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)

Cerebral ischemia triggers acute inflammation, which exacerbates primary brain damage. Activation of the innate immune system is an important component of this inflammatory response. Inflammation occurs through the action of proinflammatory cytokines, such as TNF, IL-1 beta and IL-6, that alter blood flow and increase vascular permeability, thus leading to secondary ischemia and accumulation of immune cells in the brain. Production of these cytokines is initiated by signaling through Toll-like receptors (TLRs) that recognize host-derived molecules released from injured tissues and cells. Recently, great strides have been made in understanding the regulation of the innate immune system, particularly the signaling mechanisms of TLRs. Negative feedback inhibitors of TLRs and inflammatory cytokines have now been identified and characterized. It is also evident that lipid rafts exist in membranes and play a role in receptor-mediated inflammatory signaling events. In the present review, using this newly available large body of knowledge, we take a fresh look at studies of ischemic tolerance. Based on this analysis, we recognize a striking similarity between ischemic tolerance and endotoxin tolerance, an immune suppressive state characterized by hyporesponsiveness to lipopolysaccharide (LPS). In view of this analogy, and considering recent discoveries related to molecular mechanisms of endotoxin tolerance, we postulate that inhibition of TLR and proinflammatory cytokine signaling contributes critically to ischemic tolerance in the brain and other organs. Ischemic tolerance is a protective mechanism induced by a variety of preconditioning stimuli. Tolerance can be established with two temporal profiles: (i) a rapid form in which the trigger induces tolerance to ischemia within minutes and (ii) a delayed form in which development of protection takes several hours or days and requires de-novo protein synthesis. The rapid form of tolerance is achieved by direct interference with membrane fluidity, causing disruption of lipid rafts leading to inhibition of TLR/cytokine signaling pathways. In the delayed form of tolerance, the preconditioning stimulus first triggers the TLR/cytokine inflammatory pathways, leading not only to inflammation but also to simultaneous upregulation of feedback inhibitors of inflammation. These inhibitors, which include signaling inhibitors, decoy receptors, and anti-inflammatory cytokines, reduce the inflammatory response to a subsequent episode of ischemia. This novel interpretation of the molecular mechanism of ischemic tolerance highlights new avenues for future investigation into the prevention and treatment of stroke and related diseases.
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PMID:Inhibition of toll-like receptor and cytokine signaling--a unifying theme in ischemic tolerance. 1554 25

Implants of collagen-fibronectin gels containing Bcl-2-transduced human umbilical vein endothelial cells (Bcl-2-HUVECs) induce the formation of human endothelial cell (EC)/murine vascular smooth muscle cell (VSMC) chimeric vessels in immunodeficient mice. Microfil casting of the vasculature 60 d after implantation reveals highly branched microvascular networks within the implants that connect with and induce remodeling of conduit vessels arising from the abdominal wall circulation. Approximately 85% of vessels within the implants are lined by Bcl-2-positive human ECs expressing VEGFR1, VEGFR2, and Tie-2, but not integrin alpha(v)beta(3). The human ECs are seated on a well formed human laminin/collagen IV-positive basement membrane, and are surrounded by mouse VSMCs expressing SM-alpha actin, SM myosin, SM22alpha, and calponin, all markers of contractile function. Transmission electron microscopy identified well formed EC-EC junctions, chimeric arterioles with concentric layers of contractile VSMC, chimeric capillaries surrounded by pericytes, and chimeric venules. Bcl-2-HUVEC-lined vessels retain 70-kDa FITC-dextran, but not 3-kDa dextran; local histamine rapidly induces leak of 70-kDa FITC-dextran or India ink. As in skin, TNF induces E-selectin and vascular cell adhesion molecule 1 only on venular ECs, whereas intercellular adhesion molecule-1 is up-regulated on all human ECs. Bcl-2-HUVEC implants are able to engraft within and increase perfusion of ischemic mouse gastrocnemius muscle after femoral artery ligation. These studies show that cultured Bcl-2-HUVECs can differentiate into arterial, venular, and capillary-like ECs when implanted in vivo, and induce arteriogenic remodeling of the local mouse vessels. Our results support the utility of differentiated EC transplantation to treat tissue ischemia.
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PMID:Induction, differentiation, and remodeling of blood vessels after transplantation of Bcl-2-transduced endothelial cells. 1562 6

The role of NF-kappaB in cardiac physiology and pathophysiology has been difficult to delineate due to the inability to specifically block NF-kappaB signaling in the heart. Cardiac-specific transgenic models have recently been developed that repress NF-kappaB activation by preventing phosphorylation at specific serine residues of the inhibitory kappaB (IkappaB) protein isoform IkappaBalpha. However, these models are unable to completely block NF-kappaB because of a second signaling pathway that regulates NF-kappaB function via Tyr42 phosphorylation of IkappaBalpha. We report the development of transgenic (3M) mouse lines that express the mutant IkappaBalpha(S32A,S36A,Y42F) in a cardiac-specific manner. NF-kappaB activation in cardiomyopathic TNF-1.6 mice is completely blocked by the 3M transgene but only partially blocked (70-80%) by the previously described double-mutant 2M [IkappaBalpha(S32A,S36A)] transgene, which demonstrates the action of two proximal pathways for NF-kappaB activation in TNF-alpha-induced cardiomyopathy. In contrast, after acute stimuli including administration of TNF-alpha and ischemia-reperfusion (I/R), NF-kappaB activation is blocked in both 2M and 3M transgenic mice. This result suggests that phosphorylation of the regulatory Ser32 and Ser36 predominantly mediates NF-kappaB activation in these situations. We show that infarct size after I/R is reduced by 70% in 3M transgenic mice, which conclusively demonstrates that NF-kappaB is involved in I/R injury. In summary, we have engineered novel transgenic mice that allow us to distinguish two major proximal pathways for NF-kappaB activation. Our results demonstrate that the serine and tyrosine phosphorylation pathways are differentially activated during different pathophysiological processes (cardiomyopathy and I/R injury) and that NF-kappaB contributes to infarct development after I/R.
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PMID:Cardiac-specific blockade of NF-kappaB in cardiac pathophysiology: differences between acute and chronic stimuli in vivo. 1569 59

Acute myocardial infarction (AMI) is a myocardial necrosis occurring due to persistent coronary ischemia, in which inflammation plays an important role and heart failure is a common complication. The present work was undertaken to clarify the role of Tumor Necrosis Factor Alpha (TNF-alpha) in acute myocardial infarction (AMI). The study was conducted on 20 newly diagnosed AMI patients and 10 healthy age and sex matched controls. Sequential estimation of plasma TNF alpha level was carried out at admission, 24 and 48 hours post admission using ELISA. AMI patients showed a significant increase of plasma TNF-alpha level on admission, and 24 hours post admission but not after 48 hours. However, a significant increase was still seen at 48 hours post admission in patients with signs of heart failure but not in those without signs of heart failure. A significant positive correlation was found between plasma TNF-alpha level and CPK level at admission. On the other hand a significant negative correlation was found between these 2 parameters at 24 and 48 hours post admission. It is concluded that TNF-alpha may be an early marker of myocardial damage because of the early increase of its level after ischemic injury instead of being late consequence of extensive tissue necrosis. TNF-alpha level may be an important indicator of the severity of AMI and the occurrence of heart failure.
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PMID:Tumor necrosis factor alpha in patients with acute myocardial infarction. 1572 84

The inhibitor of NF-kappaB (I-kappaB) kinase (IKK) complex consists of 3 subunits, IKK1, IKK2, and NF-kappaB essential modulator (NEMO), and is involved in the activation of NF-kappaB by various stimuli. IKK2 or NEMO constitutive knockout mice die during embryogenesis as a result of massive hepatic apoptosis. Therefore, we examined the role of IKK2 in TNF-induced apoptosis and ischemia/reperfusion (I/R) injury in the liver by using conditional knockout mice. Hepatocyte-specific ablation of IKK2 did not lead to impaired activation of NF-kappaB or increased apoptosis after TNF-alpha stimulation whereas conditional NEMO knockout resulted in complete block of NF-kappaB activation and massive hepatocyte apoptosis. In a model of partial hepatic I/R injury, mice lacking IKK2 in hepatocytes displayed significantly reduced liver necrosis and inflammation than wild-type mice. AS602868, a novel chemical inhibitor of IKK2, protected mice from liver injury due to I/R without sensitizing them toward TNF-induced apoptosis and could therefore emerge as a new pharmacological therapy for liver resection, hemorrhagic shock, or transplantation surgery.
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PMID:Deletion of IKK2 in hepatocytes does not sensitize these cells to TNF-induced apoptosis but protects from ischemia/reperfusion injury. 1596 93

Previous studies demonstrated that C1-inhibitor (C1-INH), a complement and contact-kinin systems inhibitor, is neuroprotective in cerebral ischemia. To investigate the mechanism of this action, we evaluated the expression of neurodegeneration and inflammation-related factors in mice subjected to 2-h ischemia and 2 or 46 h reperfusion. C1-INH significantly dampened the mRNA expression of the adhesion molecules P-selectin and ICAM-1 induced by the ischemic insult. It significantly decreased the pro-inflammatory cytokine (TNF alpha, IL-18) and increased the protective cytokine (IL-6, IL-10) gene expression. C1-INH treatment prevented the decrease of NFH gene, a marker of cellular integrity and counteracted the increase of pro-caspase 3, an apoptosis index. Furthermore, C1-INH markedly inhibited the activation and/or recruitment of microglia/macrophage, as shown by immunohistochemistry. In conclusion, C1-INH exerts an anti-inflammatory and anti-apoptotic action on ischemia-reperfusion injury. Our present and past data support a major effect of C1-INH on cell recruitment from the vasculature to the ischemic site.
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PMID:C1-inhibitor protects against brain ischemia-reperfusion injury via inhibition of cell recruitment and inflammation. 1583 56

The immune system of higher vertebrates consists of two components: the innate and adaptive immunity. While the adaptive immune system relies on somatically generated and clonally selected antigen receptors, the innate immune system detects the presence of pathogens by their evolutionarily highly conserved, relatively invariant structural motifs. Interestingly, recent data suggest that activation of the innate immune system could play an important role in various diseases without the direct involvement of infectious pathogens. For example, a number of inflammatory cytokines, including TNF (tumor necrosis factor), IL (interleukin)-1beta, IL-6 and IL-8, as well as iNOS (inducible nitric oxide synthase), all components of innate immunity, are also implicated in ischemia/reperfusion injury, and in the abnormal myocardial remodeling characteristic of chronic heart failure. Understanding of the regulation and activation of the innate immune system in diseases not obviously related to an immune response to specific pathogen could provide new therapeutic targets for cardiovascular diseases. Thus, in this review, we provide a general overview of the components of innate immunity with a focus on humoral factors, their role in the response to foreign pathogens, and their potential role in the response to tissue injury (i.e., the "Expanded Self-Non-Self" and the "Danger" theories of immune activation).
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PMID:Innate immunity and the heart. 1585 84

Nutritional supplementation with glutamine, arginine and their precursors has been proposed to contribute to the protection against ischemia-reperfusion-related injuries. The aim of this study was to evaluate in an isolated perfused rat liver model the preventive effect of a 4-day oral ornithine alpha-ketoglutarate (OKG) supplementation against warm ischemia-reperfusion (I-R) injury, and the involvement of nitric oxide synthesis. Rats were fed a controlled regimen supplemented with either OKG (5 g kg(-1); n=15) or an isonitrogenous mixture of non-essential amino acids (Control; n=6) for 4 days. Livers were subsequently prepared for isolated perfusion experiments, including a 45 min no-flow ischemic period. The OKG-treated group was divided into two groups according to the absence (OKG; n=8) or presence of a NO-synthase inhibitor, L-N(omega)-nitro-arginine methyl ester (OKG L-NAME; n=7) during liver perfusion. Liver cytolysis after ischemia was demonstrated by an elevated alanine aminotransferase release during the last 15 min of reperfusion that was significantly higher in the OKG-L-NAME group. Tumor necrosis factor alpha (TNF(alpha)) production was transiently increased only in the control group just after ischemia. At the end of the reperfusion period, liver superoxide dismutase activity was significantly lower in the OKG-L-NAME group compared to control animals. Dietary OKG administration had only a limited effect in this model of mild hepatic I-R, leading mainly to reduced TNF(alpha) production. As the content of lipid peroxidation products was not modified, it seems that OKG acts on the inflammatory response rather than on oxidative reactions. This action can tentatively be attributed to the role of OKG as a glutamine precursor rather than to the synthesis of arginine and nitric oxide.
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PMID:Does dietary ornithine alpha-ketoglutarate supplementation protect the liver against ischemia-reperfusion injury? 1589 23

Heme oxygenase (HO) has been shown to be important for attenuating the overall production of reactive oxygen species (ROS) through its ability to degrade heme and to produce carbon monoxide (CO), biliverdin/bilirubin, and the release of free iron. Excess free heme catalyzes the formation of ROS, which may lead to endothelial cell (EC) dysfunction as seen in numerous pathological conditions including hypertension and diabetes, as well as ischemia/reperfusion injury. The upregulation of HO-1 can be achieved through the use of pharmaceutical agents, such as metalloporphyrins and some HMG-CoA reductase inhibitors. Among other agents, atrial natriretic peptide and donors of nitric oxide (NO) are important modulators of the heme-HO system, either through induction of HO-1 or the biological activity of its products. Gene therapy and gene transfer, including site- and organ-specific targeted gene transfer, have become powerful tools for studying the potential role of HO-1/HO-2 in the treatment of various cardiovascular diseases as well as diabetes. HO-1 induction by pharmacological agents or gene transfer of human HO-1 into endothelial cells (ECs) in vitro increases cell-cycle progression and attenuates Ang II, TNF-, and heme-mediated DNA damage; administration in vivo acts to correct blood pressure elevation following Ang II exposure. Moreover, site-specific delivery of HO-1 to renal structures in spontaneously hypertensive rats (SHR), specifically to the medullary thick ascending limb of the loop of Henle (mTALH), has been shown to normalize blood pressure and provide protection to the mTAL against oxidative injury. In other cardiovascular situations, delivery of human HO-1 to hyperglycemic rats significantly lowers superoxide (O(2)(-)) levels and prevents EC damage and sloughing of vascular EC into the circulation. In addition, administration of human HO-1 to rats in advance of ischemia/reperfusion injury considerably reduces tissue damage. The ability to upregulate HO-1 through pharmacological means or through the use of gene therapy may offer therapeutic strategies for cardiovascular disease in the future. This review discusses the implications of HO-1 delivery during the early stages of cardiovascular system injury or in early vascular pathology and suggests that pharmacological agents that regulate HO activity or HO-1 gene delivery itself may become powerful tools for preventing the onset or progression of certain cardiovascular pathologies.
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PMID:Heme oxygenase and the cardiovascular-renal system. 1592 76

Mitogen-activated protein kinase (MAPK) 3/MAPK1 (also known as ERK1/ERK2) plays an important role in the signal transduction pathways. To our knowledge, however, its role in the development of testicular ischemia-reperfusion injury has not yet been investigated. Therefore, we studied the pattern of MAPK3/MAPK1 activation in a experimental model of testicular ischemia-reperfusion injury. We also investigated MAPK8 to understand whether an association exists between these two MAPKs. Adult male Sprague-Dawley rats were subjected to 1 h of testicular ischemia followed by 24 h of reperfusion or to a sham testicular ischemia-reperfusion. Animals were randomized to receive PD98059, which is an inhibitor of MAPK3/MAPK1 (10 mg/kg i.p. administered immediately after detorsion), or its vehicle. The time course of MAPK3/MAPK1, MAPK8, and tumor necrosis factor (TNF; also known as TNF alpha) expression and a histological examination in both the ischemic-reperfused testis and the contralateral one were performed. In both testes, MAPK3/MAPK1 and MAPK8 expression appeared following 10 min of reperfusion and reached their highest activation after 30 min. The MAPK levels slowly decreased, and no significant expression of either kinase was observed following 2 h of reperfusion. Expression of TNF was evident after 1 h of reperfusion and reached its maximum increase after 3 h. PD98059 blunted MAPK3/MAPK1 and MAPK8, reduced TNF expression, and improved the testicular damage caused by ischemia-reperfusion injury in both testes. These data emphasize that MAPK3/MAPK1 has a role in testicular damage and that its blockade might have a future therapeutic role for the management of patients with unilateral testicular torsion.
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PMID:Evidence for a role of mitogen-activated protein kinase 3/mitogen-activated protein kinase in the development of testicular ischemia-reperfusion injury. 1594 43


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