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)

1. Ischaemia-reperfusion injury in the kidney is associated with a loss of autoregulation, an increase in renal vascular resistance (RVR), a decrease of renal blood flow (RBF) and ultimately acute renal failure. The aim of this study was to investigate the role of the release of endogenous nitric oxide (NO) in the recovery of RBF after ischaemic injury of the renal vascular bed. 2. Anaesthetized rats (thiopentone sodium; 120 mg kg-1, i.p.) were submitted to acute renal ischaemia followed by 2 or 6 h of reperfusion (I/R). Reperfusion was associated with a significant reduction in RBF, an increase in RVR, and an impairment of the vasodilator effect of acetylcholine (ACh). 3. NG-nitro-L-arginine methyl ester (L-NAME, 30 micrograms kg-1 min-1, i.v., n = 5) significantly prevented the recovery of RBF after I/R injury. Similarly, inhibition of prostanoid formation with indomethacin (5 mg kg-1, i.v., n = 4) significantly enhanced the rise in RVR associated with I/R injury. 4. Infusion of L-arginine (L-Arg; 1 or 3 mg kg-1 min-1, i.v., n = 5 and 4, respectively) or D-Arg (1 mg kg-1 min-1, i.v., n = 6), starting 30 min after occlusion, did not improve the recovery of RBF. Furthermore, infusion of L-Arg (20 mg kg-1 min-1 for 15 min; n = 4) had no effect on the I/R-induced impairment of the vasodilator responses to ACh. 5. To elucidate the relative importance of the constitutive and inducible NO synthase isoforms for the formation of NO after I/R, calcium-dependent (constitutive) and calcium-independent (inducible) NO synthase activities were measured in kidney homogenates obtained from ischaemic or non-ischaemic kidneys. A calcium-independent NO synthase activity was not detectable in kidney homogenates obtained from either sham-operated control rats or from animals subjected to I/R. Moreover, dexamethasone(3 mg kg-1, i.v., 60 min prior to I/R, n = 6), an inhibitor of the induction of NO synthase,had no effect on either RBF or RVR in rats subjected to I/R. In contrast to I/R, lipopolysaccaride(LPS, endotoxin; 5 mg kg-1, i.p., n = 3) caused a significant induction of a calcium-independent NO synthase activity in the kidney.6. These results confirm the importance of the release of vasodilator cyclo-oxygenase metabolites in the compromised renal circulation and indicate that the formation of NO derived from the constitutive, but not the inducible NO synthase, is also important for the maintenance of RBF after I/R injury of the renal vascular bed.
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PMID:Support of renal blood flow after ischaemic-reperfusion injury by endogenous formation of nitric oxide and of cyclo-oxygenase vasodilator metabolites. 768 1

There are still controversies concerning the concept and diagnosis of multiple systems organ failure (MSOF), since the term does not precisely define its true nature, and its differential diagnosis with other irrelevant clinical conditions, such as senile dysfunction of organs, agonal state, etc, remains unclarified. Our studies on both human burn patients and rat model by means of electron spin resonance (ESR) showed that there was an excessive generation of free oxygen radicals resulting in lipid peroxidation of cell membrane of various tissues. The intestine seemed to be particularly sensitive to hypoperfusion-reperfusion injury, as diamine oxidase activity of the ileum was lowered and translocation of bacteria occurred, indicating failure of intestinal mucosal barrier function. Concomitant determinations of plasma endotoxin (LPS) and tumor necrosis factor alpha (TNFa) levels showed significant elevation, especially in patients who finally developed MSOF. The data suggested that intestinally derived bacteria and/or LPS exacerbate the systemic responses initiated by ischemia reperfusion injury and the presence of large amounts of devitalized tissue. Early diagnosis is important in order to improve the prognosis. However, current criteria of diagnosis for MSOF do not conduce to an early diagnosis, as they only describe the end stage manifestations, while our therapeutic strategy should be directed against different levels of initiators, systemic mediators, and effectors of injury. Therefore, it is important to emphasize the role of septic responses in the development of the syndrome. We propose that the name of the syndrome be changed to "sepsis with organ dysfunction" or "mediator injury of organs".
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PMID:The concept and diagnosis of multiple systems organ failure. 780 37

Adenosine is an endogenous nucleoside that can modulate the function of cells involved in the inflammatory response, such as polymorphonuclear leukocytes (PMN) and monocytes. Production and release of cytokines by activated mononuclear phagocytes is an important event in the pathogenesis of ischemia-reperfusion injury, a pathologic phenomenon that is associated with excessive ATP catabolism and subsequent local release of adenosine. The "retaliatory" metabolite adenosine has been shown to interfere with PMN function, thereby attenuating the deleterious consequences of ischemia and reperfusion. In this study, we demonstrate that adenosine inhibits the production of TNF-alpha, IL-6, and IL-8 by LPS-activated human monocytes with a differential potency. The A2 receptor-specific adenosine analogues 2-chloroadenosine and 5'-N-ethylcarboxamidoadenosine (NECA) were most effective in attenuating LPS-induced cytokine production, whereas the A1-selective adenosine analogue N6-cyclopentyladenosine (CPA) was less effective, indicating that inhibition of cytokine production by adenosine is primarily an A2 receptor-mediated event. The observed inhibitory effects were not restricted to endotoxin-induced cytokine production, because adenosine also inhibited TNF-alpha production by monocytes stimulated with the proinflammatory cytokine IL-1 beta. Again, 2-chloroadenosine and NECA reduced IL-beta-induced TNF-alpha production more potently than CPA. In contrast, adenosine enhanced production of IL-6 and IL-8 by monocytes stimulated with IL-1 beta. Furthermore, only 2-chloroadenosine, but not NECA, strongly inhibited cytokine-induced IL-6 and IL-8 production. These results suggest an additional A2 receptor-mediated mechanism of retaliatory action of adenosine under pathologic conditions where cytokine production by activated mononuclear phagocytes is involved, such as ischemia-reperfusion injury and septic shock.
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PMID:Differential regulatory effects of adenosine on cytokine release by activated human monocytes. 793 Jun 19

This study addresses the hypothesis that endotoxin (LPS) is an important proximal mediator of remote organ dysfunction following intestinal reperfusion. Sprague-Dawley rats underwent intestinal ischemia for 120 min followed by 60 min of reperfusion (IIR). Animals underwent pretreatment with polymyxin B (PMB, 200 micrograms, sc) or the induction of tolerance to LPS prior to assignment to the IIR or sham group. Controls received equal volumes of normal saline. Lung and intestinal injury was quantitated using an edema index. Bile flow was quantitated by measuring the volume of bile produced per 15 min. The intestinal edema index of IIR animals pretreated with PMB was nearly 50% less than that of saline-treated animals sustaining the same injury (P < 0.05). The induction of LPS tolerance reduced the edema index of IIR animals by 28% compared to the saline-treated IIR group (P < 0.05). Neither treatment reduced this parameter to that of sham-operated controls (P < 0.05). The lung edema index of animals pretreated with PMB was 50% of that of saline-treated IIR animals (P < 0.05). This remained significantly greater than that of sham-operated controls (P < 0.05). LPS tolerance did not affect the lung edema index of animals sustaining IIR. Bile flow rates following IIR were not significantly affected by PMB or LPS tolerance. These data do not support the hypothesis that LPS is an important proximal mediator of the remote organ injury associated with IIR. However, they do suggest that LPS may be one of many mediators responsible for this injury.
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PMID:Endotoxemia and remote organ injury following intestinal reperfusion. 801 13

Inflammatory reactions induce the production of reactive oxygen species (ROS): the reverse sequence of these events is also true. Moreover, many components of these reactions interact with a synergistic effect. In this short comprehensive review we analyze some of these interactions which may have pathological effects. Inflammatory reactions are triggered off by exogenous or endogenous aggressions and are characterized by cellular and vascular events. The activated leucocytes leave the circulating blood and reach the site of the aggression where they release a large amount of ROS as well as the content of their granules. The granular content is made in a large part by molecules with killing and degradative activities such as myeloperoxidase, defensins, elastase, collagenase, cathepsins and lysozyme. The inflammatory reaction is beneficial for humans when its effects are limited to the pathogens. The insufficiency of a component of the inflammatory reaction such as the production of ROS which is seen, for example in chronic granulomatous disease, leads to severe and recurrent bacterial infections. In other situations inflammatory reactions are deleterious because they are directed against normal tissues instead or in addition to pathogens. In some cases the behaviour of the phagocytes is modified because they have been primed by inflammatory molecules such tumor necrosis factor, LPS, interleukins or interferons. Priming often leads to a decreased speed of locomotion of the leucocytes with an increased susceptibility to their stimuli. The combination of these effects leads to a premature release by the phagocytes of their killing and degradative factors. Production of ROS such as that seen during irradiation, drug metabolism, or ischemia followed by reperfusion for example, induces inflammatory reactions with a secondary amplification of ROS production. Acute ROS production can also lead to thrombosis, whereas chronic ROS production can induce a chronic inflammatory reaction of the endothelium with atherosclerosis as a possible consequence. Some examples are also given to show that ROS might control positively or negatively the activity of inflammatory molecules. The multiplicity of the cross reactions between ROS and inflammation allows to suggest that drugs that disconnect these two events might be therapeutically used.
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PMID:[Reactive oxygen species and inflammation]. 801 8

Gut ischemia/reperfusion (I/R) induces lung injury by a mechanism that involves neutrophils (PMNs). We have previously shown that endotoxin (LPS), when administered after gut I/R, amplifies this lung injury, while treatment with LPS prior to gut I/R prevents lung injury. The purpose of this study was to determine whether LPS pretreatment (Pre Rx) alters the PMN inflammatory component of the gut I/R injury. Specifically, we focused on whether LPS Pre Rx effected (i) PMN stem cell proliferation, (ii) gut I/R-induced PMN priming, and (iii) gut I/R-induced PMN lung sequestration. Bone marrow was harvested from normal and LPS-pretreated (0.5 mg/kg, ip, 3 days prior) rats, and colony forming units--granulocyte/macrophage (CFU-GM) were quantitated using a soft agar culture technique. In another experiment, normal and LPS-pretreated rats were subjected to gut I/R (45 min superior mesenteric artery occlusion/6 hr reperfusion), and blood and lungs were then harvested. The in vivo priming of PMN was assessed by measuring the difference in superoxide production (O2-) with and without the activating stimulus, N-formylmethionyl-leveyl-phenylalanine (fMLP). The quantity of myeloperoxidase (MPO) was used as an index of the number of PMN sequestered in lung tissue.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Endotoxin pretreatment inhibits neutrophil proliferation and function. 804 Nov 48

Previous studies in vitro have shown an important role for intercellular adhesion molecule-1 (ICAM-1) in adherence interactions of canine neutrophils with canine jugular vein endothelial cells and in cytotoxicity of canine neutrophils for adult cardiac myocytes. To evaluate the regulation of ICAM-1 in myocardial inflammation and its role in the pathogenesis of myocardial ischemia and reperfusion, a series of in vivo and ex vivo studies were performed in canine animals. Systemic administration of LPS elicited ICAM-1 mRNA in several tissues, including myocardium, which demonstrated increasing ICAM-1 staining on intercalated discs of cardiac myocytes. In ischemia and reperfusion protocols: (a) ICAM-1 mRNA was found in ischemic segments within 1 h of reperfusion and in both ischemic and normally perfused segments by 24 h of reperfusion; (b) expression of ICAM-1 was detected in cardiac myocytes in the ischemic region by 6 h of reperfusion; increased expression was seen thereafter as a function of time; (c) post-ischemic (but not preischemic) cardiac lymph collected at intervals from 1 to 24 h after reperfusion elicited ICAM-1 mRNA, ICAM-1 expression, and ICAM-1-dependent neutrophil adhesion in canine jugular vein endothelial cells and in cardiac myocytes with peak cytokine activity seen by 1 h; (d) extravascular localization of neutrophils was detected in ischemic areas only, and was associated with endothelium bearing high levels of ICAM-1 within 1 h of reperfusion; infiltration increased thereafter in association with increasing levels of ICAM-1 mRNA in myocardial segments and increasing levels of ICAM-1 expression on cardiac myocytes. These findings provide the first direct evidence for inflammatory regulation of ICAM-1 in ischemic and reperfused canine myocardium. They support the hypothesis that ICAM-1 participates in neutrophil-mediated myocardial damage.
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PMID:Regulation of intercellular adhesion molecule-1 (ICAM-1) in ischemic and reperfused canine myocardium. 810 98

Intestinal ischemia is considered a major factor in the development of necrotizing enterocolitis (NEC). Despite this, the majority of affected infants lack documentation of clinical events associated with obvious gut hypoperfusion. Recent evidence in adults suggests that endotoxin may impair flow in the microcirculation through alterations in erythrocyte deformability. As the gut serves as a semipermeable reservoir of endotoxin in the stressed neonate, such localized activity may result in intestinal ischemia at the microcirculatory level through alterations in the red cell membrane. This study evaluates the role of endotoxin on neonatal erythrocyte membrane viscosity. Paired anticoagulated whole blood specimens were obtained from the umbilical cord of 10 neonates at delivery. Samples were incubated with either 2 micrograms/mL of E coli endotoxin (LPS) or an equal volume of saline (control). Following incubation, erythrocytes were isolated, washed, and incorporated with the fluorescent membrane probe TMA-DPH. Membrane viscosity was assessed by spectroscopic analysis of the fluorescent emissions induced by excitation of the probe at 365 nm. Results were calculated as anisotropy and analyzed for differences by ANOVA. Endotoxin resulted in a significant increase in red cell membrane viscosity as compared to control (LPS 291.2 +/- 5.1 v Control 271.7 +/- 3.3, P < .01). As the effects of endotoxin are known to be primarily the result of white blood cell (WBC) activation, this study was repeated in an additional 10 neonates in whom WBCs were removed prior to endotoxin/saline incubation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of endotoxin on the neonatal erythrocyte. 846 42

The complement activation products C3a and C3a desArg are generated in the course of trauma, infection, tissue injury, and ischemia. We have investigated the effects of C3a and C3a desArg on gene expression and protein synthesis of TNF-alpha and IL-1 beta in PBMC. Neither C3a nor C3a desArg alone induced detectable protein or mRNA levels for TNF-alpha and IL-1 beta. C3a modulated LPS-induced TNF-alpha and IL-1 beta synthesis. In nonadherent PBMC, C3a suppressed LPS-induced synthesis of TNF-alpha (20-71% decrease by 0.2-10 microgram/ml of C3a, p less than 0.01) and IL-1 beta (19-57% decrease by 0.5-10 microgram/ml of C3a, p less than 0.01), independently of endogenous production of PGE2. C3a also suppressed LPS-induced mRNA levels for TNF-alpha and IL-1 beta. In contrast, in adherent PBMC, C3a at 5 to 20 microgram/ml enhanced LPS-induced TNF-alpha (75-188% increase, p less than 0.001) and IL-1 beta (119-274% increase, p less than 0.001) synthesis. C3a enhanced TNF-alpha and IL-1 beta mRNA levels in LPS-stimulated adherent cells. Furthermore, C3a desArg shared with C3a the ability to modulate LPS-induced mRNA and protein synthesis for TNF-alpha and IL-1 beta. These results suggest that C3a, thought to be proinflammatory, and C3a desArg, thought to be biologically inactive, are modulators of inflammation. Both C3a and C3a desArg may enhance cytokine synthesis by adherent monocytes at local inflammatory sites, while inhibiting the systemic synthesis of proinflammatory cytokines by circulating cells.
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PMID:A new biologic role for C3a and C3a desArg: regulation of TNF-alpha and IL-1 beta synthesis. 861 73

Adenosine is a potent endogenous antiinflammatory agent released by cells under metabolically unfavorable conditions. Its effects on the production of IL-10 by human monocytes were presently investigated. Pre-incubation with adenosine dose-dependently enhanced IL-10 release by TNF stimulated human monocytes (+29, +58, and +116% at 1, 10, and 100 muM, respectively.) Adenosine also significantly enhanced IL-10 production after hydrogen peroxide and LPS stimulation and dose-dependently inhibited TNF secretion. Pre-incubation was not mandatory to achieve these effects, since addition of adenosine at the time of or 30 min after the stimulus led to the same results. Blocking IL-10 with anti-IL-10 mAbs partially restored adenosine-induced TNF inhibition. The enhanced IL-10 production was not observed when cells were preincubated with adenosine A1 or A2 receptor agonists (R-phenylisopropyladenosine, 5'-N-ethylcarboxamido-adenosine, and 2-chloroadenosine) and was not affected by pretreatment with theophyllin, an antagonist of both A1 and A2 receptors, or with dipyridamole, an inhibitor of adenosine cellular uptake. In conclusion, adenosine, in the submillimolar concentration range, increases IL-10 secretion by stimulated monocytes. This phenomenon participates in TNF inhibition, a known property of adenosine, but is not mediated through the occupancy of A1 or A2 receptors. This may represent a novel antiinflammatory property of adenosine by which it could modulate inflammation and limit ischemia-reperfusion injury.
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PMID:Adenosine enhances IL-10 secretion by human monocytes. 866 14


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