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)

We tested a hypothesis that interactions between fibronectin (FN), the major extracellular matrix component, and its integrin alpha 4 beta 1 receptor is important in the development of ischemia/reperfusion injury of steatotic liver transplants. We examined the effect of connecting segment-1 (CS1) peptide-facilitated blockade of FN-alpha 4 beta 1 interaction in a well-established steatotic rat liver model of ex vivo cold ischemia followed by iso-transplantation. In this model, CS1 peptides were administered through the portal vein of steatotic Zucker rat livers before and after cold ischemic storage. Lean Zucker recipients of fatty liver transplants received an additional 3-day course of CS1 peptides after transplant. CS1 peptide therapy significantly inhibited the recruitment of T lymphocytes, neutrophil activation/infiltration, and repressed the expression of proinflammatory tumor necrosis factor-alpha and interferon-gamma. Moreover, it resulted in selective inhibition of inducible nitric oxide synthase expression, peroxynitrite formation, and hepatic necrosis. Importantly, CS1 peptide therapy improved function/histological preservation of steatotic liver grafts, and extended their 14-day survival in lean recipients from 40% in untreated to 100% in CS1-treated OLTs. Thus, CS1 peptide-mediated blockade of FN-alpha 4 beta 1 interaction protects against severe ischemia/reperfusion injury experienced otherwise by steatotic OLTs. These novel findings document the potential of targeting FN-alpha 4 beta 1 in vivo interaction to increase the transplant donor pool through modulation of marginal steatotic livers.
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PMID:Fibronectin-alpha 4 beta 1 integrin-mediated blockade protects genetically fat Zucker rat livers from ischemia/reperfusion injury. 1265 15

Inflammation has been reported to play an important role in cardiac surgery under cardiopulmonary bypass due to systemic endotoxemia. In order to develop strategies against this injury in future we studied the combined effect of a number of inflammatory mediators in myocardial ischemia/reperfusion. Coronary sinus blood samples of ten patients undergoing coronary artery bypass graft surgery (CABG) were obtained at three time intervals (1) before onset of bypass (2) 30 min after cross clamp, and (3) 10 min after removal of cross clamp. The samples were subjected to evaluate levels of nitric oxide byproducts (nitrite and nitrate and citrulline), inflammatory cytokines (interleukin-2, interferon-gamma and interleukin-6), adhesion molecules, (CD62L and CD54), ratio of cell surface markers (CD4/CD8 and TCRalphabeta/gammadelta) cell activation markers (CD69 and HLA DR) and second messengers (protein kinase C, inositol 1,4,5 triphosphate and intracellular calcium levels). Ischemia and further reperfusion resulted in significant rise in nitrite and nitrate levels (p < 0.001), interleukin-6 (p < 0.01), CD62L (p < 0.001), CD69 (p < 0.05), protein kinase C (p < 0.001) and intracellular calcium (p < 0.001). A fall in CD4/CD8 ratio was observed on reperfusion. These changes during CABG show that ischemia/reperfusion leads to a release of an array of pro-inflammatory mediators of tissue injury, which could lead to pathophysiological changes. Hence the study suggests the need of some protective therapies against these inflammatory markers.
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PMID:Release of pro-inflammatory mediators during myocardial ischemia/reperfusion in coronary artery bypass graft surgery. 1284 27

Giant-cell arteritis is an immune-mediated disease characterized by granulomatous infiltrates in the wall of medium-size and large arteries. The immunopathology consists of 2 components. Excessive cytokine production (for example, of interleukin-1 and interleukin-6) induces systemic inflammation with an exuberant acute-phase response. In parallel, interferon-gamma, which is released by T cells captured in the arterial wall, activates tissue-injurious macrophages. In response to the immune injury, the artery generates hyperplasia of the intima that leads to luminal occlusion and subsequent tissue ischemia. Despite the systemic character of the disease, distinct vascular territories are preferentially affected. On the basis of the predominant involvement, clinical subtypes can be distinguished: cranial giant-cell arteritis with ischemic complications in the eye, the face, and the central nervous system; large-vessel giant-cell arteritis with occlusions in the subclavian or axillary vessels; aortic giant-cell arteritis; giant-cell arteritis presenting as an intense systemic inflammatory syndrome with nonstenosing vasculitis; and "isolated" polymyalgia rheumatica with myalgias, systemic inflammation, and subclinical vasculitis. Temporal artery biopsy remains the diagnostic procedure of choice to detect arteritis in cranial vessels. In other vascular territories, giant-cell arteritis is most commonly diagnosed by vascular imaging. Laboratory studies characteristically document the marked elevations of nonspecific acute-phase reactants, such as C-reactive protein and erythrocyte sedimentation rate. Cytokines, such as interleukin-6, that induce the acute-phase reaction are currently being explored as more sensitive biological markers of disease activity. Corticosteroids are highly effective in suppressing systemic inflammation, but they do not eliminate the immune responses in the vessel wall. In general, the clinical outcome of giant-cell arteritis is excellent, and efforts must now concentrate on tailoring therapies to the needs of the individual patient.
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PMID:Giant-cell arteritis and polymyalgia rheumatica. 1367 49

Periventricular leukomalacia (PVL), the major lesion underlying cerebral palsy in survivors of prematurity, is characterized by focal periventricular necrosis and diffuse gliosis of immature cerebral white matter. Causal roles have been ascribed to hypoxiaischemia and maternal-fetal infection, leading to cytokine responses, inflammation, and oligodendrocyte cell death. Because interferon-gamma (IFN-gamma) is directly toxic to immature oligodendrocytes, we tested the hypothesis that it is expressed in PVL (N = 13) compared to age-adjusted controls (N = 31) using immunocytochemistry. In PVL, IFN-gamma immunopositive macrophages were clustered in necrotic foci, and IFN-gamma immunopositive reactive astrocytes were present throughout the surrounding white matter (WM). The difference in the number of IFN-gamma immunopositive glial cells/high power field (IFN-gamma score, Grades 0-3) between PVL cases (age-adjusted mean 2.59+/-0.25) and controls (age-adjusted mean 1.39+/-0.16) was significant (p<0.001). In the gliotic WM, the IFN-gamma score correlated with markers for lipid peroxidation, but not nitrative stress. A subset of premyelinating (04+) oligodendrocytes expressed IFN-gamma receptors in PVL and control cases, indicating that these cells are vulnerable to IFN-gamma toxicity via receptor-mediated interactions. In PVL, IFN-gamma produced by macrophages and reactive astrocytes may play a role in cytokine-induced toxicity to premyelinating oligodendrocytes as part of a cytokine response stimulated by ischemia and/or infection.
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PMID:Interferon-gamma expression in periventricular leukomalacia in the human brain. 1577 42

The pro-inflammatory cytokine interferon-gamma (IFNgamma) has traditionally been associated with inflammatory CNS disease and more recently with ischemia-induced pathology. Using a murine model of focal cerebral ischemia, we found no evidence for induction of IFNgamma mRNA after permanent middle cerebral artery occlusion. In addition, we found that mice deficient in IFNgamma or IFNgamma receptors developed neocortical infarcts similar in size to those in wild type. In contrast, MBP promoter-IFNgamma-transgenic mice consistently developed significantly larger infarcts than non-transgenic mice. Because IFNgamma is a potent activator of microglia-macrophages, we investigated the involvement of microglial-macrophage-derived TNF in the larger infarcts. Numbers of TNF mRNA-expressing microglia-macrophages and levels of TNF mRNA and TNF in IFNgamma-transgenic and non-transgenic mice were similar. Furthermore, the ischemic brain damage in IFN-gamma-transgenic mice was unaffected by recombinant soluble TNF receptor I. Taken together, the data argues against a role for IFNgamma in cerebral ischemia under normal conditions. However, when present, IFNgamma significantly exacerbates ischemia-induced brain damage by mechanisms that appear to be independent of TNF or synergistic neurotoxic interactions of IFNgamma and TNF Irrespective of the mechanism(s) involved, this enhancing effect of IFNgamma on ischemia-induced neurotoxicity may need to be considered in diseases where immune IFNgamma is involved, such as multiple sclerosis.
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PMID:A role for interferon-gamma in focal cerebral ischemia in mice. 1545 93

During the transplant process, the graft is exposed to numerous events, which may enhance its immunogenicity. In particular, factors related to brain death, such as hemodynamic instability and systemic release of cytokines, cold preservation on harvesting, and reperfusion injury, are known to accumulate in harm, conveying a proinflammatory state to the graft before transplant. Alloimmune reactivity is initiated when the host immune system detects non-self-antigens in the context of "danger signals." Eliminating these danger signals by modifying the graft before transplant has the potential to attenuate the alloimmune response. The molecules, which mediate danger signals, have not yet been fully identified. Free oxygen radicals and interferon-gamma are important candidates. One of the most important protective mechanisms against oxidative stress is the heme oxygenase 1 system. Up-regulation of heme oxygenase 1 in grafts has been shown to prevent ischemia-reperfusion damage and improve long-term graft survival in various transplant models. The benefit of blocking the action of interferon-gamma in kidney transplants is less clear because the compound plays such a complex and pivotal role in the immune response, and experimental data with interferon-gamma receptor knockout mice are conflicting. It has recently become clear that catecholamines are important graft-modifying agents. Dopamine is capable of stimulating the induction of protective enzymes like heme oxygenase-1 (HO-1) rendering the organ more resistant to the insult of ischemia/reperfusion and inflammation. Retrospective clinical data suggest that treatment of brain-dead organ donors with catecholamines is associated with less rejection and a better long-term graft survival of kidneys transplanted from these donors. Catecholamines can also modulate cytokine production and prevent cold-induced damage. Other substances, such as proteoglycans and phosphatidylethanolamine-bound hyaluronic acid, may interfere with the actions of interferon-gamma. Further studies of these compounds in experimental animal models and in prospective randomized clinical trials will help establish their efficacy in donor pretreatment. It is important to underscore that donor pretreatment will have great advantages for the recipient because an improved long-term graft survival could thus be achieved cost-efficiently and without great effort or side effects.
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PMID:Preconditioning strategies to limit graft immunogenicity and cold ischemic organ injury. 1555 55

Inflammatory processes play a crucial role in the pathogenesis of atherosclerosis and other vascular disorders. We hypothesized that ischemia of the ductus arteriosus might initiate an active inflammatory response that could play a role in ductus remodeling and permanent closure. To test this hypothesis, we studied effects of postnatal ductus construction on inflammatory processes and remodeling in late-gestation fetal and newborn baboons, and preterm newborn baboons. After postnatal ductus constriction, the expression of several genes known to be essential for atherosclerotic remodeling [vascular cell adhesion molecule (VCAM)-1, E-selectin, IL-8, macrophage colony stimulating factor-1, CD154, interferon-gamma, IL-6, and tumor necrosis factor-alpha] was increased in the ductus wall. We were unable to detect intercellular adhesion molecule (ICAM)-1, ICAM-2, P-selectin, monocyte chemoattractant protein-1, or IL-1 by either real-time PCR or immunohistochemistry. VCAM-1, which is newly expressed by luminal cells of the closed ductus, is an important ligand for the mononuclear cell adhesion receptor VLA4. After postnatal constriction, VLA4+ monocytes/macrophages (CD68+ and CD14+) and, to a lesser extent, T-lymphocytes adhered to the ductus wall. Neutrophils and platelets were not observed. The extent of postnatal neointimal remodeling (both endothelial cell layering and subendothelial space thickening) was associated with the degree of mononuclear cell adhesion. Similarly, the extent of vasa vasorum ingrowth correlated with the invasion of CD68+ cells, from the adventitia into the muscle media. Based on these data, we conclude that the inflammatory response following postnatal ductus constriction may be as necessary for ductus remodeling as it is for atherosclerotic remodeling.
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PMID:The role of monocyte-derived cells and inflammation in baboon ductus arteriosus remodeling. 1561 59

The immune system is a system of dynamic equilibrium, with inflammatory responses (mediated by T helper type 1 cells, interleukin [IL]-1beta, interferon-gamma, and tumor necrosis factor-alpha [TNF-alpha]) being balanced by anti-inflammatory responses (mediated by T regulatory type 1 cell, T helper type 3 cells, IL-4, IL-10, and transforming growth factor-beta). Therefore, neutralization of inappropriate inflammatory cytokines is a therapeutic strategy that has been attempted in many chronic inflammatory conditions, mostly targeting TNF-alpha, using either monoclonal antibodies or modified receptor proteins (etanercept). There is functional redundancy among the inflammatory cytokines. For example, in addition to TNF-alpha, both IL-1beta and IL-6 are elevated in patients with chronic heart failure (CHF); thus neutralizing the activity of TNF-alpha alone may be an inadequate approach in this patient group. Immune-modulation therapy (IMT) results in downregulation of proinflammatory cytokine levels and upregulation of anti-inflammatory cytokines. This alteration in the balance between proinflammatory and anti-inflammatory cytokines may be more appropriate than neutralizing the activity of a single cytokine in the treatment of conditions such as CHF. Several animal studies investigating the effect of IMT in inflammatory conditions including allergic contact hypersensitivity, ischemia reperfusion injury, and atherogenesis are reviewed.
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PMID:Biologic effects and basic science of a novel immune-modulation therapy. 1592 61

Peroxisome proliferator-activated receptors (PPARs) are involved in energy expenditure, regulation of inflammatory processes, and cellular protection in peripheral tissues. Among the different types of PPARs, PPARbeta is the only one to be widely expressed in cortical neurons. Using PPARbeta knockout (KO) mice, we report here a detailed investigation of the role of PPARbeta in cerebral ischemic damage, associated inflammatory and antioxidant processes as well as food intake regulation after middle cerebral artery occlusion (MCAO). The PPARbeta KO mice had a two-fold increase in infarct size compared with wild-type (WT) mice. Brain oxidative stress was dramatically enhanced in these KO mice, as documented by an increased content of malondialdehyde, decreased levels of glutathione and manganese superoxide dismutase, and no induction of uncoupling protein 2 (UCP2) mRNA. Unlike WT mice, PPARbeta KO mice showed a marked increase of prooxidant interferon-gamma but no induction of nerve growth factor and tumor necrosis factor alpha after MCAO. In WT mice, MCAO resulted in inflammation-specific transient hyperphagia from day 3 to day 5 after ischemia, which was associated with an increase in neuropeptide Y (NPY) mRNA. This hyperphagic phase and NPY mRNA induction were not observed in PPARbeta KO mice. Furthermore, our study also suggests for the first time that UCP2 is involved in MCAO food intake response. These data indicate that PPARbeta plays an important role in integrating and regulating central inflammation, antioxidant mechanisms, and food intake after MCAO, and suggest that the use of PPARbeta agonists may be of interest for the prevention of central ischemic damage.
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PMID:Increased infarct size and lack of hyperphagic response after focal cerebral ischemia in peroxisome proliferator-activated receptor beta-deficient mice. 1609 19

The current models of liver ischemia/reperfusion injury (IRI) in mice are largely limited to a warm ischemic component. To investigate the mechanism of hepatic "cold" IRI, we developed and validated a new mouse model of prolonged cold preservation followed by syngeneic orthotopic liver transplantation (OLT). Two hundred and forty-three OLTs with or without rearterialization and preservation in University of Wisconsin solution at 4 degrees C were performed in Balb/c mice. The 14-day survivals in the nonarterialized OLT groups were 92% (11/12), 82% (9/11), and 8% (1/12) after 1-hour, 6-hour and 24-hour preservation, respectively. In contrast, hepatic artery reconstruction after 1-hour, 6-hour, and 24-hour preservation improved the outcome as evidenced by 2-week survival of 100% (12/12), 100% (10/10), and 33% (4/12), respectively, and diminished hepatocellular damage (serum alanine aminotransferase /histology). Moreover, 24-hour (but not 1-h) cold preservation of rearterialized OLTs increased hepatic CD4+ T-cell infiltration and proinflammatory cytokine (tumor necrosis factor-alpha, interleukin 2, interferon-gamma) production, as well as enhanced local apoptosis, and Toll-like receptor 4/caspase 3 expression. These cardinal features of hepatic IRI validate the model. In conclusion, we have developed and validated a new mouse model of IRI in which hepatic artery reconstruction was mandatory for long-term animal survival after prolonged (24-h) OLT preservation. With the availability of genetically manipulated mouse strains, this model should provide important insights into the mechanism of antigen-independent hepatic IRI and help design much needed refined therapeutic means to combat hepatic IRI in the clinics.
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PMID:Inflammatory responses in a new mouse model of prolonged hepatic cold ischemia followed by arterialized orthotopic liver transplantation. 1618 55


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