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)

Previous studies have demonstrated that both cytomegalovirus (CMV) infection and prolonged cold ischemia of the allograft (CI) are associated with chronic rejection of renal transplants. The purpose of this study is to investigate the effect of CMV infection, of CI and of the combination of both, on the progression of chronic rejection, and to obtain a more detailed insight in their effects on the expression of adhesion molecules. Therefore, a rat transplantation model was used. Lewis recipients of renal allografts (with and without CI) from MHC-incompatible Brown Norway rats were inoculated with rat CMV or left uninfected. CMV infection alone resulted in an increased influx of CD4+ cells and macrophages early after infection, and in an increase in glomerular sclerosis and intima proliferation. CI caused an increase in infiltrating NK cells and an effect on intimal proliferation, glomerular sclerosis, and tubular atrophy. When CMV infection and CI were combined, an additive effect could be measured. This was however not the case for the function of the kidney. The creatinin showed a synergistic effect of the two influencing factors. Due to the CMV infection, an increase in CD49d cells was detected. CI resulted in an increase in CD18 cells and an increase in the expression of CD62P on vessels, and CD54 and CD44 on tubules. When CMV infection and CI were combined, all the effects caused by CMV and CI alone were present in an additional way. The results of the present study suggest that special attention should be paid to the recipient of an ischemically injured graft when either the donor or the recipient is CMV-infected. The patterns seen in histology, the infiltration of leukocytes and the expression of adhesion molecules, suggest that CI and CMV infection both have an effect on rejection, but act by different mechanisms.
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PMID:Effects of cytomegalovirus infection and prolonged cold ischemia on chronic rejection of rat renal allografts. 1074 91

Gut ischemia-reperfusion (G-IR) induces a systemic inflammatory response, in which leukocyte contribution to this injury in distant organs is important. ICAM-1 as well as CD11/CD18 have been involved in leukocyte infiltration in liver and lungs. CD44 adhesion molecule plays an essential role in other inflammatory processes such as rheumatoid arthritis and allergic contact dermatitis, however its implication in G-IR has not been described. In order to establish a possible role of CD44 in the development of systemic inflammation by G-IR, we have studied CD44 mRNA expression by RT-PCR in a murine model of gut ischemia reperfusion. Animals subjected to G-IR showed an increased number of CD44 variable isoforms expressed in liver and spleen compared to non-treated animals or animals subjected to laparotomy. This finding indicates that G-IR specifically induces the expression of different CD44 variable isoforms. Liver CD44 upregulation in animals subjected to G-IR suggests a contribution of this molecule to lymphocyte activation and migration to this injured organ. Moreover, increased isoform expression in spleen may be induced by the proinflammatory environment resulting from a systemic depuration activity.
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PMID:[Isoforms modulation of CD44 adhesion molecule in a murine model of ischemia and intestinal reperfusion]. 1143 5

Osteopontin (OPN) is a secreted glycoprotein in both phosphorylated and non-phosphorylated forms. It contains an Arg-Gly-Asp cell-binding sequence and a thrombin-cleavage site. OPN is mainly present in the loop of Henle and distal nephrons in normal kidneys in animals and humans. After renal damage, OPN expression may be significantly up-regulated in all tubule segments and glomeruli. Studies utilizing OPN gene-deficient mice, antisense-treated or anti-OPN-treated animals have demonstrated that OPN promotes accumulation of macrophages, and may play a role in macrophage-mediated renal injury, but that the effect may be mild and short-lived. On the other hand, OPN has some renoprotective actions in renal injury, such as increasing tolerance to acute ischemia, inhibiting inducible nitric oxide synthase and suppressing nitric oxide synthesis, reducing cell peroxide levels and promoting the survival of cells exposed to hypoxia, decreasing cell apoptosis and participating in the regeneration of cells. In addition, OPN is associated with renal stones, but whether it acts as a promoter or inhibitor of stone formation is controversial. It has been demonstrated that OPN receptors include two families: integrin and CD44. The OPN integrin receptors include alpha(v)beta(3), alpha(v)beta(1), alpha(v)beta(5) and alpha(9)beta(1), and alpha(4)beta(1). In normal human kidneys, standard CD44 is expressed most dominantly. Different OPN functions are mediated via distinct receptors. Parathyroid hormone, vitamin D(3), calcium, phosphate and some cytokines increase OPN expression in vitro or in vivo, whereas female sex hormones and angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists decrease OPN expression in some renal damage states.
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PMID:Expression, roles, receptors, and regulation of osteopontin in the kidney. 1170 81

CD44 is a transmembrane glycoprotein known to be involved in endothelial cell recognition, lymphocyte trafficking, and regulation of cytokine gene expression in inflammatory diseases. In the present study, we demonstrated that the expression of CD44 mRNA was induced in a mouse model of cerebral ischemia. A potential role of CD44 in ischemic brain injury was investigated using CD44-deficient (CD44-/-) mice. Over 50% (p < 0.05, n = 14) and 78% (p < 0.05, n = 10) reduction in ischemic infarct was observed in CD44-/- mice compared with that of wild-type mice following transient (30 min ischemia) and permanent (24 h) occlusion of the middle cerebral artery (MCAO), respectively. Similarly, significant improvement was observed in neurological function in CD44-/- mice as evidenced by spontaneous and forced motor task scores. The marked protection from ischemic brain injury in CD44-/- mice was associated with normal physiological parameters, cytokine gene expression, astrocyte and microglia activation as compared with wild-type mice. However, in CD44-/- mice, significantly lower expression of soluble interleukin-1beta protein was noted after brain ischemia. Our data provide new evidence on the potential role of CD44 in brain tissue in response to ischemia and may suggest that this effect might be associated with selective reduction in inflammatory cytokines such as interleukin-1beta.
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PMID:CD44 deficiency in mice protects brain from cerebral ischemia injury. 1243 88

Adhesion molecules contribute to ischemia-reperfusion injury by increasing the endothelial adhesion and extravasation of leukocytes. Scientific evidence suggests that presurgical treatment with dehydroepiandrosterone may protect the microvasculature against this damage, but the exact mechanism is not known. The purpose of this study was to investigate the effects of presurgical dehydroepiandrosterone treatment on microcirculatory hemodynamic parameters and the expression of adhesion molecules in a rat cremaster muscle flap model. Twenty male rats were randomly assigned to three experimental groups. In group I (n = 5), the muscle flaps did not receive presurgical treatment. In group II (n = 6), propylene glycol (30 mg/kg), the vehicle for dehydroepiandrosterone, was injected intravenously before ischemia was induced. In group III (n = 9), dehydroepiandrosterone (30 mg/kg) was injected intravenously before ischemia was induced. All flaps were subjected to 6 hours of ischemia and 90 minutes of reperfusion. Microcirculatory variables (functional capillary density, red blood cell velocity in the main flap arteriole, and numbers of rolling, sticking, and transmigrating leukocytes), blood levels of three adhesion molecules (L-selectin, Mac-1 integrin, and CD44), and the numbers of leukocytes expressing those molecules were analyzed. Analysis of the microcirculatory parameters revealed that dehydroepiandrosterone treatment before ischemia had significant preservative effects on the red blood cell velocity and functional capillary density 30 and 90 minutes after reperfusion, compared with the control and vehicle-treated groups. Leukocyte-endothelial cell interactions were also affected by dehydroepiandrosterone treatment, as reflected by significant decreases in the numbers of sticking and transmigrating leukocytes 30 and 90 minutes after reperfusion. In dehydroepiandrosterone-treated animals, leukocytes exhibited lower levels of expression of adhesion molecules after the onset of ischemia, compared with the control groups. In this study, intravenous dehydroepiandrosterone administration reduced the activation of leukocytes and improved red blood cell velocity and capillary perfusion in the muscle flap microcirculation during ischemia-reperfusion injury. This protective effect was most likely the result of delayed expression of Mac-1 integrin, L-selectin, and CD44 molecules on leukocytes.
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PMID:Dehydroepiandrosterone protects the microcirculation of muscle flaps from ischemia-reperfusion injury by reducing the expression of adhesion molecules. 1279 71

Osteopontin (OPN) is a glyco-phosphoprotein that is expressed and secreted by numerous human cancers. OPN functions in cell adhesion, chemotaxis, macrophage-directed interleukin-10 (IL-10) suppression, stress-dependent angiogenesis, prevention of apoptosis, and anchorage-independent growth of tumor cells by regulating cell-matrix interactions and cellular signaling through binding with integrin and CD44 receptors. While constitutive expression of OPN exists in several cell types, induced expression has been detected in T-lymphocytes, epidermal cells, bone cells, macrophages, and tumor cells in remodeling processes such as inflammation, ischemia-reperfusion, bone resorption, and tumor progression. Recently, substantial evidence has linked OPN with the regulation of metastatic spread by tumor cells. However, the molecular mechanisms that define the role of OPN in tumor metastasis are incompletely understood. Transcriptional regulators that contribute to the induction of OPN expression have received significant attention as potential modulators of the OPN-mediated metastatic phenotype. The following review will discuss the molecular structure of OPN, the evidence for its functional role in tumor cell metastasis, the downstream signals that activate invasive mechanisms, and the recent reports concerning regulation of OPN transcription.
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PMID:The role of Osteopontin in tumor metastasis. 1550 63

Cellular hypoxia, characterizing tumors, ischemia, and inflammation induce recruitment of monocytes/macrophages, immobilize them at the hypoxic site, and alter their function. To migrate across the extracellular matrix and as part of their inflammatory functions, monocytes and macrophages secrete proteases, including matrix metalloproteinase-9 (MMP-9), whose expression is induced by proinflammatory cytokines [e.g., tumor necrosis factor alpha (TNF-alpha)]. We show that hypoxia (<0.3% O2 for 48 h) reduced the output of TNF-alpha-induced proMMP-9 by threefold (P < 0.01) in the U937 monocytic cell line and in primary human monocytes. TNF-alpha induced MMP-9 transcription by threefold, but no significant difference was observed in MMP-9 mRNA steady-state between normoxia and hypoxia, which inhibited the trafficking of proMMP-9 via secretory vesicles and increased the intracellular accumulation of proMMP-9 in the cells by 47% and 62% compared with normoxia (P < 0.05), as evaluated by zymography of cellular extracts and confocal microscopy, respectively. Secretion of proMMP-9 was reduced by the addition of cytochalazin B or nocodazole, which inhibits the polymerization of actin and tubulin fibers, or by the addition of the Rho kinase inhibitor Y27632, suggesting the involvement of the cytoskeleton and the Rho GTPases in the process of enzyme secretion. Furthermore, attachment of proMMP-9 to the cell membrane increased after hypoxia via its interactions with surface molecules such as CD44. In addition, the reduced migration of monocytes in hypoxia was shown to be mediated, at least partially, by secreted MMP-9. Thus, hypoxia post-translationally reduced the secreted amounts of proMMP-9 by using two mutually nonexclusive mechanisms: mostly, inhibition of cellular trafficking and to a lesser extent, attachment to the membrane.
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PMID:Hypoxia reduces the output of matrix metalloproteinase-9 (MMP-9) in monocytes by inhibiting its secretion and elevating membranal association. 1643 97

Recent evidence has demonstrated that hyaluronan synthase 2 mRNA is up-regulated after brain ischemia. After a cerebral ischemic event, microglia and macrophages are the major inflammatory cells and are activated by hyaluronan (HA). However, it is unclear how these cells compare with regard to HA responsiveness. We show here that peritoneal macrophages and RAW 264.7 macrophages produced more than five- and 10-fold more tumor necrosis factor-alpha (TNF-alpha) than primary microglia and BV-2 microglia, respectively. Antibody blockade study showed that CD44, Toll-like receptor-4 receptor and the receptor for HA-mediated motility were responsible for HA-induced TNF-alpha release. Furthermore, HA induced higher levels of phosphorylated MAPK in RAW 264.7 cells when compared with BV-2 cells. HA-mediated TNF-alpha production required p38 MAPK, extracellular-regulated kinase and c-Jun N-terminal kinase phosphorylation in both cell types. The levels of HA-induced TNF-alpha mRNA expression in BV-2 cells were only twofold lower compared with RAW 264.7 cells, suggesting that a translational event is involved in the differential production of TNF-alpha. Western blot analysis revealed that HA treatment resulted in more rapid phosphorylation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and more effective dissociation of 4E-BP1 from eukaryotic initiation factor 4E in RAW 264.7 cells than in BV-2 cells. Additionally, HA-induced phosphorylation of 4E-BP1 was dependent on MAPK signaling, indicating that RAW 264.7 cells exhibited higher levels of hyperphosphorylated 4E-BP1 possibly due to the overactivation of MAPK. The results suggest that resident microglia and blood-derived monocytes/macrophages exhibit differential sensitivities in response to extracellular mediators after brain ischemia.
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PMID:Translational event mediates differential production of tumor necrosis factor-alpha in hyaluronan-stimulated microglia and macrophages. 1657 52

Severe ischemia-reperfusion injury (IRI) predisposes to long-term impairment in kidney function both in patients and experimentally through unknown mechanisms. Given emerging evidence implicating lymphocytes in the pathogenesis of early injury to kidney, liver, and lung after IRI, we hypothesized that kidney IRI would potentially release or expose normally sequestered antigens that would lead to proliferation of antigen-recognizing lymphocytes. This, in turn, would directly participate in progressive kidney injury. To test this hypothesis, we purified splenic lymphocytes from C57BL/6 mice with severe renal IRI or sham operation 6 wk postischemia and transferred these cells to normal mice. Donor mice with IRI had significant fibrosis and cellular inflammation. The recipient mice were followed for 6 or 12 wk. Donor lymphocytes were found to traffic into recipient kidney. Twelve weeks after transfer, kidneys from mice which received IRI-primed lymphocytes exhibited significantly increased urinary albumin excretion compared with lymphocytes from sham mice. Splenic CD3(+), CD4(+), CD3(+)CD25(+), and CD4(+)CD44(+) counts were significantly increased in mice after lymphocyte transfer from IRI mice vs. mice with lymphocytes from sham mice. These data demonstrate that lymphocytes from IRI mice can traffic to recipient kidney and directly mediate albuminuria. These data identify a novel mechanism by which initial kidney injury predisposes to long-term dysfunction and identify lymphocytes as potential therapeutic targets for progressive renal diseases.
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PMID:Transfer of lymphocytes from mice with renal ischemia can induce albuminuria in naive mice: a possible mechanism linking early injury and progressive renal disease? 1675 31

Ischemia/reperfusion (I/R) injury in the kidney involves hemodynamic and cellular dysfunctions as well as leukocyte infiltration. Functional recovery occurs via cell proliferation and/or migration. To determine the roles of hyaluronan (HA) and its main receptor CD44 in renal postischemic processes, we compared their localization and expression with that of neutrophils, macrophages, and PCNA-positive (regenerative) cells as characterized by immunohistochemistry, up to 28 days after I/R in uninephrectomized rats. Observations covered all kidney zones, i.e. cortex (C), outer and inner stripes of outer medulla (OSOM, ISOM), and inner medulla (IM). In controls, HA was localized to the interstitium of IM and ISOM, and CD44 was mostly present on the basolateral membranes of collecting ducts in ISOM, the thin descending limb of Henle's loop and macula densa cells. After I/R, HA and CD44 staining appeared in C and OSOM at 12 h and persisted throughout the regenerative period, i.e. until day 7. Thereafter, they regressed but remained associated with remodeling areas. CD44 expression was found de novo on the apical pole of regenerating, not fully differentiated tubular cells and on some interstitial cells. It was prominent on all infiltrating neutrophils, as soon as 2 h post-I/R, and on 30% of the macrophages, including those in late HA-rich inflammatory granulomas. CD44 is probably involved in early leukocyte infiltration, in tubular regeneration, and in macrophage activity, while HA modifies the physico-chemical environment of interstitial and migrating cells. Based on its presence in remodeling areas, the HA-CD44 pair may be implicated in persistent postichemic inflammation as observed in chronic allograft nephropathy.
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PMID:Dynamics of hyaluronan, CD44, and inflammatory cells in the rat kidney after ischemia/reperfusion injury. 1678 59


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