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)

To assess the relationship between interstitial capillary density and interstitial macrophages we prospectively measured these factors in situ in 110 patients with chronic kidney disease. Macrophage numbers and urinary MCP-1/CCL2 levels significantly correlated inversely with capillary density which itself significantly correlated inversely with chronic damage and predicted disease progression. In 54 patients with less than 20% chronic damage, there was a significant correlation between the urinary albumin to creatinine ratio and MCP-1/CCL2, and MCP-1/CCL2 and macrophages but not between MCP-1/CCL2 and capillary density. Conversely, in 56 patients with over 20% chronic damage there was no correlation between MCP-1/CCL2 and macrophages but there were significant inverse correlations between capillary density and both macrophages and chronic damage. The expression of VEGF mRNA significantly correlated with macrophage infiltration, capillary density and chronic scarring. In an ischemic-hypertensive subgroup there was upregulation of the hypoxia marker carbonic anhydrase IX and with over 20% chronic damage an increased macrophage to CCR2 ratio. Our study shows that proteinuria and MCP-1/CCL2 are important for macrophage recruitment in early disease. As renal scarring evolves, alternative pathways relating to progressive tissue ischemia secondary to obliteration of the interstitial capillary bed predominate.
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PMID:The role of capillary density, macrophage infiltration and interstitial scarring in the pathogenesis of human chronic kidney disease. 1867 Apr 2

Ischemia/reperfusion (I/R) injury during small intestinal transplantation (SITx) frequently causes complications including dysmotility, inflammation and organ failure. Recent evidence indicates hydrogen inhalation eliminates toxic hydroxyl radicals. Syngeneic, orthotopic SITx was performed in Lewis rats with 3 h of cold ischemic time. Both donor and recipient received perioperative air or 2% hydrogen inhalation. SITx caused a delay in gastrointestinal transit and decreased jejunal circular muscle contractile activity 24 h after surgery. Hydrogen treatment resulted in significantly improved gastrointestinal transit, as well as jejunal smooth muscle contractility in response to bethanechol. The transplant induced upregulation in the inflammatory mediators CCL2, IL-1 beta, IL-6 and TNF-alpha were mitigated by hydrogen. Hydrogen significantly diminished lipid peroxidation compared to elevated tissue malondialdehyde levels in air-treated grafts demonstrating an antioxidant effect. Histopathological mucosal erosion and increased gut permeability indicated a breakdown in posttransplant mucosal barrier function which was significantly attenuated by hydrogen treatment. In recipient lung, hydrogen treatment also resulted in a significant abatement in inflammatory mRNA induction and reduced neutrophil recruitment. Hydrogen inhalation significantly ameliorates intestinal transplant injury and prevents remote organ inflammation via its antioxidant effects. Administration of perioperative hydrogen gas may be a potent and clinically applicable therapeutic strategy for intestinal I/R injury.
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PMID:Hydrogen inhalation ameliorates oxidative stress in transplantation induced intestinal graft injury. 1872 97

Reactive oxygen species (ROS) play a crucial role in ischemia-reperfusion (IR) injury after lung transplantation. We hypothesized that NADPH oxidase derived from bone marrow (BM) cells contributes importantly to lung IR injury. An in vivo mouse model of lung IR injury was employed. Wild-type C57BL/6 (WT) mice, p47(phox) knockout (p47(phox)-/-) mice, or chimeras created by BM transplantation between WT and p47(phox)-/- mice were assigned to either Sham (left thoracotomy) or six study groups that underwent IR (1 h left hilar occlusion and 2 h reperfusion). After reperfusion, pulmonary function was assessed using an isolated, buffer-perfused lung system. Lung injury was assessed by measuring vascular permeability (via Evans blue dye), edema, neutrophil infiltration (via myeloperoxidase [MPO]), lipid peroxidation (via malondialdyhyde [MDA]), and expression of proinflammatory cytokines. Lung IR resulted in significantly increased MDA in WT mice, indicative of oxidative stress. WT mice treated with apocynin (an NADPH oxidase inhibitor) and p47(phox)-/- mice displayed significantly reduced pulmonary dysfunction and injury (vascular permeability, edema, MPO, and MDA). In BM chimeras, significantly reduced pulmonary dysfunction and injury occurred after IR in p47(phox)-/--->WT chimeras (donor-->recipient) but not WT-->p47(phox)-/- chimeras. Induction of TNF-alpha, IL-17, IL-6, RANTES (CCL5), KC (CXCL1), MIP-2 (CXCL2), and MCP-1 (CCL2) was significantly reduced after IR in NADPH oxidase-deficient mice and p47(phox)-/--->WT chimeras but not WT-->p47(phox)-/- chimeras. These results indicate that NADPH oxidase-generated ROS specifically from BM-derived cells contributes importantly to lung IR injury. NADPH oxidase may represent a novel therapeutic target for the treatment of IR injury after lung transplantation.
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PMID:NADPH oxidase in bone marrow-derived cells mediates pulmonary ischemia-reperfusion injury. 1878 74

Peroxisome proliferator-activated receptor (PPAR)-gamma is a ligand-activated transcription factor of nuclear hormone receptor superfamily. Thiazolidinedione rosiglitazone is a potent agonist of PPARgamma which was shown to induce neuroprotection in animal models of focal ischemia and spinal cord injury. We currently evaluated the therapeutic potential of rosiglitazone (6 mg/kg at 5 min, 6 h and 24 h; i.p.) following controlled cortical impact (CCI)-induced traumatic brain injury (TBI) in adult mice. CCI injury increased the cortical PPARgamma mRNA levels which were further elevated by rosiglitazone treatment. In addition, rosiglitazone treatment significantly decreased the cortical lesion volume measured at 7 days compared to vehicle treatment (by 56+/-7%; p<0.05; n=6/group). Following TBI, the spared cortex of the rosiglitazone group showed significantly less numbers of GSI-B4(+) activated microglia/macrophages and ICAM1(+) capillaries, and curtailed induction of pro-inflammatory genes IL6, MCP1 and ICAM1 compared to vehicle group. Rosiglitazone-treated mice also showed significantly less number of TUNEL(+) apoptotic neurons and curtailed induction of caspase-3 and Bax, compared to vehicle control. In addition, rosiglitazone significantly enhanced the post-TBI expression of the neuroprotective chaperones HSP27, HSP70 and HSP32/HO1, and the anti-oxidant enzymes catalase, Cu/Zn-SOD and Mn-SOD, compared to vehicle. Treatment with GW9662 (a specific PPARgamma antagonist) prevented all the above PPARgamma-mediated actions. Thus, PPARgamma activation confers neuroprotection after TBI by anti-inflammatory, anti-apoptotic and anti-oxidative mechanisms.
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PMID:PPARgamma agonist rosiglitazone is neuroprotective after traumatic brain injury via anti-inflammatory and anti-oxidative mechanisms. 1894 87

The cell body or soma in the dosal root ganglion (DRG) is normally excitable and this excitability can increase and persist after an injury of peripheral sensory neurons. In a rat model of radicular pain, an intraforaminal implantation of a rod that chronically compressed the lumbar DRG ("CCD" model) resulted in neuronal somal hyperexcitability and spontaneous activity that was accompanied by hyperalgesia in the ipsilateral hind paw. By the 5th day after onset of CCD, there was a novel upregulation in neuronal expression of the chemokine, monocyte chemoattractant protein-1 (MCP-1 or CCL2) and also its receptor, CCR2. The neurons developed, in response to topically applied MCP-1, an excitatory response that they normally do not have. CCD also activated non-neuronal cells including, for example, the endothelial cells as evidenced by angiogenesis in the form of an increased number of capillaries in the DRG after 7 days. A working hypothesis is that the CCD induced changes in neurons and non-neuronal cells that may act together to promote the survival of the injured tissue. The release of ligands such as CCL2, in addition to possibly activating nociceptive neurons (maintaining the pain), may also act to preserve injured cells in the face of ischemia and hypoxia, for example, by promoting angiogenesis. Thus, somal hyperexcitability, as often said of inflammation, may represent a double edged sword.
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PMID:Hyperexcitable neurons and altered non-neuronal cells in the compressed spinal ganglion. 1895 66

Regenerative responses after hypoxia-ischemia (HI) were investigated in the immature (P9) and juvenile (P21) mouse striatum and cortex by postischemic 5-bromo-2-deoxyuridine labeling and phenotyping of labeled cells 4 weeks later. HI stimulated the formation of new cells in striatum and cortex in immature, growing brains (P9), but when brain growth was finished (P21) proliferation could be stimulated only in striatum, not in cortex. However, the relative increase was higher in P21 (460%) than P9 striatum (50%), though starting from a lower level at P21. Starting from this lower level, HI-induced proliferation in P21 striatum reached the same level as in P9 striatum, but not higher. Phenotyping revealed that low levels of neurogenesis were still present in nonischemic P9 cortex and striatum, but only in striatum at P21. Ischemia-induced neurogenesis was found only in P9 striatum. Ischemia-induced gliogenesis occurred in P9 and P21 striatum as well as P9 cortex, but not in P21 cortex. Hence, the regenerative response was stronger in striatum than cortex, and stronger in P9 than P21 cortex. The biggest ischemia-induced change was the 49-fold increase in P21 striatal microglia, and this was accompanied by increased inflammation, as judged by the size and numbers of CCL2- and interleukin-18-positive cells.
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PMID:Age-dependent regenerative responses in the striatum and cortex after hypoxia-ischemia. 1898 54

Several members of the chemokine family play an important role in reparative fibrosis and are involved in the pathogenesis of remodeling following myocardial infarction. Chemokines may regulate the fibrotic process through recruitment and activation of mononuclear cell subsets and fibroblast progenitors (fibrocytes), by exerting direct effects on resident fibroblasts, and by modulating angiogenesis. Monocyte Chemoattractant Protein (MCP)-1/CCL2 is the best studied chemokine in cardiac fibrosis. Disruption of the MCP-1 axis reduces fibrosis attenuating dilation of the infarcted ventricle. In addition, MCP-1 signaling is activated in response to insults that do not cause cardiomyocyte death, such as brief ischemia or pressure overload and regulates fibrous tissue deposition in experimental models of fibrotic non-infarctive cardiomyopathy. Understanding the role of chemokine-mediated interactions in the development of cardiac fibrosis may identify novel therapeutic targets for treatment of patients with heart failure.
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PMID:Chemokines and cardiac fibrosis. 1948 9

Ischemia-reperfusion (IR) triggers tissue injury by activating innate immunity, for example, via TLR2 and TLR4. Surprisingly, TLR signaling in intrinsic renal cells predominates in comparison to intrarenal myeloid cells in the postischemic kidney. We hypothesized that immune cell activation is specifically suppressed in the postischemic kidney, for example, by single Ig IL-1-related receptor (SIGIRR). SIGIRR deficiency aggravated postischemic acute renal failure in association with increased renal CXCL2/MIP2, CCL2/MCP-1, and IL-6 mRNA expression 24 h after IR. Consistent with this finding interstitial neutrophil and macrophage counts were increased and tubular cell necrosis was aggravated in Sigirr-deficient vs wild-type IR kidneys. In vivo microscopy revealed increased leukocyte transmigration in the postischemic microvasculature of Sigirr-deficient mice. IL-6 and CXCL2/MIP2 release was much higher in Sigirr-deficient renal myeloid cells but not in Sigirr-deficient tubular epithelial cells after transient hypoxic culture conditions. Renal IR studies with chimeric mice confirmed this finding, as lack of SIGIRR in myeloid cells largely reproduced the phenotype of renal IR injury seen in Sigirr(-/-) mice. Additionally, clodronate depletion of dendritic cells prevented the aggravated renal failure in Sigirr(-/-) mice. Thus, loss of function mutations in the SIGIRR gene predispose to acute renal failure because SIGIRR prevents overshooting tissue injury by suppressing the postischemic activation of intrarenal myeloid cells.
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PMID:Resident dendritic cells prevent postischemic acute renal failure by help of single Ig IL-1 receptor-related protein. 1969 46

The proangiogenic action of human adipose tissue-derived mesenchymal stem cells (hASCs) transplantation has been shown to be mediated by secretory factors. In this study, we determined if human granulocyte chemotactic protein-2(GCP2) or monocyte chemoattractant protein-1(MCP1) is involved in the proangiogenic action of hASCs transplantation in the hindlimb ischemia model. hASCs secrete GCP2 and MCP1, which leads to increased tubule formation. The downregulation of GCP2 or MCP1 decreased MCP1 and GCP2 secretion, respectively, whereas the external addition of GCP2 or MCP1 increased MCP1 and GCP2, respectively. Additionally, the treatment of GCP2 and MCP1 increased VEGF secretion, while the downregulation of GCP2 and MCP1 showed the opposite effect on VEGF secretion. Downregulation of GCP2 and MCP1 expression also inhibited hASCs-induced proangiogenic action, while the overexpression of GCP2 increased it. Finally, the downregulation of MCP1 or VEGF inhibited the GCP2 overexpression-induced increase in blood flow recovery. Taken together, these data indicate that the proangiogenic action of hASCs transplantation is mediated by the interaction between GCP2, MCP1 and VEGF, which are secreted from the transplanted cells.
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PMID:The role of chemokines in proangiogenic action induced by human adipose tissue-derived mesenchymal stem cells in the murine model of hindlimb ischemia. 1991 Jun 91

Ischemia reperfusion (IR) activates TLRs causing subsequent sterile inflammation, for example in postischemic acute renal failure. Unexpectedly, TLR signaling predominates in intrinsic renal cells and not in intrarenal APCs in the postischemic kidney. We hypothesized that certain factors suppress APC activation and thereby limit sterile renal inflammation, for example, IFN regulatory factor 4 (IRF-4), an inducible inhibitor of LPS signaling. Oxidative stress was a trigger for IRF4 induction in myeloid cells in vitro as well as in CD45(+)/CD11c+ cells in the postischemic kidney. Lack of IRF4 aggravated acute renal failure 24 h after renal artery clamping together with increased intrarenal expression of TNF-alpha, IL-6, CXCL2, and CCL2 as well as excessive tubular necrosis and peritubular neutrophil influx as compared with wild-type IR kidneys. This effect almost entirely depended on the role of IRF4 to suppress TNF-alpha release by intrarenal APCs because either clodronate liposome depletion of these cells or TNF-alpha blockade with etanercept entirely abrogated the aggravation of cytokine expression and acute renal failure in Irf4-deficient mice. Thus, loss-of-function mutations in the IRF4 gene predispose to IR injury because the postischemic induction of IRF4 in resident APCs like CD11c(+) dendritic cells, suppresses them to secrete TNF-alpha, and thereby limits inappropriate immunopathology.
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PMID:Ischemia reperfusion induces IFN regulatory factor 4 in renal dendritic cells, which suppresses postischemic inflammation and prevents acute renal failure. 2060 97


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