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)

Although glycosylphosphatidyl-inositol (GPI) linked membrane proteins do not possess transmembrane or cytosolic sequences they elicit transmembrane signals. Using microscopic fluorescence imaging and resonance energy transfer (RET) techniques we have shown that certain pro-inflammatory GPI-linked membrane proteins can interact with leukocyte beta 2 integrins (complement receptor type 3 (CR3) and 4 (CR4) and the leukocyte function-associated antigen-1 (LFA-1)). For example, physical associations between CR3 and Fc gamma RIIIB, CR3 and urokinase receptors, and CR3 and CD14 (lipopolysaccharide receptor) have been found. Although Fc gamma RIIIB appears to be constitutively associated with CR3, urokinase receptors and CD14 associations with CR3 are influenced by their ligation status and cell function (e.g. adherence and locomotion). CR3-to-urokinase receptor interactions have been confirmed by immunoprecipitation techniques. Immunoprecipitation of CR3 from Brij-58 lysates after biotinylation of neutrophil membranes revealed proteins of M(r) = 40,000, 50,000, 74,000 and 120,000, in addition to bands corresponding to the integrin alpha and beta chains. Cell functions such as transmembrane signaling and superoxide release/priming have been linked to these interactions. Importantly, reagents that affect the lectin-like site of CR3, such as N-acetyl-D-glucosamine, alpha-methyl-D-mannoside and beta-glucan alter these interactions and, in parallel, leukocyte functions. Thus, the interactions of GPI-linked proteins and integrins can be highly dynamic events linked to cell activities. Our studies suggest that it may be possible to develop new drugs directed at the lectin-like site of beta 2 integrins that block GPI-linked protein-to-integrin coupling thereby controlling inflammatory cell processes including cell adherence, locomotion and activation. Such drugs may be useful in clinical conditions such as ischemia-reperfusion injury, sepsis, arthritis and others.
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PMID:Ectodomain interactions of leukocyte integrins and pro-inflammatory GPI-linked membrane proteins. 922 70

Septic shock is an increasingly important clinical condition, characterized by systemic hypotension, ischemia, and ultimately organ failure. In Gram negative infection, the bacterial cell wall component, lipopolysaccharide (endotoxin, LPS), has been strongly linked to the pathophysiological responses that result in septic shock. LPS is bound in plasma to a protein called LPS-binding protein (LBP), which facilitates the binding of LPS to a cell surface receptor, CD14. Binding to CD14 stimulates cell signaling mechanisms that result in the production of inflammatory cytokines. However, the events which follow LPS binding to CD14 and which lead to the production of cytokines remain unclear. It has recently become evident that a number of phosphorylation cascades including MAP kinase pathways and NF-kappaB activation pathway are initiated by exposure of cells to LPS. These cascades act at both the transcriptional and translational levels to regulate cytokine production. This review will focus on the signaling pathways that are initiated by LPS and the cellular effects of the signaling pathways.
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PMID:Cellular activation mechanisms in septic shock. 956 Mar 58

Analysis of gene expression in a mouse model of unilateral ureteral obstruction (UUO) revealed significant induction of CD14 mRNA in kidneys with obstructed ureters. Immunocytochemical analysis indicated that CD14 was upregulated in tubular epithelial cells and this upregulation was not attributable to infiltration of the kidneys by mononuclear cells. This induction of CD14 mRNA was found to occur in BALB/C, C57BL/6, C3H/HeN, and C3H/HeJ mice during UUO. Ischemia/reperfusion of kidneys also induced CD14 mRNA. Mice lacking either of the tumor necrosis factor-alpha receptor (TNFR) genes were also studied; the induction of CD14 was blunted in TNFR 1-knockout mice but not in TNFR2-knockout mice. Apoptosis of tubular cells in lipopolysaccharide-resistant CH3/HeJ mice was significantly (P: < 0. 05) less than that in lipopolysaccharide-responsive CH3/HeN mice during UUO. These results suggest that CD14 is acutely induced in tubular epithelial cells in two mouse models of renal injury. This induction is regulated by tumor necrosis factor-alpha, through TNFR1. CD14 may participate in the apoptosis of tubular epithelial cells on a more chronic basis by activating a pathway that is absent or deficient in C3H/HeJ mice.
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PMID:Induction of CD14 in tubular epithelial cells during kidney disease. 1096 93

Endotoxins (lipopolysaccharides, LPSs) are potent bacterial poisons, and they are always present in the intestine in considerable numbers. Stress, such that as a resulting from multiple injuries, burns, hypovolemia, hypoxia, intestinal ischemia, and surgery can lead to a breakdown of the gut barrier, allowing endotoxins to enter the systemic circulation via translocation. However, estimating the biological activity of translocated circulating endotoxins and identification of the mechanisms regulating their biological activities remain complex problems. CD14 has been found to exist as a soluble protein in the serum and as a glycosylphosphatidylinositol (GPI)-anchored protein of myeloid lineage cells. It plays key roles in both LPS-induced activation and in LPS internalization by cells. In this article, we outline: (i) the biological activity of circulating endotoxin; and (ii) the role of membrane and/or soluble CD14 regulating the bioactivity of circulating endotoxin in a human model of postoperative endotoxemia.
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PMID:Pathophysiological relevance of the CD14 receptor in surgical patients: biological activity of endotoxin is regulated by the CD14 receptor. 1175 18

CD14, a key pattern recognition receptor of the innate immune system, is a surface molecule on monocytic cells involved in cellular activation. We investigated 18 autopsy cases of focal cerebral infarctions (FCI) by immunohistochemistry to examine CD14 expression following ischemia. Controls confirmed constitutive CD14 expression by few perivascular cells. In contrast to quiescent CD14- parenchymal microglial cells, following ischemia activated microglia/macrophages expressed abundant CD14. In FCI, CD14+ cells increased both in perivascular spaces and in brain parenchyma within 1-2.5 days and remained elevated until late stages. Early CD14 expression suggests an essential part of CD14 in the acute inflammatory response following stroke.
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PMID:Infiltrating CD14+ monocytes and expression of CD14 by activated parenchymal microglia/macrophages contribute to the pool of CD14+ cells in ischemic brain lesions. 1202 Sep 62

Adult marrow-derived cells have been shown to contribute to various nonhematologic tissues and, conversely, primitive cells isolated from nonhematopoietic tissues have been shown to reconstitute hematopoiesis. Circulating endothelial progenitor cells (EPCs) have been reported to be at least partially donor derived after allogeneic bone marrow transplantation, and shown to contribute to neovascularization in murine ischemia models. However, it is unknown whether these EPCs are actually clonally derived from the same population of stem and progenitor cells that reconstitute hematopoiesis, or from another cell population found in the marrow or mobilized blood that is transferred during transplantation. To approach this question, we characterized circulating EPCs and also endothelial cells from large vessels harvested at autopsy from rhesus macaques previously transplanted with retrovirally transduced autologous CD34-enriched peripheral blood stem cells (PBSCs). Endothelial cells were grown in culture for 21-28 days and were characterized as CD31(+) CD14(-) via flow cytometry, as acLDL(+) UEA-1(+) via immunohistochemistry, and as Flk-1(+) by reverse transcriptase-polymerase chain reaction (RT-PCR). Animals had stable vector marking in hematopoietic lineages of 2-15%. Neither cultured circulating EPCs collected in steady state (n = 3), nor endothelial cells grown from large vessels (n = 2), had detectable retroviral marking. EPCs were CD34(+) and could be mobilized into the circulation with granulocyte colony-stimulating factor. Under ex vivo culture conditions, in which CD34(+) cells were optimized to transduce hematopoietic progenitor and stem cells, there was a marked depletion of EPCs. Transduction of EPCs was much more efficient under conditions supporting endothelial cell growth. Further elucidation of the origin and in vivo behavior of EPCs may be possible, using optimized transduction conditions and a vascular injury model.
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PMID:Analysis of origin and optimization of expansion and transduction of circulating peripheral blood endothelial progenitor cells in the rhesus macaque model. 1248 99

Circulating endothelial progenitor cells (EPC) are incorporated into newly formed capillaries, enhance neovascularization after hind limb ischemia and improve cardiac function after ischemic injury. Incorporated progenitor cells may also promote neovascularization and cardiac regeneration by releasing factors, which act in a paracrine manner to support local angiogenesis and mobilize tissue residing progenitor cells. Therefore, we analyzed the expression profile of cytokines in human peripheral blood-derived EPC as opposed to human umbilical vein endothelial cells (HUVEC), human microvascular endothelial cells (HMVEC), and CD14(+) monocytes by microarray technology. A gene tree analysis revealed a distinct expression pattern of angiogenic growth factors in EPC, mature endothelial cells, and CD14(+) monocytes. VEGF-A, VEGF-B, SDF-1, and IGF-1 mRNA levels were higher in EPC as compared to HUVEC or HMVEC. The enhanced mRNA expression was paralleled by a significant release of VEGF, SDF-1, and IGF-1 protein into the cell culture supernatant of EPC. Moreover, immunohistological analysis of ischemic limbs from nude rats revealed that VEGF is also released from recruited human EPC in vivo. As a functional consequence, conditioned medium of EPC induced a strong migratory response of mature endothelial cells, which was significantly inhibited by VEGF and SDF-1 neutralizing antibodies. Finally, conditioned medium of EPC significantly stimulated the migration of cardiac resident c-kit(+) progenitor cells in vitro. Taken together, EPC exhibit a high expression of angiogenic growth factors, which enhanced migration of mature endothelial cells and tissue resident cardiac progenitor cells. In addition to the physical contribution of EPC to newly formed vessels, the enhanced expression of cytokines may be a supportive mechanism to improve blood vessel formation and cardiac regeneration after cell therapy.
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PMID:Soluble factors released by endothelial progenitor cells promote migration of endothelial cells and cardiac resident progenitor cells. 1632 97

Bone marrow cell implantation (BMI) has been utilized to treat patients with limb and heart ischemia. BMI provides angiogenic precursors and angiogenic cytokine-producing cells, especially erythroid cells. In this study, we induced in vitro angiogenesis cultures and in vivo BMI simulation using a murine limb ischemia model to examine the role of erythroid cells and the effect of erythropoietin (EPO). Human erythroid colonies (BFU-e) induced capillary networks around the colonies in vitro. Erythroid cells in human bone marrow produced vascular endothelial growth factor and placental growth factor. The angiogenic effects of erythroid cells were further amplified in the presence of EPO. Limb-ischemic mice were treated with BMI +/- EPO, and limb survival, blood flow recovery, and muscle histology were analyzed. Treatment with whole bone marrow cells + EPO significantly improved limb survival and blood flow. The cumulative effects of EPO on BMI induced and increase in capillary number and artery enlargement. Erythroid cells were essential for the in vivo effects of BMI, and CD14-positive cells supported the biological effects. In addition to the direct effect of EPO on angiogenesis, EPO showed indirect effect on angiogenesis through amplifying the angiogenic effects by erythroid cells supported by CD14-positive cells.
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PMID:Erythroid cells play essential roles in angiogenesis by bone marrow cell implantation. 1660 82

Endothelial precursor cells (EPCs) cultured from adult bone marrow (BM) have been shown to mediate neovasculogenesis in murine models of vascular injury. We sought to directly compare umbilical cord blood (UCB)- and BM-derived EPC surface phenotypes and in vivo functional capacity. UCB and BM EPCs derived from mononuclear cells (MNC) were phenotyped by surface staining for expression of stromal (Stro-1, CXCR4, CD105, and CD73), endothelial (CD31, CD146, and vascular endothelial [VE]-cadherin), stem cell (CD34 and CD133), and monocyte (CD14) surface markers and analyzed by flow cytometry. The nonobese diabetic/severe combined immunodeficiency murine model of hind-limb ischemia was used to analyze the potential of MNCs and culture-derived EPCs from UCB and BM to mediate neovasculogenesis. Histologic evaluation of the in vivo studies included capillary density as a measure of neovascularization. Surface CXCR4 expression was notably higher on UCB-derived EPCs (64.29%+/-7.41%) compared with BM (19.69%+/-5.49%; P=.021). Although the 2 sources of EPCs were comparable in expression of endothelial and monocyte markers, BM-derived EPCs contained higher proportions of cells expressing stromal cell markers (CD105 and CD73). Injection of UCB- or BM-derived EPCs resulted in significantly improved perfusion as measured by laser Doppler imaging at days 7 and 14 after femoral artery ligation in nonobese diabetic/severe combined immunodeficiency mice compared with controls (P<.05). Injection of uncultured MNCs from BM or UCB showed no significant difference from control mice (P=.119; P=.177). Tissue samples harvested from the lower calf muscle at day 28 demonstrated increased capillary densities in mice receiving BM- or UCB-derived EPCs. In conclusion, we found that UCB and BM-derived EPCs differ in CXCR4 expression and stromal surface markers but mediate equivalent neovasculogenesis in vivo as measured by Doppler flow and histologic analyses.
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PMID:Direct comparison of umbilical cord blood versus bone marrow-derived endothelial precursor cells in mediating neovascularization in response to vascular ischemia. 1663 94

The hierarchy of endothelial progenitor cells (EPCs) in human umbilical cord blood has been disclosed. In this study we compare, for the first time, the angiogenic potential difference between two types of EPCs. We cultured mononuclear cells (MNCs) isolated from human umbilical cord blood using endothelial cell-conditioned medium and obtained two types of EPCs, referred to as circulating angiogenic cells (CACs) and high proliferative potential endothelial progenitor cells (HPP-EPCs). Both types of cells possess characteristics of EPCs, including expressing CD31, VE-cadherin, KDR and von Willebrand factor, uptake of Ac-LDL and binding to lectin. However, unlike CACs, which express CD14 but not CD133, HPP-EPCs express CD133 but not CD14. Also, unlike CACs, HPP-EPCs display stronger proliferation and clonogenic potential in vitro and show stronger ability to promote vascular growth in the hind-limb model of ischemia in mice (BALB/C-nu) in vivo.
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PMID:Angiogenic potential difference between two types of endothelial progenitor cells from human umbilical cord blood. 1702 Aug 9


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