Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several studies suggest that cyclooxygenase (COX)-2 plays a pivotal role in the progression of ischaemic brain damage. In the present study, we investigated the effects of selective inhibition of COX-2 with nimesulide (12 mg/kg) and selective inhibition of COX-1 with valeryl salicylate (VAS, 12-120 mg/kg) on prostaglandin E(2) (PGE(2)) levels, myeloperoxidase (MPO) activity, Evans blue (EB) extravasation and infarct volume in a standardized model of transient focal cerebral ischaemia in the rat. Post-ischaemic treatment with nimesulide markedly reduced the increase in PGE(2) levels in the ischaemic cerebral cortex 24 h after stroke and diminished infarct size by 48% with respect to vehicle-treated animals after 3 days of reperfusion. Furthermore, nimesulide significantly attenuated the blood-brain barrier (BBB) damage and leukocyte infiltration (as measured by EB leakage and MPO activity, respectively) seen at 48 h after the initial ischaemic episode. These studies provide the first experimental evidence that COX-2 inhibition with nimesulide is able to limit BBB disruption and leukocyte infiltration following transient focal cerebral ischaemia. Neuroprotection afforded by nimesulide is observed even when the treatment is delayed until 6 h after the onset of ischaemia, confirming a wide therapeutic window of COX-2 inhibitors in experimental stroke. On the contrary, selective inhibition of COX-1 with VAS had no significant effect on the evaluated parameters. These data suggest that COX-2 activity, but not COX-1 activity, contributes to the progression of focal ischaemic brain injury, and that the beneficial effects observed with non-selective COX inhibitors are probably associated to COX-2 rather than to COX-1 inhibition.
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PMID:Post-ischaemic treatment with the cyclooxygenase-2 inhibitor nimesulide reduces blood-brain barrier disruption and leukocyte infiltration following transient focal cerebral ischaemia in rats. 1717 64

This study investigates the ability of a single, low dose of apolipoprotein (apo) A-I, the main lipoprotein of high density lipoproteins (HDL), to inhibit acute vascular inflammation in normocholesterolemic New Zealand White rabbits. Acute vascular inflammation was induced in the animals by placing a non-occlusive, silastic collar around the left common carotid artery. The animals (n=5/group) received a single, low dose infusion of saline or lipid-free apoA-I at the time of, or 3 or 9h after collar insertion. The animals were sacrificed 24h post-collar insertion. Inflammatory markers in the artery wall were quantitated immunohistochemically. The saline-treated animals exhibited substantial pan-arterial inflammation, which was inhibited by a single apoA-I infusion (2 or 8 mg/kg) at the time of collar insertion. A single 8 mg/kg infusion of lipid-free apoA-I administered 3h post-collar insertion reduced neutrophil recruitment into the vessel wall, and MPO expression, as well as endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) by >85% (p<0.01 for all). A single 8 mg/kg infusion of lipid-free apoA-I administered 9h after collar insertion decreased VCAM-1 expression, neutrophil infiltration and MPO expression by 88% (p<0.001), 47% (p<0.01), and 90% (p<0.01), respectively. This indicates that a single low dose infusion of apoA-I administered after the onset of acute inflammation in carotid arteries decreases neutrophil infiltration and inhibits neutrophil and endothelial cell activation. These findings have potential implications for treating acute vascular inflammation in conditions such as acute coronary and stroke syndromes.
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PMID:Low dose apolipoprotein A-I rescues carotid arteries from inflammation in vivo. 1758 10

Post-translational modification and functional impairment of proteins through carbamylation is thought to promote vascular dysfunction during end-stage renal disease. Cyanate, a reactive species in equilibrium with urea, carbamylates protein lysine residues to form epsilon-carbamyllysine (homocitrulline), altering protein structure and function. We now report the discovery of an alternative and quantitatively dominant mechanism for cyanate formation and protein carbamylation at sites of inflammation and atherosclerotic plaque: myeloperoxidase-catalyzed oxidation of thiocyanate, an anion abundant in blood whose levels are elevated in smokers. We also show that myeloperoxidase-catalyzed lipoprotein carbamylation facilitates multiple pro-atherosclerotic activities, including conversion of low-density lipoprotein into a ligand for macrophage scavenger receptor A1 recognition, cholesterol accumulation and foam-cell formation. In two separate clinical studies (combined n = 1,000 subjects), plasma levels of protein-bound homocitrulline independently predicted increased risk of coronary artery disease, future myocardial infarction, stroke and death. We propose that protein carbamylation is a mechanism linking inflammation, smoking, uremia and coronary artery disease pathogenesis.
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PMID:Protein carbamylation links inflammation, smoking, uremia and atherogenesis. 1791 60

Methicillin-resistant Staphylococcus aureus (MRSA)-related pneumonia and/or sepsis are a frequent serious menace. The aim of the study was to establish a standardized and reproducible model of MRSA-induced septic pneumonia to evaluate new therapies. Sheep were operatively prepared for chronic study. After 5 days' recovery, tracheostomy was performed under anesthesia, and smoke injury was induced by inhalation of cotton smoke (48 breaths, <40 degrees C). Methicillin-resistant S. aureus (AW6) (approximately 2.5x10(11) colony-forming units) was instilled into the airway by a bronchoscope. After the injury, animals were awakened and maintained on mechanical ventilation by 100% oxygen for first 3 h, and thereafter, oxygen concentration was adjusted according to blood gases. The sheep were resuscitated by lactated Ringer solution with an initial rate of 2 mL kg(-1) h(-1) that was further adjusted according to hematocrit. Study groups include (1) sham (noninjured, nontreated; n=6), (2) S+MRSA (exposed to smoke inhalation and MRSA, nontreated; n=6), and (3) smoke (exposed to smoke inhalation alone; n=6). Injured (S+MRSA) animals showed the signs of severe sepsis-related multiple organ failure 3 h after insult. Cardiovascular morbidity was evidenced by severe hypotension, with increased heart rate, cardiac output, left atrial pressure and severely decreased systemic vascular resistance index, and left ventricle stroke work index. Pulmonary dysfunction was characterized by deteriorated gas exchange (PaO2/FIO2 and pulmonary shunt) and increased ventilatory pressures. The S+MRSA group showed significantly greater lung tissue water content, myeloperoxidase activity, and cytokine production compared with uninjured sham animals. Microvascular hyperpermeability was evidenced by marked fluid retention (fluid net balance), decreased plasma protein with decreased plasma oncotic pressure, and increased pulmonary microvascular pressure. All these changes were accompanied by 6- to 7-fold increase in plasma nitrite/nitrate and increased production of reactive nitrogen species in lung. The smoke inhalation alone had a little or no effect on these variables. This model closely mimics hyperdynamic human sepsis. The excessive production of NO may be extensively involved in the pathogenic process.
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PMID:Novel ovine model of methicillin-resistant Staphylococcus aureus-induced pneumonia and sepsis. 1788 44

This review focuses on the morphological features of atherosclerosis and the involvement of oxidative stress in the initiation and progression of this disease. There is now consensus that atherosclerosis represents a state of heightened oxidative stress characterized by lipid and protein in the vascular wall. Reactive oxygen species (ROS) are key mediators of signaling pathways that underlie vascular inflammation in atherogenesis, starting from the initiation of fatty streak development, through lesion progression, to ultimate plaque rupture. Plaque rupture and thrombosis result in the acute clinical complications of myocardial infarction and stroke. Many data support the notion that ROS released from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, myeloperoxidase (MPO), xanthine oxidase (XO), lipoxygenase (LO), nitric oxide synthase (NOS) and enhanced ROS production from dysfunctional mitochondrial respiratory chain, indeed, have a causatory role in atherosclerosis and other vascular diseases. Moreover, oxidative modifications in the arterial wall can contribute to the arteriosclerosis when the balance between oxidants and antioxidants shifts in favour of the former. Therefore, it is important to consider sources of oxidants in the context of available antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase and transferases thiol-disulfide oxidoreductases and peroxiredoxins. Here, we review also the mechanisms in which they are involved in order to accelerate the pace of the discovery and facilitate development of novel therapeutic approaches.
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PMID:Atherosclerosis and oxidative stress. 1807 94

Neural stem cell (NSC) transplantation has been investigated as a means to reconstitute the damaged brain after stroke. In this study, however, we investigated the effect on acute cerebral and peripheral inflammation after intracerebral haemorrhage (ICH). NSCs (H1 clone) from fetal human brain were injected intravenously (NSCs-iv, 5 million cells) or intracerebrally (NSCs-ic, 1 million cells) at 2 or 24 h after collagenase-induced ICH in a rat model. Only NSCs-iv-2 h resulted in fewer initial neurologic deteriorations and reduced brain oedema formation, inflammatory infiltrations (OX-42, myeloperoxidase) and apoptosis (activated caspase-3, TUNEL) compared to the vehicle-injected control animals. Rat neurosphere-iv-2 h, but not human fibroblast-iv-2 h, also reduced the brain oedema and the initial neurologic deficits. Human NSCs-iv-2 h also attenuated both cerebral and splenic activations of tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and nuclear factor-kappa B (NF-kappaB). However, we observed only a few stem cells in brain sections of the NSCs-iv-2 h group; in the main, they were detected in marginal zone of spleens. To investigate whether NSCs interact with spleen to reduce cerebral inflammation, we performed a splenectomy prior to ICH induction, which eliminated the effect of NSCs-iv-2 h transplantation on brain water content and inflammatory infiltrations. NSCs also inhibited in vitro macrophage activations after lipopolysaccharide stimulation in a cell-to-cell contact dependent manner. In summary, early intravenous NSC injection displayed anti-inflammatory functionality that promoted neuroprotection, mainly by interrupting splenic inflammatory responses after ICH.
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PMID:Anti-inflammatory mechanism of intravascular neural stem cell transplantation in haemorrhagic stroke. 1866 89

Elevated activities of matrix metalloproteinases (MMPs) following ischemic stroke have been shown to mediate ischemic injury as well as neurovascular remodeling. The extracellular MMP inducer (EMMPRIN) is a 58-kDa cell surface glycoprotein, which has been known to play a key regulatory role for MMP activities. The roles of EMMPRIN in stroke injury are not clearly understood. In this study, we investigated changes of EMMPRIN in a mouse model of permanent focal cerebral ischemia, and examined potential association between EMMPRIN and MMP-9 expression. Adult male CD-1 mice were subjected to permanent focal ischemia by intraluminal occlusion of the left middle cerebral artery (MCAO) under anesthesia. EMMPRIN expression was markedly upregulated in the peri-infarct area at 2-7 days after ischemia compared to the contralateral non-ischemic hemisphere by Western blot analysis. Immunofluorescent double staining demonstrated that EMMPRIN signals co-localized with vwF-positive endothelial cells and GFAP-positive peri-vascular astrocytes. In contrast, EMMPRIN signal did not co-localize with NeuN-positive neurons, or MPO-positive neutrophils. Dual fluorescent staining revealed that EMMPRIN co-localized with MMP-9. Our data also demonstrated that increased EMMPRIN expression correlated with increased MMP-9 levels in a temporal manner. In summary, we report for the first time that EMMPRIN expression was significantly increased in a mouse model of permanent focal cerebral ischemia. The spatial and temporal association between increased EMMPRIN expression and elevated MMP-9 levels suggest that EMMPRIN may modulate MMP-9 activity, and participate in neurovascular remodeling after ischemic stroke.
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PMID:Upregulation of EMMPRIN after permanent focal cerebral ischemia. 1816 15

Ischemic post-conditioning (Post-cond) is a phenomenon in which intermittent interruptions of blood flow in the early phase of reperfusion can protect organ from ischemia/reperfusion (I/R) injury. Recent studies demonstrated ischemic Post-cond reduced infarct size in cerebral I/R injury. However, the molecular mechanisms underlying this phenomenon are not completely understood. As inflammation is known to be detrimental to the neurological outcome during the acute phase after stroke, we investigated whether ischemic Post-cond played its protective role in preventing post-ischemic inflammation in the rat middle cerebral artery occlusion model. Rats were treated with ischemic Post-cond after 60 min of occlusion (beginning of reperfusion). The infarct volume and myeloperoxidase activity were assessed at 24 h. The lipid peroxidation levels was evaluated by malondialdehyde assay and the expressions of interleukin-1beta, tumor necrosis factor-alpha, and intercellular adhesion molecule 1 were studied by RT-PCR or western blotting. Ischemic Post-cond decreased myeloperoxidase activity and expressions of interleukin-1beta, tumor necrosis factor-alpha, and intercellular adhesion molecule 1. Ischemic Post-cond also reduced infarct volume and lipid peroxidation levels. These findings indicated that ischemic Post-cond may be a promising neuroprotective approach for focal cerebral I/R injury and it is achieved, at least in part, by the inhibition of inflammation.
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PMID:Ischemic post-conditioning protects brain and reduces inflammation in a rat model of focal cerebral ischemia/reperfusion. 1824 11

We performed a multicenter study to test the hypothesis that tidal liquid ventilation (TLV) would improve cardiopulmonary, lung histomorphological, and inflammatory profiles compared with conventional mechanical gas ventilation (CMV). Sheep were studied using the same volume-controlled, pressure-limited ventilator systems, protocols, and treatment strategies in three independent laboratories. Following baseline measurements, oleic acid lung injury was induced and animals were randomized to 4 hours of CMV or TLV targeted to "best PaO2" and PaCO2 35 to 60 mm Hg. The following were significantly higher (p < 0.01) during TLV than CMV: PaO2, venous oxygen saturation, respiratory compliance, cardiac output, stroke volume, oxygen delivery, ventilatory efficiency index; alveolar area, lung % gas exchange space, and expansion index. The following were lower (p < 0.01) during TLV compared with CMV: inspiratory and expiratory pause pressures, mean airway pressure, minute ventilation, physiologic shunt, plasma lactate, lung interleukin-6, interleukin-8, myeloperoxidase, and composite total injury score. No significant laboratories by treatment group interactions were found. In summary, TLV resulted in improved cardiopulmonary physiology at lower ventilatory requirements with more favorable histological and inflammatory profiles than CMV. As such, TLV offers a feasible ventilatory alternative as a lung protective strategy in this model of acute lung injury.
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PMID:Multicenter comparative study of conventional mechanical gas ventilation to tidal liquid ventilation in oleic acid injured sheep. 1849 75

Streptococcus pneumoniae, a gram-positive bacteria, is the most common cause of community-acquired pneumonia. It is a common cause of septic shock with multiple organ dysfunction syndrome (MODS) resulting in significant mortality. Gram-positive mouse models of sepsis with MODS are required to examine mechanisms of immune responses in severe sepsis. To assess whether lung infection due to S. pneumoniae in a nonventilated mouse model can induce multiple organ dysfunction. S. pneumoniae, SPN 15814 strain, harvested at log phase, was injected intratracheally in C57BL/6 mice at OD 600 between 0.35 and 0.63. A dose of bacteria at OD 600 = 0.63 conferred approximately 30% mortality in 36 h. Lung pneumonia was assessed by histology, lung myeloperoxidase activity, and lung bacterial load; intestinal epithelial barrier integrity was assessed by measuring blood-to-lumen clearance of Cr-EDTA; renal function was assessed by measuring plasma creatinine and urea; and myocardiac function was assessed using an isolated perfused mouse heart model. S. pneumoniae-induced pneumonia resulted in neutrophil infiltration into the lungs and increased lung bacterial load. Although relatively few bacteria gained access to the blood stream, the pneumonia was accompanied by increased intestinal epithelial barrier permeability, increased plasma creatinine, and decreased cardiac output and stroke volume. These data clearly show that intratracheal S. pneumoniae induced not only pneumonia but also MODS, despite the fact that few organisms gain access to the blood stream. This model can be used as a good gram-positive model of sepsis and MODS for further studies.
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PMID:Characterization of S. pneumoniae pneumonia-induced multiple organ dysfunction syndrome: an experimental mouse model of gram-positive sepsis. 1882 50


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