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)

The authors have previously reported a model of ischemic bowel necrosis produced in the rat by synthetic platelet-activating factor (PAF) or a combination of PAF and bacterial endotoxin. Because rat platelets are refractory to PAF and thromboemboli were not found in the mesenteric or intestinal microvasculature, they suspected that secondary mediators were involved in the pathogenesis of bowel necrosis. They have found the following lipoxygenase products of arachidonic acid, especially leukotrienes (LT), probably played an important role in the pathogenesis of bowel necrosis, because diethylcarbamazine (an inhibitor for LTA synthesis) and FPL55712 (LT antagonist) ameliorated, and at times completely prevented, the lesions. NDGA (a nonspecific lipoxygenase inhibitor) was less effective, probably because of its additional effect on cyclooxygenase inhibition. Verapamil, a calcium channel blocker, ameliorated the disease. Thromboxane A2, a potent vasoconstrictor, was probably not responsible for the ischemia of the gastrointestinal tract. This is suggested by the ineffectiveness of OKY-046 in preventing bowel necrosis. Prostaglandin (PG) E1 infusion often prevented the bowel necrosis, which suggested beneficial effects of vasodilating PGs, probably released as a defense mechanisms. Indomethacin aggravated the disease, probably by inhibiting PG release and shifting the metabolic pathway toward the lipoxygenase pathway. Antihistamine and antiserotonin had no effect, which suggested that these mediators were not involved in the pathogenesis of bowel necrosis. Shock produced by PAF was probably not the only cause of bowel necrosis, because reversal of the hypotension did not always prevent the development of bowel necrosis. Hemoconcentration (increased vasopermeability) and leukopenia induced by PAF did not correlate with the development or severity of bowel necrosis.
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PMID:Platelet-activating factor-induced ischemic bowel necrosis. An investigation of secondary mediators in its pathogenesis. 308 Aug 95

Recombinant gamma interferon (r-GIFN) demonstrates in vitro and in vivo characteristics that contrast with those of alpha and beta interferons. It has relatively weak antiviral properties, yet relatively potent immunomodulatory effects. A phase I trial was performed with r-GIFN (specific activity 2.6 X 10(6) IU/mg protein), administered as a continuous intravenous (IV) infusion over 24 hours for five days (Cl X 5) and repeated every 28 days. This schedule was chosen based on the short half-life of r-GIFN in animal systems and the in vitro augmentation of biologic effects with continuous exposure to interferons. Twenty-one patients with refractory solid tumors received 46 evaluable courses of therapy. The dose-limiting toxicities included fever, flu-like symptoms, cardiovascular toxicity, and neurotoxicity. The cardiovascular toxicity included hypotension and one episode of cardiac ischemia with chest pain. Neurotoxicity consisted of lethargy and confusion. These toxicities were reversible, and although dose-limiting, occurred sporadically throughout all dosage levels. Mild to moderately severe non-dose-limiting toxicities included nausea and vomiting, leukopenia, and liver function abnormalities. Other infrequent toxicities included hypocalcemia, diarrhea, constipation, and alopecia. The maximally tolerated dose of r-GIFN on this schedule is 0.5 X 10(6) IU/m2/d. Partial responses were seen in one patient with metastatic melanoma and in one patient with renal cell carcinoma. Toxicity and antitumor activity were seen at doses where interferon serum levels could not be detected by radioimmunoassay. In addition, the toxicity and antitumor activity seen were at much lower doses than previously described for shorter infusion schedules of other recombinant gamma interferon preparations. Differences in biologic activity of interferon preparations and/or differences in scheduling may account for this variability. Although this study defines a recommended phase II dose of r-GIFN based on the maximally tolerated dose, the optimal therapeutic index may exist at a lower dosage level.
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PMID:A phase I clinical trial of recombinant DNA gamma interferon. 310 84

The inflammatory response to trauma induces release of platelet activating factor (PAF), which promotes leukocyte adherence to the vascular endothelium. Ischemia and reperfusion induces inflammatory reactions that play a role in reperfusion injury, and here we investigate the role of both PAF and of leukocytes in damage to reperfused rat liver. The experimental procedure consisted of the temporary interruption of blood flow to the left lateral and medial lobes of the rat liver in vivo, and subsequent reperfusion after defined periods. Rats were pretreated either with the PAF-antagonist WEB-2170 or with vinblastine to induce leukopenia, and compared with controls. The postischemic liver blood flow and liver oxyhemoglobin saturation were recorded using an He-Ne Laser doppler flowmeter and photometer. Reperfusion after 30 and 45 min of ischemia was associated with partial recovery to normal values and was inversely proportional to the duration of ischemia. In the WEB-2170-treated group, liver flow and hemoglobin saturation upon reperfusion did not show significant differences when compared with the untreated control groups, suggesting that inhibition of PAF activity did not protect against the microcirculatory disturbance induced by ischemia and reperfusion in the liver. In contrast, rats made leukopenic by treatment with vinblastine showed significantly better recovery of blood flow and hemoglobin saturation than the control group after 45 min of ischemia. Thus, we found that although PAF alone did not appear to have a pivotal role in the cascade of reperfusion injury, the effect of leukocytes is critical.
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PMID:Rat liver blood flow after ischemia and reperfusion. The effects of the platelet-activating factor antagonist WEB-2170 and of removing circulating leukocytes. 819 4

The levels of ATP, ADP, and AMP in heart, brain, and kidney suffering from 10-min ischemia after decapitation in rats were determined by a modified reverse-phase HPLC set with uv detection. The ischemic depletion of ATP was alleviated and the total amount of high energy phosphates was markedly reduced by the treatment of po cyclophosphamide 20 and 100 mg.kg-1 x 3 d. The protective effect on depleting the total amount of high energy phosphates which was better preserved than ATP in ischemic organs by cyclophosphamide was evidenced in a dose-related manner. Cyclophosphamide induced leukopenia in circulating blood. Two reasons for the anti-arrhythmic effect of cyclophosphamide are suggested: 1) the depletion of leukocyte reduced the plugging effect of neutrophil in myocardial capillaries; 2) blocking the KATP channel by elevating ATP level in myocardium.
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PMID:[Protective effect on ischemic depletion of nucleotide phosphates in heart, brain, and kidney by cyclophosphamide]. 823 13

The contribution of granulocytes and their byproducts to acute gastric mucosal lesion (AGML) is unclear. Our previous study showed that granulocytes produced O2- in the gastric mucosa of rats treated with 300 mg/kg of cinchophen (cinchophen ulcer, CU) and in rats subjected to 30 min-ischemia-reperfusion (IR). The present study investigated the effects of granulocytes and O2- on microcirculatory injury (MCI) in the gastric mucosa in both models. To evaluate MCI, we measured the amount of extravasated Evans blue, and monitored changes in blood flow and the formation of vascular casts in the gastric mucosa of rats with and without leukopenia. Mucosal levels of interleukin-8 (IL-8) were also measured, to determine granulocyte migration into the stomach. Our findings were: (1) IL-8 was decreased 30-45 min after CU injection (C-I) or after the start of occlusion (S-O), and levels had increased 90 min after either treatment. (2) Evans blue increased 120-150 min after C-I or S-O. These increases were lower in leukopenic than in non-leukopenic rats. (3) The blood flow decreased after C-I or reperfusion and continued at the same level during the 180-min measurement period. In CU leukopenic rats, the blood flow decreased slowly and was restored gradually. In IR leukopenic rats, the blood flow did not decrease. (4) There was a partial lack of capillary network, narrowing of capillaries, and extravasation of resin 90-120 min after C-I and S-O, and the disturbances were reduced in leukopenic rats in both models. (5) The extravasation of resin was reduced by the administration of superoxide dismutase (SOD) at the time O2- from granulocytes was being produced. (6) These reductions in the extravasation of resin due to leukopenia or SOD were smaller in CU than in IR rats. These findings indicate that granulocytes and O2- contribute to some extent to the MCI in CU rats.
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PMID:Effects of activated granulocytes and O2- on microcirculatory injury in acute gastric mucosal lesion in rats induced by sodium cinchophen. 868 May 32

Few studies have correlated the occurrence of leukocytes with the time course of ischemia-reperfusion (I-R)-induced tissue injury in skeletal muscle. The goal of this study was to test the hypothesis that leukocytes were responsible for not only the onset, but progression of parenchymal cell injury within skeletal muscle following no-flow ischemia. Thirteen male Wistar rats (150-250 g) were randomly allocated to either a control (no I-R; n = 3), I-R (n = 5), or a leukopenic I-R group (n = 5). Under halothane anesthesia, the extensor digitorum longus muscle was prepared for intravital microscopy to allow video recording of microvascular perfusion and leukocyte flow behavior following 3 hr no-flow ischemia of the hindlimb. Tissue injury was assessed as the ratio of ethidium bromide (impermeant dye)-labeled nuclei to bisbenzimide (permeant dye)-labeled nuclei (E/B). During reperfusion, the I-R group showed a progressive decline in the number of perfused capillaries (N(C)) (from 19.37 +/- 0.04 to 3.34 +/- 1.18), while leukopenic and control rats were not significantly different. In the I-R group, the number of rolling leukocytes increased from 4.05 +/- 1.93 to 14.77 +/- 1.33 at the onset of reperfusion and remained stable throughout the reperfusion period. The number of stuck leukocytes, in the I-R group, progressively increased from 1.41 +/- 0.01 prior to ischemia to 4.66 +/- 0.01 at the onset of reperfusion to 11.96 +/- 0.01 after 90 min. The index of tissue injury (EIB) increased asymptotically from 0.60 +/- 0.02 to 0.95 +/- 0.01 after 90 min of reperfusion in the I-R group, while leukopenia significantly reduced both the magnitude of tissue injury (i.e., 35% reduction from untreated I-R group) and the onset of such injury. In spite of the benefit afforded by leukopenia, evidence of tissue injury persisted (20% above control baseline level). We conclude that although leukocytes were responsible for the onset of parenchymal injury in skeletal muscle following 3 hr no-flow ischemia they are not the sole mediators of such injury.
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PMID:Leukocyte activity and tissue injury following ischemia-reperfusion in skeletal muscle. 899 28

The participation of activated leukocytes and subsequent production of chemical mediators has been well accepted in the pathophysiology of hypoxic-ischemic injury. This study was performed to see the effects of leukocytes on hippocampal neuronal damage in transient global ischemia induced by 10-min occlusion of bilateral common carotid arteries (CCAs) with reperfusion for various times, and in complete unilateral ischemia induced by 24-hr ligation of left CCA. Leukopenia was induced by intraperitoneal injection of cyclophosphamide for 4 days. The results showed that hippocampal neuronal damages were worse at 6-hr reperfusion in leukopenic experimental group than in the control group. In comparison, 24-hr and 3-day reperfusion leukopenic groups showed less numbers of damaged neurons and milder changes. The 5-day reperfusion group showed inconsistent changes. Unilateral CCA occlusion showed extensive infarction in 83.3% of gerbils in the control group, compared to 25% of gerbils in the experimental group (p<0.05). These results strongly suggest that the number of peripheral leukocytes were closely related to the development of delayed neuronal damage of hippocampus in transient global ischemia and the incidence of infarction induced by 24-hr unilateral CCA ligation.
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PMID:The effects of peripheral leukocytes on the hippocampal neuronal changes in transient global ischemia and unilateral cerebral hemispheric infarction. 1040 74

We examined whether activated protein C (APC) reduces ischemia/reperfusion (I/R)-induced renal injury by inhibiting leukocyte activation. In a rat model, intravenous administration of APC markedly reduced I/R-induced renal dysfunction and histological changes, whereas intravenous administration of dansyl glutamylglycylarginyl chloromethyl ketone-treated factor Xa (DEGR-FXa; active-site-blocked factor Xa), heparin or diisopropyl fluorophosphate-treated APC (DIP-APC; inactive derivative of ARC) had no effect. Furthermore, APC significantly inhibited the I/R-induced decrease in renal tissue blood flow and the increase in the vascular permeability, whereas neither DEGR-FXa, heparin, nor DIP-APC produced such effects. Renal I/R-induced increases in plasma levels of fibrin degradation products were significantly inhibited by APC, DEGR-FXa, and heparin. These observations suggest that APC reduces I/R-induced renal injury independently of its anticoagulant effects but in a manner dependent on its serine protease activity. Renal levels of tumor necrosis factor-alpha (TNF-alpha), rat interleukin-8, and myeloperoxidase were significantly increased after renal I/R. These increases were significantly inhibited by APC but not by DEGR-FXa, heparin, or DIP-APC. Leukocytopenia produced effects similar to those of APC. These findings strongly suggest that APC protects against I/R-induced renal injury not by inhibiting coagulation abnormalities but by inhibiting activation of leukocytes that play an important role in I/R-induced renal injury. Inhibition of leukocyte activation by APC could be explained by the inhibitory activity of TNF-alpha. (Blood. 2000;95:3781-3787)
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PMID:Activated protein C reduces ischemia/reperfusion-induced renal injury in rats by inhibiting leukocyte activation. 2354 58

Methylprednisolone (MPS) is the only therapeutic agent currently available for traumatic spinal cord injury (SCI). However, little is known about its therapeutic mechanisms. We have demonstrated that tumor necrosis factor-alpha (TNF-alpha) plays a critical role in posttraumatic SCI in rats. Since MPS has been shown to inhibit TNF-alpha production in vitro, it is possible that MPS can reduce SCI by inhibiting TNF-alpha production. To examine this possibility, we investigated the effect of MPS on TNF-alpha production in injured segments of rat spinal cord. Leukocytopenia and high-dose intravenous administration of MPS markedly reduced the motor disturbances observed following spinal cord trauma. Both treatments also reduced the intramedullary hemorrhages observed histologically 24 hr posttrauma. Leukocytopenia significantly reduced tissue levels of both TNF-alpha mRNA and TNF-alpha, 1 and 4 hr posttrauma, respectively, and it also inhibited the accumulation of leukocytes in the injured segments 3 hr posttrauma, while MPS had no effects. Lipid peroxidation and vascular permeability at the site of spinal cord lesion were both significantly increased over time after the induction of SCI, peaking 3 hr posttrauma. These events were significantly reduced in animals with leukocytopenia and in those given anti-P-selectin monoclonal antibody compared to sham-operated animals. Administration of MPS significantly inhibited both the increase in lipid peroxidation and the vascular permeability. These findings suggested that MPS reduces the severity of SCI, not by inhibiting the production of TNF-alpha at the site of spinal cord trauma, but by inhibiting activated leukocyte induced lipid peroxidation of the endothelial cell membrane. This suggests that MPS may attenuate spinal cord ischemia by inhibiting the increase in endothelial permeability at the site of spinal cord injury.
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PMID:Methylprednisolone reduces spinal cord injury in rats without affecting tumor necrosis factor-alpha production. 1139 56

The hepatic reticuloendothelial system (RES) is the primary mechanism for removing circulating bacteria from the systemic circulation. While Kupffer cells are important for this process, leukocytes appear to play a significant role as well. Hepatic leukocyte accumulation following ischemia/reperfusion or cytokine stimulation is well documented, but its contribution to phagocytic killing by the hepatic RES is not fully understood. We evaluated the role of leukocytes in general, and leukocyte-endothelial adhesion in particular, in hepatic RES function. This was done by inducing confirmed leukopenia with cyclophosphamide or by blocking leukocyte-endothelial adhesion molecules with specific blocking antibodies. Hepatic phagocytic clearance (HPC) and hepatic phagocytic killing (HKE) of systemically intravenously injected E. coli were assayed and quantitated by a validated dual isotope label technique. HPC among the various experimental groups and respective controls varied only slightly, with no statistically significant differences observed. Leukopenia or CD11b blockade each significantly decreased the HKE relative to the controls. Antibody blockade of certain other adhesion molecules had no significant effect on HKE (or HPC). The role of leukocytes in killing systemically circulating bacteria is an integral component of hepatic RES function. This capability of the leukocyte appears to be dependent, in part, on the adhesion molecule, Mac-1.
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PMID:Hepatic killing but not clearance of systemically circulating bacteria is dependent upon peripheral leukocytes via Mac-1 (CD11b/CD18). 1263 May 27


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