Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with critical limb ischemia (CLI) have low levels of endothelial progenitor cells (EPC). Iloprost has been demonstrated to stimulate vascular endothelial growth factor (VEGF) and promote angiogenesis. We investigated the effects of iloprost on EPC levels in vivo in CLI patients. Twenty-three patients with stage III and IV CLI were treated with iloprost for four weeks, improving clinical and instrumental parameters. Mononuclear cells isolated from peripheral blood were cultured to obtain "early" EPC, evaluated counting adherent cells with double positivity for acetylated low-density lipoprotein uptake and Ulex Europaeus lectin at flow cytometry. These cells also co-expressed the monocyte markers CD14 and CD45. Iloprost increased EPC number in the whole patient population: pre-treatment median: 13,812/ml; range: 1,263-83,648/ml; post-treatment median: 23,739/ml; range: 3,385-99,251/ml; p = 0.035, irrespective of age, sex, disease stage or atherosclerosis risk factors. In conclusion, iloprost increases EPC number in peripheral blood in vivo. Such an effect may have therapeutic relevance.
 ...
PMID:The prostacyclin analogue iloprost increases circulating endothelial progenitor cells in patients with critical limb ischemia. 1898 32

Activated protein C (APC) is a serine protease with anticoagulant and direct cytoprotective activities. Early postischemic APC application activates the cellular protein C pathway in brain endothelium and neurons, which is neuroprotective. Whether late APC administration after a transient ischemic attack is neuroprotective and whether APC influences brain repair is not known. Here, we determined safety and efficacy of late APC and tissue-plasminogen activator (tPA) administrations in a mouse model of transient brain ischemia. tPA given at 6 h after onset of ischemia killed all mice within 2 d, whereas APC given at 6 or 24 h after ischemia onset improved significantly functional outcome and reduced spread of the ischemic lesion. At 7 d postischemia, APC multiple dosing (0.8 mg/kg, i.p.) at 6-72 or 72-144 h enhanced comparably cerebral perfusion in the ischemic border by approximately 40% as shown by in vivo lectin-FITC angiography, blocked blood-brain barrier leakage of serum proteins, and increased the number of endothelial replicating cells by 4.5- to 4.7-fold. APC multidosing at 6-72 h or 72-144 h increased proliferation of neuronal progenitor cells in the subventricular zone (SVZ) by 40-50% and migration of newly formed neuroblasts from the SVZ toward the ischemic border by approximately twofold. The effects of APC on neovascularization and neurogenesis were mediated by protease-activated receptor 1 and were independent of the reduction by APC of infarction volume. Our data show that delayed APC administration is neuroprotective and mediates brain repair (i.e., neovascularization and neurogenesis), suggesting a significant extension of the therapeutic window for APC intervention in postischemic brain.
 ...
PMID:Activated protein C promotes neovascularization and neurogenesis in postischemic brain via protease-activated receptor 1. 1903 71

Ischemic brain injury is a dynamic process that involves oxidative stress, inflammation, and cell death, as well as activation of endogenous adaptive and regenerative mechanisms depending on activation of transcription factors such as hypoxia inducible factor 1-alpha (HIF-1alpha). Because CoCl2 activates HIF-1alpha, we described a new focal-hypoxia model by direct intracerebral CoCl2 injection. Adult male Wistar rats were intracerebrally injected with CoCl2 (2 microl-50 mM), in frontoparietal cortex of right hemisphere, and saline (2 microl) in the contralateral hemisphere. In slides of fixed brains at 1, 6, 9, 24 h or 5 day after treatment, TTC, histochemistry (toluidine blue, Hoescht-33342, TUNEL), immunostaining (HIF-1alpha, GFAP), Lycopersicon esculentum lectin staining, and electron microscopy (EM) were performed. Immediately after 1 h post CoCl2 injection, HIF-1alpha stabilization and neuronal nuclear shrinkage and cromathin condensation were observed by immunostaining and EM, respectively. Neuronal apoptotic nuclear morphology and GFAP immunoreactivity and lectin maximal reactivity were detected during 6-9 h. Ultrastructural alterations of morphology included edematous perinuclear cytoplasm, organelles and endoplasmic reticulum (RE) enlargement, mitochondrial swelling with increased matrix density, and deposits of electron-dense material. Neurons showed particular nuclear indentations. Astrocytes and oligodendrocytes presented alterations in both nuclei and RE with dilated lumen and altered mitochondrias, and all these ultrastructural changes became detectable at day 5. CoCl2 cortical injection mimics focal brain ischemia, inducing neuronal death and glial activation. This model brings the opportunity to develop focal ischemia in selected brain areas to study their functional consequences and potential pharmacological therapies for in vivo models of stroke.
 ...
PMID:Neuronal and glial alterations due to focal cortical hypoxia induced by direct cobalt chloride (CoCl2) brain injection. 1938 68

Ischemia-reperfusion (I/R) injury provides a substantial limitation to further improvements in the development of therapeutic strategies for ischemia-related diseases. Studies in animal I/R models, including intestinal, hindlimb, kidney, and myocardial I/R models, have established a key role of the complement system in mediation of I/R injury using complement inhibitors and knock-out animal models. As complement activation has been shown to be an early event in I/R injury, inhibiting its activation or its components may offer tissue protection after reperfusion. However, clinical study results using complement inhibitors have largely been disappointing. Therefore, identification of a more specific pathogenic target for therapeutic intervention seems to be warranted. For this purpose more detailed knowledge of the responsible pathway of complement activation in I/R injury is required. Recent evidence from in vitro and in vivo models suggests involvement of both the classic and the lectin pathways in I/R injury via exposition of neo-epitopes in ischemic membranes. However, most of these findings have been obtained in knock-out murine models and have for a large part remained unconfirmed in the human setting. The observation that the relative role of each pathway seems to differ among organs complicates matters further. Whether a defective complement system protects from I/R injury in humans remains largely unknown. Most importantly, involvement of mannose-binding lectin as the main initiator of the lectin pathway has not been demonstrated at tissue level in human I/R injury to date. Thus, conclusions drawn from animal I/R studies should be extrapolated to the human setting with caution.
 ...
PMID:Complement-mediated ischemia-reperfusion injury: lessons learned from animal and clinical studies. 1947 97

Changes in carbohydrate metabolism in brain injury and the involvement of numerous glycoproteins in the subsequent restoration phenomena orientated this paper towards reporting on glucidic radical distribution in postinjured brain tissue. Samples from nine patients suffering severe head injuries and three matched controls were studied. Autopsies were performed up to 24 h postmortem; brains were fixed in formalin and samples were taken from contusional, pericontusional and different brain regions including the anterior cingulum and corpus callosum, parasagittal gyrus, putamen, hippocampus and opercular areas embedded in paraffin. Hematoxylin-eosin staining, immunoreaction with glial fibrillary acid protein (GFAP) and biotin-conjugated lectins (RCA, UEA, PNA, concanavalin A (Con A) and WGA) were used. Contusion and related phenomena such as ischemia induced changes in lectin expression in several elements of the nervous tissue. Endothelial cells of contused areas were positive for RCA, UEA and progressively for WGA and Con A, which could be related to hemorheological disturbances inducing secondary brain damage. Neurons in affected areas were also stained for Con A and UEA, with some processes being delineated. Axonal swellings showed particular affinity to any lectin. Reactive astrocytes displaying only mild staining to WGA in cell bodies were strongly positive for GFAP, showing different patterns of reactivity in the cortex and in white matter.
 ...
PMID:Changes in glucidic radicals in contused human brains. 1951 44

Apoptotic cells are potent complement activators; and proposed mechanisms include IgM-mediated classical pathway activation, C-reactive protein (CRP)-mediated classical pathway activation, and IgM-mediated lectin pathway activation. While complement activation is beneficial in clearing apoptotic cells, the resulting complement-mediated inflammation may extend damage to the surrounding cells and tissues, as observed in ischemia/reperfusion injury. We previously engineered and characterized a single-chain Fv against C1q globular heads (scFv(QuVHVL)) that blocked C1q binding to immobilized IgG and to IgG-sensitized cells, and thereby inhibited IgG-mediated classical pathway activation [Hwang H.Y., Duvall M.R., Tomlinson S., Boackle R.J., 2008. Highly specific inhibition of C1q globular-head binding to human IgG: a novel approach to control and regulate the classical complement pathway using an engineered single-chain antibody variable fragment. Molecular Immunology 45, 2570-2580]. In the present study, this scFv(QuVHVL) was examined for its ability to restrict complement deposition on apoptotic cells in the presence of fresh normal human serum (NHS). Interestingly, the addition of scFv(QuVHVL) to NHS decreased C1-mediated C4b deposition on apoptotic cells by 60% as compared to appropriate buffer-treated control serum. By inhibiting initiation of the early complement components, the subsequent C3b and membrane attack complex depositions were inhibited by 70%. Apoptotic cells may acquire serum CRP, a known classical complement pathway activator. It was observed that scFv(QuVHVL) blocked C1 binding to CRP and blocked CRP-mediated classical pathway activation using an ELISA format. However, under the experimental conditions used, the addition of exogenous CRP to apoptotic cells did not further increase the levels of C4b, C3b, or MAC deposition significantly, suggesting predominance by other activation mechanisms, such as antibody-C1-mediated complement activation. In summary, the results indicated that C1-mediated classical pathway activation was a highly significant mechanism for complement activation by apoptotic cells. In the future, specific inhibition of classical complement pathway activation by a humanized form of scFv(QuVHVL) may be useful in reducing inadvertent damage to healthy bystander tissue in a variety of acute, complement-mediated inflammatory conditions, including ischemia/reperfusion injury.
 ...
PMID:Specific inhibition of the classical complement pathway with an engineered single-chain Fv to C1q globular heads decreases complement activation by apoptotic cells. 1958 84

Complement activation has been shown to play an important role in the inflammation and tissue injury following myocardial ischemia and reperfusion (MI/R). Several recent studies from our laboratory demonstrated the importance of mannose-binding lectin (MBL) as the initiation pathway for complement activation and the resulting pathological effects following MI/R. However, other studies from the past suggest an important role of the classical pathway and perhaps natural antibodies. In the present study, we used newly generated genetically modified mice that lack secreted IgM (sIgM), MBL-A, and MBL-C (sIgM/MBL null) in a plasma reconstitution mouse model of MI/R. Following 30 min of ischemia and 4 h of reperfusion, left ventricular ejection fractions were significantly higher in sIgM/MBL null mice reconstituted with MBL null or sIgM/MBL null plasma compared with reconstitution with wild-type (WT) plasma or WT mice reconstituted with WT plasma following MI/R. Serum troponin I concentration, myocardial polymorphonuclear leukocyte infiltration, and C3 deposition were dependent on the combined presence of sIgM and MBL. These results demonstrate that MI/R-induced complement activation, inflammation, and subsequent tissue injury require both IgM and MBL. Thus MBL-dependent activation of the lectin pathway may not be completely antibody independent in I/R models.
 ...
PMID:Myocardial ischemia and reperfusion injury is dependent on both IgM and mannose-binding lectin. 1974 70

Recent work reveals that the innate immune system is able to recognize self-targets and initiate an inflammatory response similar to that of pathogens. One novel example of this innate autoimmunity is ischemia/reperfusion (I/R) injury, in which reperfusion of the ischemic tissues elicits an acute inflammatory response activated by natural IgM (nIgM) binding to ischemia-specific self-antigens, which are non-muscle myosin heavy chains type II (NMHC-II) subtype A and C. Subsequently, the complement lectin pathway is activated and eventually tissue injury occurs. Although earlier studies in the intestinal model showed that the classical complement pathway did not initiate I/R injury, C1q deposition was still observed in the local injured tissues by imaging analysis. Moreover, the involvement of the alternative complement pathway became unclear due to conflicting reports using different knockout mice. To explore the immediate downstream pathway following nIgM-ischemic antigen interaction, we isolated the nIgM-ischemic antigen immunocomplexes from the local tissue of animals treated in the intestinal I/R injury model, and examined the presence of initial molecules of three complement pathways. Our results showed that mannan-binding lectin (MBL), the early molecule of the lectin pathway, was present in the nIgM-ischemic Ag immunocomplex. In addition, C1q, the initial molecule of the classical pathway was also detected on the immunocomplex. However, Factor B, the early molecule in the alternative pathway, was not detected in the immunocomplex. To further examine the role of the alternative pathway in I/R injury, we utilized Factor B knockout mice in the intestinal model. Our results showed that Factor B knockout mice were not protected from local tissue injury, and their complement system was activated in the local tissues by nIgM during I/R. These results indicated that the lectin complement pathway operates immediately downstream of the nIgM-ischemic antigen interaction during intestinal I/R. Furthermore, the classical complement pathway also appears to interact with the of nIgM-ischemic antigen immunocomplex. Finally, the alternative complement pathway is not involved in I/R injury induction in the current intestinal model.
 ...
PMID:Early complement factors in the local tissue immunocomplex generated during intestinal ischemia/reperfusion injury. 2000 73

A number of institutes have reported on the successful production of alpha-galactosyltransferase knockout (GalT-KO) pigs. After producing such pigs, hyperacute rejection appeared to no longer be a problem. However, acute vascular rejection (AVR)/acute humoral xenograft rejection (AHXR) is defined as a rejection that begins within 24 h after transplantation and gradually destroys the graft. The origin of AVR/AHXR continues to be a controversial topic, but is generally thought to be initiated by xeno-reactive antibodies, including non-Gal antibodies and subsequent activation of the graft endothelium, the complement and the coagulation systems. The complement is activated via the classical pathway by non-Gal antigens and ischemia-reperfusion injury, via the alternative pathway, especially on islets, and via the lectin pathway. Therefore the complement system is still an important recognition and effector mechanism of AVR/AHXR. In addition, quite recently, based on the relationship between complement and coagulation systems, a new pathway has been proposed. All complement regulatory proteins (CRPs) have the ability to regulate complement activation in different ways. Therefore, to effectively protect xenografts against AVR/AHXR, it appears reasonable to employ not only one but several CRPs including anti-complement drugs. Non-Gal antigens, such as the Hanganutziu-Deicher antigen, is still present on GalT-KO grafts. The further assessment of antigens continues to be an important issue in the area of clinical xenotransplantation. The above conclusions suggest that the expression of human CRPs on GalT-KO grafts is necessary. Moreover, multilateral inhibition of complement activation is required in conjunction with the regulation of the coagulation system.
 ...
PMID:Complement regulation in the GalT KO era. 2014 85

Ischemia-reperfusion injury is the major cause of delayed graft function in transplanted kidneys, an early event significantly affecting long-term graft function and survival. Several studies in rodents suggest that the alternative pathway of the complement system plays a pivotal role in renal ischemia-reperfusion injury. However, limited information is currently available from humans and larger animals. Here we demonstrated that 30 minutes of ischemia resulted in the induction of C4d/C1q, C4d/MLB, and MBL/MASP-2 deposits in a swine model of ischemia-reperfusion injury. The infusion of C1-inhibitor led to a significant reduction in peritubular capillary and glomerular C4d and C5b-9 deposition. Moreover, complement-inhibiting treatment significantly reduced the numbers of infiltrating CD163(+), SWC3a(+), CD4a(+), and CD8a(+) cells. C1-inhibitor administration led to significant inhibition of tubular damage and tubular epithelial cells apoptosis. Interestingly, we report that focal C4d-deposition colocalizes with C1q and MBL at the peritubular and glomerular capillary levels also in patients with delayed graft function. In conclusion, we demonstrated the activation and a pathogenic role of classical and lectin pathways of complement in a swine model of ischemia-reperfusion-induced renal damage. Therefore, inhibition of these two pathways might represent a novel therapeutic approach in the prevention of delayed graft function in kidney transplant recipients.
 ...
PMID:Therapeutic targeting of classical and lectin pathways of complement protects from ischemia-reperfusion-induced renal damage. 2015 Apr 32


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>