Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rewarming victims of hypothermia such as divers or immersion victims, participants in winter sports and military operations, and surgical patients on cardiopulmonary bypass (CPB) may lead to vascular instability, multiorgan failure, shock, and even death. While the causes of these rewarming symptoms are unknown, they may be related to bacterial lipopolysaccharide (LPS) translocated from the intestines into the circulation due to splanchnic ischemia. We have determined LPS during the cooling (to 31.5 degrees-34.0 degrees C) and rewarming phases of hypothermic surgery in 11 patients at the Stanford University Medical Center. During rewarming, there was an LPS spike in 6/11, in one more patient there was an LPS spike during surgery but not during rewarming, and in 4/11 there was no rise in LPS, i.e., a temporary endotoxemia occurred in 7/11 (63.6%) patients, usually at the commencement of rewarming. All four patients with no LPS spike received dexamethasone for at least 7 days before surgery. We propose that hypothermia reduced splanchnic blood flow (BF), causing ischemic damage to the gut wall and translocation of LPS from the gut into the vascular space. Upon rewarming, splanchnic BF is restored, the translocated LPS transits from the splanchnic to the systemic circulations as a bolus, and the gut wall is healed. No sequelae occurred in these patients because of their adequately functioning immune systems. However, had they been immunocompromised, symptoms might have occurred. Rewarming of accident victims probably also incurs a similar risk of endotoxemia, and dexamethasone may have protected the gut wall. Further studies are indicated.
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PMID:Rewarming from hypothermia leads to elevated plasma lipopolysaccharide concentrations. 1081 33

Classic ischemic preconditioning transiently (30 to 120 minutes) protects the myocardium against subsequent lethal ischemia/reperfusion injury. After dissipation of this acute protection, a second window of protection (SWOP) appears 12 to 24 hours later; this SWOP lasts up to 3 days. Several triggers induce a SWOP, including brief repetitive cycles of coronary artery occlusion, rapid ventricular pacing, stimulation of adenosine A(1) receptors, and administration of wall fragments of Gram-negative bacteria, such as lipopolysaccharide (LPS). The aim of this study was to investigate whether lipoteichoic acid (LTA), a cell wall fragment of Gram-positive bacteria, can induce a SWOP in a rat model of left anterior descending coronary artery (LAD) occlusion (25 minutes) and reperfusion (2 hours). Thus, 166 male Wistar rats were pretreated (2 to 24 hours) with saline, LTA (1 mg/kg IP), or LPS (1 mg/kg IP) and subjected to LAD occlusion/reperfusion. Pretreatment with LTA or LPS for 16 hours led to a substantial, approximately 65%, reduction in infarct size and a reduction in the release of cardiac troponin T into the plasma. The dose of LTA used had no toxic effect (on any of the parameters studied), whereas the same dose of LPS caused a time-dependent activation of the coagulation system and liver injury. By use of RNase protection assays, it was determined that LPS caused a time-dependent induction of tumor necrosis factor-alpha, interleukin-1beta, and manganese superoxide dismutase mRNA content in the heart, whereas LTA failed to induce manganese superoxide dismutase. LPS also caused an upregulation of the expression of intercellular adhesion molecule-1 and P-selectin, whereas LTA downregulated these molecules and attenuated the accumulation of polymorphonuclear granulocytes caused by myocardial ischemia/reperfusion. This study demonstrates for the first time that pretreatment with LTA at 8 to 24 hours before myocardial ischemia significantly reduces (1) infarct size, (2) cardiac troponin T, and (3) the histological signs of tissue injury in rats subjected to LAD occlusion and reperfusion. The mechanism(s) underlying the observed cardioprotective effects of LTA warrants further investigation but is likely to be related to its ability to inhibit the interactions between the coronary vascular endothelium and polymorphonuclear granulocytes. Therefore, LTA represents a novel and promising agent capable of enhancing myocardial tolerance to ischemia/reperfusion injury.
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PMID:Lipoteichoic acid induces delayed protection in the rat heart: A comparison with endotoxin. 1084 67

The etiology of Parkinson's disease is not known. Nevertheless a significant body of biochemical data from human brain autopsy studies and those from animal models point to an on going process of oxidative stress in the substantia nigra which could initiate dopaminergic neurodegeneration. It is not known whether oxidative stress is a primary or secondary event. Nevertheless, oxidative stress as induced by neurotoxins 6-hydroxydopamine and MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) has been used in animal models to investigate the process of neurodegeneration with intend to develop antioxidant neuroprotective drugs. It is apparent that in these animal models radical scavengers, iron chelators, dopamine agonists, nitric oxide synthase inhibitors and certain calcium channel antagonists do induce neuroprotection against such toxins if given prior to the insult. Furthermore, recent work from human and animal studies has provided also evidence for an inflammatory process. This expresses itself by proliferation of activated microglia in the substantia nigra, activation and translocation of transcription factors, NF kappa-beta and elevation of cytotoxic cytokines TNF alpha, IL1-beta, and IL6. Both radical scavengers and iron chelators prevent LPS (lipopolysaccharide) and iron induced activation of NF kappa-B. If an inflammatory response is involved in Parkinson's disease it would be logical to consider antioxidants and the newly developed non-steroid anti-inflammatory drugs such as COX2 (cyclo-oxygenase) inhibitors as a form of treatment. However to date there has been little or no success in the clinical treatment of neurodegenerative diseases per se (Parkinson's disease, ischemia etc.), where neurons die, while in animal models the same drugs produce neuroprotection. This may indicate that either the animal models employed are not reflective of the events in neurodegenerative diseases or that because neuronal death involves a cascade of events, a single neuroprotective drug would not be effective. Thus, consideration should be given to multi-neuroprotective drug therapy in Parkinson's disease, similar to the approach taken in AIDS and cancer therapy.
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PMID:Neuroprotective strategies in Parkinson's disease using the models of 6-hydroxydopamine and MPTP. 1086 45

Multiple organ dysfunction and death are common sequelae after mesenteric ischemia-reperfusion injury as seen with mesenteric revascularization and thoracoabdominal aortic aneurysm repair. A second insult such as bacterial pneumonia occurring subsequent to the ischemia-reperfusion injury may contribute to these untoward effects. We hypothesized the sequential visceral/lower torso ischemia-reperfusion and endotoxemia in a murine model would increase the magnitude of the proinflammatory cytokine response and decrease survival. C57BL/6 mice underwent 20 min of supraceliac occlusion (IR), sham laparotomy (LAP), or no initial insult (CTRL) followed by intraperitoneal injection of a lethal dose of endotoxin (LPS [lipopolysaccharide 50 mg/kg] or saline vehicle at 24 h. Serum cytokine levels were measured by enzyme-linked immunosorbent assay (IL-10, IL-6) or WEHI bioassay [tumor necrosis factor (TNF)], and survival was determined at 5 days. The role of IL-10 on the TNF response and survival was examined in a subset of mice given mouse anti IL-10 IgM (25 mg/kg intraperitoneally) 2 h prior to the initial insult. Survival after LPS was significantly different (P < 0.05) among the treatment groups (IR, 64%; LAP, 55%; CTRL, 11%) and appeared to trend directly with the magnitude of the initial operation. The serum IL-10 levels in the IR and LAP groups were significantly increased 4 h after the initial insult and remained elevated at 24 h. Peak serum TNF levels after LPS were significantly lower in the IR and LAP groups. Administration of anti IL-10 IgM resulted in uniform mortality and a significant increase in the peak TNF levels after LPS administration for all initial treatment groups. Endogenous production of IL-10 following laparotomy down-regulates the TNF response and improves survival after endotoxemia.
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PMID:Laparotomy prevents lethal endotoxemia in a murine sequential insult model by an IL-10-dependent mechanism. 1094 60

A low dose (0.5 mg/kg) of lipopolysaccharide (LPS), administered 72 hours before 60-minute middle cerebral artery occlusion, induced a delayed neuroprotection proven by the significant decrease (-35%) of brain infarct volume in comparison with control, whereas infarct volumes remained unchanged in rats treated 12, 24, or 168 hours before ischemia. This delayed neuroprotective effect of LPS was induced only with low doses (0.25 to 1 mg/kg), whereas this effect disappeared with a higher dose (2 mg/kg). The delayed neuroprotection of LPS was induced in the cortical part of the infarcted zone, not in the subcortical part. The beneficial effect of LPS on consequences of middle cerebral artery occlusion was suppressed by dexamethasone (3 mg/kg) and indomethacin (3 mg/ kg) administered 1 hour before LPS, whereas both drugs had no direct effect on infarct volume by themselves, suggesting that activation of inflammatory pathway is involved in the development of LPS-induced brain ischemic tolerance. Preadministration of cycloheximide, an inhibitor of protein synthesis, also blocked LPS-induced brain ischemic tolerance suggesting that a protein synthesis is also necessary as a mediating mechanism. Superoxide dismutase (SOD) could be one of the synthesized proteins because lipopolysaccharide increased SOD brain activity 72 hours, but not 12 hours, after its administration, which paralleled the development of brain ischemic tolerance. In contrast, catalase brain activity remained unchanged after LPS administration. The LPS-induced delayed increase in SOD brain content was suppressed by a previous administration of indomethacin. These data suggest that the delayed neuroprotective effect of low doses of LPS is mediated by an increased synthesis of brain SOD that could be triggered by activation of inflammatory pathway.
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PMID:Increase in endogenous brain superoxide dismutase as a potential mechanism of lipopolysaccharide-induced brain ischemic tolerance. 1095 Mar 79

We investigated the effects of nafamostat mesilate, a synthetic protease inhibitor clinically used for patients with pancreatitis or disseminated intravascular coagulopathy, on NO synthesis and apoptosis in lipopolysaccharide (LPS)-treated human trophoblasts. Nafamostat mesilate or aminoguanidine, an inhibitor of NO synthase, suppressed NO synthesis and apoptosis in trophoblasts induced by LPS. Both agents also suppressed matrix metalloproteinase-2 activity induced by LPS. LPS also stimulated secretion of IL-6 and IL-8 in cultured trophoblasts, which was suppressed by nafamostat mesilate. Protease inhibitors including nafamostat mesilate may be therapeutic agents for chorioamnionitis and various diseases including septic shock, ischemia-reperfusion injury in brain and heart, graft rejection, and acute phase inflammatory diseases, in which overproduction of NO or peroxynitrite is involved in tissue injury.
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PMID:Nafamostat mesilate, a serine protease inhibitor, suppresses lipopolysaccharide-induced nitric oxide synthesis and apoptosis in cultured human trophoblasts. 1095 57

Analysis of gene expression in a mouse model of unilateral ureteral obstruction (UUO) revealed significant induction of CD14 mRNA in kidneys with obstructed ureters. Immunocytochemical analysis indicated that CD14 was upregulated in tubular epithelial cells and this upregulation was not attributable to infiltration of the kidneys by mononuclear cells. This induction of CD14 mRNA was found to occur in BALB/C, C57BL/6, C3H/HeN, and C3H/HeJ mice during UUO. Ischemia/reperfusion of kidneys also induced CD14 mRNA. Mice lacking either of the tumor necrosis factor-alpha receptor (TNFR) genes were also studied; the induction of CD14 was blunted in TNFR 1-knockout mice but not in TNFR2-knockout mice. Apoptosis of tubular cells in lipopolysaccharide-resistant CH3/HeJ mice was significantly (P: < 0. 05) less than that in lipopolysaccharide-responsive CH3/HeN mice during UUO. These results suggest that CD14 is acutely induced in tubular epithelial cells in two mouse models of renal injury. This induction is regulated by tumor necrosis factor-alpha, through TNFR1. CD14 may participate in the apoptosis of tubular epithelial cells on a more chronic basis by activating a pathway that is absent or deficient in C3H/HeJ mice.
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PMID:Induction of CD14 in tubular epithelial cells during kidney disease. 1096 93

Intercellular adhesion molecule (ICAM)-5 (telencephalin) is unique among the ICAMs, because it is only expressed in somatodendritic membranes of telencephalic neurons. To investigate the fate of ICAM-5 during focal brain injury, we induced hypoxia-ischemia (HI) damage in adult mice by right common carotid artery ligation followed by hypoxia. ICAM-5 was detectable in serum within a 48-hour window after HI injury. In HI brain, dendritic ICAM-5 immunore-activity was abolished, but it was present in the neuropil and soma of hippocampal pyramidal, dentate granule, and some cortical and striatal neurons. After HI injury, levels of ICAM-5 protein and messenger RNA initially increased, and ICAM-5 messenger RNA expression then decreased, although protein levels continued to increase. Because HI injury induces microglial activation with increases in CD11a/CD18 (lymphocyte function antigen [LFA]-1) counterreceptors to ICAM-5, we investigated whether modulation of interactions between LFA-1 receptors and brain ICAM-5 during HI injury are associated with changes in levels of serum ICAM-5. Intracerebroventricular administration of lipopolysaccharide to activate microglia before HI injury resulted in elevated serum ICAM-5 levels compared with those in mice with only HI injury. Pretreatment with anti-LFA-1 antibodies before HI injury or LFA-1 receptor knockout mice with HI injury had markedly reduced levels of serum ICAM-5. Lipopolysaccharide levels increased, whereas LFA-1 receptor blockade or LFA-1 knockout decreased HI injury in the first 12 hours. These data suggest that during the necrotic phase of HI injury, serum ICAM-5 may be a potential marker for somatodendritic neuronal damage.
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PMID:Release of the neuronal glycoprotein ICAM-5 in serum after hypoxic-ischemic injury. 1102 42

Hepatic ischemia-reperfusion (I/R) is an important cause of organ dysfunction in the critically ill. With reperfusion, Kupffer cells release pro-inflammatory cytokines that promote endothelial cell (EC) expression of adhesion molecules such as intercellular adhesion molecule (ICAM)-1, facilitating neutrophil (PMN) infiltration. Studies suggest hypertonic saline (HTS) might exert beneficial effects on development of organ injury following shock on the basis of reduced PMN-EC interactions. We hypothesized that HTS alters expression of EC ICAM-1 and thus minimizes PMN-mediated injury. To test our hypothesis, we used an in vivo model of hepatic I/R and an in vitro model of activated EC. Rats underwent 30 min of hepatic ischemia after pretreatment with HTS (7.5% NaCl, 4cc/kg ia) or normal saline (NS). At 4 h reperfusion, plasma was taken for aspartate aminotransferase (AST) and liver tissue was harvested for assessment of hepatic ICAM-1 mRNA by Northern blot analysis. Human umbilical vein endothelial cells (HUVECs) were activated by lipopolysaccharide (LPS) and exposed to hypertonic medium (350-500 mOsM). HUVEC ICAM-1 protein was measured by cell ELISA and ICAM-1 mRNA by Northern blot analysis. HTS prevented hepatic I/R injury as measured by AST. AST of shams was 282.6+/-38.1 IU/L. I/R following NS pretreatment caused significant injury (AST 973.8+/-110.9 IU/L) compared to sham (SM) (P < 0.001). Pretreatment with HTS exerted significant protection following I/R with an AST of 450.9+/-56.3 IU/L (P < 0.05). There was no significant difference in AST levels between SM and HTS groups. Reduced hepatic injury after HTS and I/R was accompanied by inhibition of I/R-induced hepatic ICAM-1 mRNA expression compared to NS treated animals (P < 0.01). Similarly, hypertonicity inhibited HUVEC LPS-induced ICAM-1 protein (LPS: 1.86+/-0.19 absorbance units; 400 mOsM +/- LPS: 1.45+/-0.14 absorbance units; 450 mOsM + LPS: 1.02+/-0.19 absorbance units, P < 0.001) and mRNA expression. Thus, hypertonicity modulates endothelial ICAM-1 expression as one possible protective mechanism against I/R injury.
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PMID:In vivo and in vitro modulation of intercellular adhesion molecule (ICAM)-1 expression by hypertonicity. 1102 65

Nuclear factor-kappaB (NF-kappa B) is a pleiotropic oxidant-sensitive transcription factor that is present in the cytosol in an inactive form complexed to an inhibitory kappaB (I kappa B) monomer. Various stimuli, including ischemia, hypoxia, free radicals, cytokines, and lipopolysaccharide (LPS), activate NF-kappa B by inducing phosphorylation of I kappa B. Phosphorylation of serine residues at positions 32 and 36 is critical for ubiquitination and degradation of I kappa B alpha with consequent migration of NF-kappa B to the nucleus. Although NF-kappa B is thought to contribute to numerous pathophysiologic processes, definitive assessment of its role has been hindered by the inability to achieve specific inhibition in vivo. Pharmacologic inhibitors of NF-kappa B are available, but their utility for in vivo studies is limited by their relative lack of specificity. Targeted ablation of genes encoding NF-kappa B subunits has not been productive in this regard because of fetal lethality in the case of p65 and functional redundancy in the Rel family of proteins. To overcome these limitations, we have created a viable transgenic mouse that expresses a phosphorylation-resistant mutant of I kappa B alpha (I kappa B alpha(S32A,S36A)) under the direction of a cardiac-specific promoter. Several transgenic lines were obtained with copy numbers ranging from one to seven. The mice exhibit normal cardiac morphology and histology. Total myocardial I kappa B alpha protein level is elevated 3.5- to 6.5-fold with a concomitant 50-60% decrease in the level of I kappa B beta. Importantly, expression of I kappa B(S32A,S36A) results in complete abrogation of myocardial NF-kappa B activation in response to tumor necrosis factor- alpha (TNF-alpha) and LPS stimulation. Thus, novel transgenic mice have been created that make it possible to achieve cardiac-specific and selective inhibition of NF-kappa B in vivo. These transgenic mice should be useful in studies of various cardiac pathophysiological phenomena that involve NF-kappa B activation, including ischemic preconditioning, heart failure, septic shock, acute coronary syndromes, cardiac allograft rejection, and apoptosis.
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PMID:Cardiac-specific abrogation of NF- kappa B activation in mice by transdominant expression of a mutant I kappa B alpha. 1113 32


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