Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple organ dysfunction syndrome (MODS) is a complication of hemorrhagic shock (HS) and related to high morbidity and mortality. Interaction of activated neutrophils and endothelial cells is considered to play a prominent role in the pathophysiology of MODS. Insight in the nature and molecular basis of endothelial cell activation during HS can assist in identifying new rational targets for early therapeutic intervention. In this study, we examined the kinetics and organ specificity of endothelial cell activation in a mouse model of HS. Anesthetized male mice were subjected to controlled hemorrhage to a MAP of 30 mmHg. Mice were killed after 15, 30, 60, or 90 min of HS. After 90 min of hemorrhagic shock, a group of mice was resuscitated with 6% hydroxyethyl starch 130/0.4. Untreated mice and sham shock mice that underwent instrumentation and 90 min of anesthesia without shock served as controls. Gene expression levels of inflammatory endothelial cell activation (P-selectin, E-selectin, vascular cell adhesion molecule 1, and intercellular adhesion molecule 1) and hypoxia-responsive genes (vascular endothelial growth factor and hypoxia-inducible factor 1alpha) were quantified in kidney, liver, lung, brain, and heart tissue by quantitative reverse-transcription-polymerase chain reaction. Furthermore, we examined a selection of these genes with regard to protein expression and localization using immunohistochemical analysis. Induction of inflammatory genes occurred early during HS and already before resuscitation. Expression of adhesion molecules was significantly induced in all organs, albeit to a different extent depending on the organ. Endothelial genes CD31 and VE-cadherin, which function in endothelial cell homeostasis and integrity, were not affected during the shock phase except for VE-cadherin in the liver, which showed increased mRNA levels. The rapid inflammatory activation was not paralleled by induction of hypoxia-responsive genes. This study demonstrated the occurrence of early and organ-specific endothelial cell activation during hemorrhagic shock, as presented by induced expression of inflammatory genes. This implies that early therapeutic intervention at the microvascular level may be a rational strategy to attenuate MODS.
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PMID:Early organ-specific endothelial activation during hemorrhagic shock and resuscitation. 1770 30

Hemorrhagic shock (HS) is an oxidative stress that causes intestinal tissue injury. Heme oxygenase 1 (HO-1) is induced by oxidative stress and is thought to play an important role in the protection of tissues from oxidative injury. We previously reported the ileum to be the most susceptible to HS-induced tissue injury site in the intestine because HO-1 induction is the lowest at this site. We also previously demonstrated that glutamine (GLN) significantly induced HO-1 in the lower intestinal tract. In the present study, we investigated whether GLN pretreatment improves HS-induced intestinal tissue injury in the ileum by HO-1 induction. Treatment of rats with GLN (0.75 g/kg, i.v.) markedly induced functional HO-1 protein in mucosal epithelial cells in the ileum. Glutamine treatment before HS (MAP of 30 mmHg for 60 min) significantly ameliorated HS-induced mucosal inflammation and apoptotic cell death in the ileum, as judged by significant decreases in gene expression of TNF-alpha, iNOS, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1, myeloperoxidase activity, the number of infiltrated neutrophils, DNA fragmentation by in situ oligo ligation assay, and activated caspase-3 expression, and by increases in gene expression of IL-10 and Bcl-2. In contrast, treatment with tin mesoporphyrin, a specific inhibitor of HO activity, abolished the beneficial effect of GLN pretreatment. These findings indicate that GLN pretreatment significantly ameliorated tissue injury in the ileum after HS by inducing HO-1. Glutamine treatment may thus protect mucosal cells from HS-induced oxidative damage via the anti-inflammatory and antiapoptotic properties of HO-1.
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PMID:Prevention of hemorrhagic shock-induced intestinal tissue injury by glutamine via heme oxygenase-1 induction. 1849 9

The cell type that normally limits the inflammatory and atherosclerotic process is the vascular endothelial cell (EC) that can be regulated by proinflammatory and various stresses. Toll-like receptor-4 (TLR4) plays an important role in the pathogenesis of atherosclerosis, in part, by activating apoptosis signal-regulating kinase 1 (ASK1) to initiate the activation of MAP kinases pathways and the expression of inflammatory genes. In the present study, we test the hypothesis that AGI-1067 acts as an anti-inflammatory agent by inhibiting the activation of ASK1 in human EC. Pretreatment of human aortic endothelial cells with AGI-1067 inhibits TLR4 ligand (LPS)-induced activation of ASK1 and the downstream p38 and c-Jun N-terminal kinase (JNK) MAP kinases. LPS dissociates two endogenous inhibitors thioredoxin-1 (Trx1) and 14-3-3 from ASK1, leading to ASK1 autoactivation. Interestingly, AGI-1067 inhibits the dissociation of Trx1, but not 14-3-3, from ASK1. However, inhibition of Trx1 dissociation from ASK1 by AGI-1067 is sufficient to suppress LPS-mediated phosphorylation of the transcription factors c-Jun and activating transcription factor 2, and inhibit LPS-induced inflammatory genes including vascular cell adhesion molecule 1, E-selectin, IL-6 and monocyte chemoattractant protein 1. Our findings suggest that AGI-1067 as a unique ASK1 inhibitor to inhibit TLR4-mediated ASK1 activation, contributing to its anti-inflammatory properties.
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PMID:A Novel ASK Inhibitor AGI-1067 Inhibits TLR-4-Mediated Activation of ASK1 by Preventing Dissociation of Thioredoxin from ASK1. 2843 45