UMLS:C0022116 - FACTA Search

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Query: UMLS:C0022116 (ischemia)
91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the past few years tumor necrosis factor (TNF), also known as cachectin, has been isolated, cloned and now human recombinant TNF is available. This cytokine has numerous actions, which can be divided into four groups: 1) antitumor function; 2) immunomodulating activity and function in the inflammatory response; 3) effects on metabolism; 4) other functions. TNF was first identified for its anticancer activity; it is able to induce hemorrhagic necrosis in subcutaneously implanted tumors, due to the induction of free radicals in tumor cells and to vascular damage. It can also activate T-lymphocytes to become lymphokine-activated killer cells (LAK cells) against tumors. TNF also plays an important role in the inflammatory response: it mediates many of the immunologic features of T-cell function and of infection, and is essential in septic shock. TNF is a cause of the hypertriglyceridemia and the cachexia that characterize chronic infections and neoplasms. In vitro this cytokine causes growth of vascular endothelial cells; this observation suggests that it could have an atherogenic role. In in vivo experiments severe hepatic ischemia-reperfusion injury results in TNF release with subsequent local and systemic injury that was significantly reduced by anti-TNF antiserum pretreatment. Thus, TNF could be a cause of ischemic tissue damage. In conclusion, while TNF is known to play many roles, the intercellular network of the cytokines is not yet sufficiently understood and so we are only just beginning to comprehend the full implication of this important molecule in both histology and pathology.
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PMID:[Tumor necrosis factor: a cytokine with multiple actions]. 156 77

Although the shock syndrome is recognized as a form of "mediator poisoning", a plethora of details is hardly converging into a coherent concept of chronological and molecular order. As a model for organ failure in septic shock, three alternative experimental approaches with a common pathology are presented: When galactosamine-sensitized mice receive either lipopolysaccharide or leukotriene D4 or tumor necrosis factor alpha they develop fulminant hepatitis within few hours with a lethal outcome within one day. Detailed pharmacological intervention studies allow to conclude that endotoxin-induced leukotriene D4 release induces a transient ischemia by the known vasoconstrictive action of this eicosanoid. A following reperfusion/reoxygenation phase gives rise to superoxide formation which inactivates alpha 1 proteinase inhibitor. Thus a serine protease becomes active which is responsible for the processing of a monocytic tumor necrosis factor alpha precursor to be released into the circulation after proteolytic cleavage. By this sequence the final central mediator of shock and sepsis becomes systematically abundant. The concept arising from these studies reconciles previously known findings and provides a link between the role of reactive oxygen species in inflammation, the balance of proteases and antiproteases in the extracellular space and the release of the cytokine tumor necrosis factor in sepsis and shock.
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PMID:Reactive oxygen species, antiproteases, and cytokines in sepsis. 179 93

PAF is a phospholipid formed from the action of phospholipase A2 upon cellular membranes in response to immunologic or hypoxic stimuli. PAF does not exist in its active form as a storage product within cells, but is synthesized rapidly after phospholipase A2 activation. A potent lipid released by multiple cell types in mammalian systems, the emerging perspective is that PAF is a major endogenous mediator influencing the pathogenesis and outcome of ischemia and conditions of circulatory shock. These effects appear to be especially relevant to the syndrome of MSOF during critical illness. All of the major criteria for validation of a shock factor have been fulfilled for PAF. First, PAF has been measured in biological fluid of animals during shock states, although this is not an easy task since PAF is formed in minute amounts and is rapidly metabolized. Nevertheless, combinations of high pressure liquid chromatography (HPLC) and bioassay methods employing washed rabbit platelets have been successfully utilized in this regard. Second, synthetic PAF has been injected into cell suspensions, isolated tissues, and live animals, where it produces most of the effects attributed to endogenous PAF released by immunologic or hypoxic stimuli. These studies have shown that PAF exerts a variety of pathophysiologic actions, including (1) cardiodepression (that is, a negative inotropic effect), (2) reductions in systemic blood pressure, (3) leakage of fluid from the microvasculature, (4) bronchoconstriction, and (5) platelet aggregation. All of these actions of PAF can initiate or exacerbate shock and ischemic injury in multiple organ systems. Third, specific PAF receptor antagonists have been found to markedly attenuate the severity of endotoxic, anaphylactic, hemorrhagic, and traumatic shock, as well as acute myocardial ischemia. In all these conditions, a variety of PAF receptor antagonists (including PAF analogues and structurally dissimilar substances) have improved survival and have retarded pathophysiologic processes believed to be important in causing tissue injury. These processes include lysosomal membrane damage and proteolysis. Moreover PAF receptor antagonists attenuate the release of secondary toxic factors in shock, such as myocardial depressant factor. Thus, administration of specific PAF receptor antagonists early in the course of circulatory shock and organ ischemia may prove to be useful therapeutic agents in a variety of life-threatening disorders. In addition to having direct actions, PAF appears to function as a pivotal agent in a chain of mediators producing tissue injury. Recent evidence suggests that tumor necrosis factors (i.e., cachectin) stim
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PMID:Induction of tissue injury and altered cardiovascular performance by platelet-activating factor: relevance to multiple systems organ failure. 265 Aug 21

Traumatology deals with two different types of shock - the early hypovolemic-traumatic, and the late, so called septic shock, which is often associated with multi-organ failure. Both types of shock are triggered by several mediator systems of humoral and cellular origin, with numerous interactions between each other. In hypovolemic-traumatic shock central events are a perfusion deficit (ischemia with reperfusion injury via the xanthine-xanthine oxidase system) and activation of the humoral axis - of coagulation, of fibrinolysis, of the complement and kallikrein-kinin system by injured tissue. Coagulation and complement are responsible for the activation of platelets and granulocytes respectively. These cells further interact with each other e.g. via platelet activation factor, which finally causes tissue damage. Granulocytes play a central role because of their ability to release oxygen radicals and neutral proteinases, which can be monitored (elastase) and probably used to predict organ failure. The gut area is less resistant to the events of shock and therefore is a "locus minoris resistentiae" for further development of endotoxemia, bacteremia, septic shock and multi-organ failure without a typical septic focus. By this "septic challenge" further mediator systems get involved, especially those of macrophages like interleukin-1 or cachectin. Similar to the activation marker of PMN-elastase, we could demonstrate that it was possible to use neopterin for monitoring macrophage activation in sepsis and organ failure. By the action of these cellular elements in microcirculation at the endothelial and interstitial level tissue damage occurs, which finally leads to individual and multi-organ failure.
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PMID:[Current findings in the pathogenesis of the shock process in traumatology]. 328 34

We studied cytotoxic effects (CTE) induced in confluent cultures of human umbilical vein endothelial cells (HUVEC) by initiators of free-radical reactions (FRR): H2O2 (10(-6)-10(-9) M), recombinant human tumor necrosis factor-[symbol; see text] (TNF-alpha, 0.05-100 ng/ml), and a combination of TNF-alpha with low-density lipoproteins (LDL, 100 microgram/ml). HUVEC were incubated with these substances for 6 or 24 h in parallel tests performed under aerobic (CO2-incubator) and ischemic conditions (a mixture of 95% N2 + 5% CO2 in RPMI-1640 medium containing no substrate additives, growth factor or protein). HUVEC viability was determined by counting cells adherent to the bottom of wells after 24 h of reincubation under aerobic conditions in the growth medium (Plating Efficiency Index). The data showed that: 1) CTE of these compounds were dose-dependent (H2O2 and TNF-alpha) and time-dependent (TNF-alpha); 2) CTE of FRR initiators and CTE of ischemia were synergistic, that is, their combination produced a greater decrease HUVEC viability than any substance examined or ischemia alone; 3) CTE of TNF-alpha observed in experiments in substrate-deficient, protein-free medium was considerably stronger than in the growth medium; 4) a combination of TNF-a and LDL caused a stronger CTE on HUVEC than either factor alone, and this synergism was more pronounced during incubation under ischemic conditions. Thus, the data indicate that FRR initiators and TNF-alpha + LDL particularly increase the severity of ischemic injuries of EC and therefore they can be factors which in hypercholesterolemic patiens predispose vascular wall to atherosclerosis.
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PMID:[Comparative evaluation of the cytotoxic effect of hydrogen peroxide and tumor necrosis factor alpha on nonischemic and ischemic endothelial cells]. 970 22

In the present study, we examined the role of nitric oxide (NO) in early-response cytokine production by using a rat model of hepatic ischemia-reperfusion (HI/R). The left and median lobes of the liver were subjected to 30 min of ischemia, followed by 4 h of reperfusion. Group I and II rats were sham-operated controls that received saline (vehicle) or N(W)-nitro-L-arginine methylester (L-NAME) (10 mg/kg, iv); group III and IV rats were subjected to HI/R and received vehicle or L-NAME (10 mg/kg, iv, 10 min before reperfusion), respectively. Administration of L-NAME to rats subjected to I/R resulted in a fourfold decrease in plasma NO levels, accompanied by a marked increase of plasma alanine aminotransferase (ALT) activity relative to group III. These changes in group IV were associated with elevation of superoxide generation in ischemic liver lobes by 2.1-fold and circulating leukocyte number by 1.42-fold, compared with group III. Normalized for expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) messenger ribonucleic acid (mRNA), expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) mRNA in ischemic liver of group IV was augmented by 207% and 175% compared with Group III. The expression of (iNOS) mRNA was also increased (223%) relative to group III. Moreover, in group IV, plasma TNF-alpha levels at 4 h of reperfusion and IL-1beta levels at 90 min and 4 h of reperfusion were significantly increased compared with group III. No statistically significant changes were observed between groups I and II in plasma ALT activity, plasma NO levels, circulating leukocyte counts, superoxide generation in the ischemic lobes of liver, and plasma TNF-a and IL-1beta concentrations. The observed enhancement of I/R injury by L-NAME is consistent with the hypothesis that endogenous NO down-regulates TNF-alpha and IL1beta generation, thereby decreasing HI/R injury.
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PMID:Role of endogenous nitric oxide in TNF-alpha and IL-1beta generation in hepatic ischemia-repefusion. 1071 79

In reconstructive microsurgery of free tissue transfer, ischemia-reperfusion (IR) injury is an unavoidable component of the procedure, which can affect free flap survival markedly. A notable amount of evidence implicates neutrophils in IR injury. Transforming necrosis factor alpha (TNF-alpha) is known to have a central role as a mediator of neutrophil activation in IR injury. The effect of inflammatory stimuli, TNF-alpha, on flow hemodynamics and leukocyte-endothelial interactions in the muscle flaps submitted to IR injury was investigated. In group 1, 6 rats were administered 1 ml of vehicle solution. In group II rats (N = 6), 1 ml of recombinant human TNF-alpha (10 ng per milliliter) was injected intra-arterially. After an hour of ischemia, the cremaster muscle flaps were monitored at 1-hour intervals during 6 hours of reperfusion. After clamp removal, the number of rolling, adhering, and transmigrating leukocytes in the TNF-alpha group was increased by 4-fold, 3-fold, and 3.5-fold respectively compared with the control group (p < 0.05). The increase in rolling leukocytes continued for as long as 3 more hours, whereas the number of adhering and transmigrating leukocytes remained high throughout the experiment. A significant increase in the diameters of the third- and fourth-order arterioles in the TNF-a group was accompanied by a decrease in the number of flowing capillaries at all intervals (p < 0.05). The effect of TNF-alpha-induced inflammation on leukocyte activation was found to be maximal during the first 3 hours of reperfusion. The vasodilatory effect of TNF-alpha was observed only on the third- and fourth-order arterioles.
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PMID:Acute alterations in muscle flap microcirculation during tumor necrosis factor alpha-induced inflammation. 1175 37

Over-production of tumor necrosis factor-alpha (TNF-alpha) following myocardial ischemia-reperfusion contributes to cardiac dysfunction, and anti-TNF-alpha has therapeutic potential for myocardial protection in cardiac surgery with obligatory ischemia. It remains unclear, however, whether myocardial TNF-alpha production occurs during ischemia and whether cardiac myocytes constitute a source of myocardial TNF-alpha. Ischemia alone has been shown to activate myocardial NF-kappaB. We hypothesized that ischemia alone is sufficient to induce myocardial TNF-alpha gene expression and peptide synthesis. We examined TNF-alpha production and NF-kappaB activation in the isolated rat heart subjected to global normothermic ischemia. Myocardial ischemia resulted in rapid IkappaB-alpha degradation and NF-kappaB activation. Immunofluorescence staining detected NF-KB intranuclear translocation primarily in myocardial interstitial cells. Ischemia alone induced a time-dependent increase in myocardial TNF-alpha. TNF-alpha peptide increased to 20.3+/-3.0 pg/mg after 25 min of ischemia (P < 0.05 vs 8.9+/-2.0 pg/mg in perfusion control). TNF-alpha was also localized to myocardial interstitial cells. Increased TNF-alpha peptide level correlated with TNF-alpha mRNA expression. We conclude that ischemia alone induces TNF-a gene expression and peptide synthesis in the myocardium that are associated with NF-kappaB activation. Non-myocytes constitute the main source of myocardial TNF-alpha following ischemia. The results suggest that therapeutic strategies attempting to decrease myocardial TNF-alpha production need to be applied before or in the early phase of ischemia.
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PMID:Ischemia alone is sufficient to induce TNF-alpha mRNA and peptide in the myocardium. 1183 86

Although tumor necrosis factor-a (TNF-alpha) has been shown to play a critical role in the pathologic process leading to ischemia/reperfusion (I/R)-induced liver injury in rats by activating neutrophils, it is not clear whether or not microthrombus formation induced by TNF-alpha contributes to the liver injury. In the present study, we investigated the role of microthrombus formation in I/R-induced liver injury in rats. Hepatic tissue levels of TNF-alpha were significantly increased after reperfusion, and these were higher in animals subjected to 120 min-hepatic I/R than in those subjected to 60 min-hepatic I/R. Fibrin deposition was observed histologically in the hepatic sinusoidal space only in animals subjected to 120 min-hepatic I/R. Both the decrease in hepatic tissue blood flow and the extent of liver injury in animals subjected to 60 min- and 120 min-hepatic I/R were significantly inhibited by pretreatment with anti-rat TNF-a antibody. Although neutrophil elastase inhibitors inhibited the decrease in hepatic tissue blood flow and reduced liver injury in animals subjected to 60 min-hepatic Y/R, anticoagulants did not show any effects. Both anticoagulants and neutrophil elastase inhibitors inhibited the decrease in hepatic tissue blood flow and reduced liver injury in animals subjected to 120 min-hepatic I/R. Therapeutic effects of anti-rat TNF-a antibody on the 120 min-I/R-induced liver injury were more marked than those of each anticoagulant or each neutrophil elastase inhibitor, and were comparable to those of combined use of anticoagulants and neutrophil elastase inhibitors. These observations strongly suggest that TNF-alpha induces I/R-induced liver injury primarily by activating neutrophils, and it exacerbates liver injury by inducing microthrombus formation when the production of TNF-alpha is further increased.
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PMID:Role of microthrombus formation in the development of ischemia/reperfusion-induced liver injury in rats. 1235 78

Preeclampsia remains a leading cause of maternal death and perinatal morbidity and still the pathophysiological mechanisms of the disease remain largely unknown. The most well accepted hypothesis for the genesis of the disease is that placental ischemia/hypoxia results from inadequate remodeling of the maternal uterine spiral arteries, which leads to a decrease in uteroplacental blood flow. Subsequently factors are released from the ischemic placenta showering the maternal vascular endothelium. These factors include a host of molecules such as the soluble VEGF receptor-1 (sFlt-1), the angiotensin II type-1 receptor autoantibody (AT1-AA), and cytokines such as TNF-a and Interleukin 6 which in turn generate widespread dysfunction of the maternal vascular endothelium. This dysfunction results in elevated circulating endothelin (ET-1), reactive oxygen species (ROS), and augmented vascular sensitivity to angiotensin II as well as decreased formation of vasodilators such as nitric oxide and prostacyclin. These alterations in vascular function lead to hypertension with multi-organ dysfunction, especially in cases of early onset preeclampsia. Therefore, identifying the connection between placental ischemia and maternal cardiovascular abnormalities is an important area of investigation.
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PMID:The role of immune activation in contributing to vascular dysfunction and the pathophysiology of hypertension during preeclampsia. 2050 23

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