrophils from mature adult mice had a higher activation state than those from young adult mice. Activation of the inflammatory transcription factor, NF-kappaB, was suppressed in whole livers from mature adult mice. In isolated liver cells, Kupffer cells showed no difference in NF-kappaB activation, but hepatocytes from mature adult mice had delayed NF-kappaB activation in response to TNF. Furthermore, isolated hepatocytes from young adult mice produced abundant amounts of the chemokine, macrophage inflammatory protein-2, whereas hepatocytes from mature adult mice produced little, if any macrophage inflammatory protein-2. Mature adult mice had much lower hepatic expression of the cytoprotective protein, heat shock protein 70, than did young adult mice. In contrast, serum heat shock protein 70 levels, which has been linked to subsequent tissue injury, were higher in mature adult mice than in young adult mice. These data suggest that there are multiple alterations at the cellular and molecular levels that contribute to enhanced postischemic liver injury in mature adult mice.
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PMID:Age-dependent responses to hepatic ischemia/reperfusion injury. 1624 27

Leukocyte infiltration of reperfused tissue is a key event in the pathogenesis of ischemia-reperfusion. However, the role of chemokine receptors Ccr1, Ccr2, and Ccr5 for each single step of the postischemic recruitment process of leukocytes has not yet been characterized. Leukocyte rolling, firm adherence, transendothelial, and extravascular migration were analyzed in the cremaster muscle of anaesthetized C57BL/6 mice using near-infrared reflected light oblique transillumination microscopy. Prior to 30 min of ischemia as well as at 5, 30, 60, 90, and 120 min after onset of reperfusion, migration parameters were determined in wild-type, Ccr1-/-, Ccr2-/-, and Ccr5-/- mice. Sham-operated wild-type mice without ischemia were used as controls. No differences were detected in numbers of rolling leukocytes among groups. In contrast, the number of firmly adherent leukocytes was increased significantly in wild-type mice as compared with sham-operated mice throughout the entire reperfusion phase. Already after 5 min of reperfusion, this increase was reduced significantly in Ccr1-/- and Ccr5-/- mice, whereas only in Ccr2-/- mice, was adherence attenuated significantly at 120 min after onset of reperfusion. Furthermore, after 120 min of reperfusion, the number of transmigrated leukocytes (>80% Ly-6G+ neutrophils) was elevated in wild-type mice as compared with sham-operated animals. This elevation was significantly lower in Ccr1-/-, Ccr2-/-, and Ccr5-/- mice. Leukocyte extravascular migration distances were comparable among groups. In conclusion, these in vivo data demonstrate that Ccr1, Ccr2, and Ccr5 mediate the postischemic recruitment of neutrophils through effects on intravascular adherence and subsequent transmigration.
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PMID:Chemokine receptors Ccr1, Ccr2, and Ccr5 mediate neutrophil migration to postischemic tissue. 1627 92

The review present the literature data and the authors findings on perspective technologies for design of active chemical and natural compounds based on small molecules for highly specific therapy and correction of a wide variety of pathophysiological conditions in humans, that show overlapping development processes and have common mediators. The following strategies are discussed: chemogenomics strategy using computer screening libraries for generating of small molecule compounds with advantageous properties; strategy of chemokine network that provide control of many processes, from immunosurveillance to inflammation and from viral infections to cancer; strategy of using cytochrome P450 enzymes that guarantee maximum bioavailability of drugs and prevent their interaction and toxic effect; strategy of using superoxide dismutase enzymes (SOD) correcting superoxide anions overproduction in tissue injury and inflammation, from ischemia, organ transplantation to AIDS and cancer; strategy of telomer maintenance directed to anticancer and antiviral therapy as well as to correction of the aging processes; and strategy of short interfering RNAs capable to induce intracellular immunity to antigens of various origin.
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PMID:[Perspective technologies for drug design]. 1630 41


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