Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To study the role of interferon-gamma (IFN-gamma) in gram-negative shock, mortality was compared in mice receiving either a monoclonal antibody to IFN-gamma (H22) or an irrelevant monoclonal antibody (L2-3D9) before or after an LD90 dose of Escherichia coli O111:B4. H22 given either 1 h before or 0.5 h after bacterial challenge protected mice from death (mortality at 48 h, 28% vs. 83%, P less than .001). Serum tumor necrosis factor-alpha (TNF alpha) levels and bacterial counts in blood and organs (liver, spleen, heart, and brain) were similar in H22-treated animals and controls. The peak serum TNF alpha levels were 95.7 +/- 16.4 ng/mL and 80.7 +/- 14.9 ng/mL in the H22 and control groups, respectively. These results indicate that IFN-gamma plays a significant role in the pathogenesis of gram-negative sepsis.
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PMID:Role of interferon-gamma in experimental gram-negative sepsis. 163 4

The expression of heat shock proteins (hsp) is probably one of the most primitive mechanisms of cellular protection from stress. Pathogens such as viruses and bacteria have recently been found to induce the heat shock gene expression. In the present study hsp-72, the stress-inducible form of hsp-70, was detected by Western blotting in samples from rat distal colon (DC), proximal colon (PC), and terminal ileum (TI), but was not found in proximal small bowel (PSB) or other organs (liver, kidney, spleen, heart, and brain) of unstressed animals. The signal intensity of hsp-72 in colon (DC > PC > TI > PSB) correlates qualitatively with the presence of normal gut microflora. hsp-72 was also observed in DC, to a lesser extent in PC, but not in TI or PSB of bacteria-free or antibiotic-treated rats. Inflammatory states induced by the intravenous administration of endotoxin (1 mg/kg), the subcutaneous injection of zymosan (1 g/kg) or by cecal ligation and puncture (sepsis) failed to increase the hsp-72 levels in rat colon or other organs. These results demonstrate that hsp-72 is expressed in normal rat colon. However, the induction of hsp-72 expression may not be due solely to the presence of resident bacteria in the gut, but instead, may be the result of a more complex process.
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PMID:Presence of the stress-inducible form of hsp-70 (hsp-72) in normal rat colon. 765 62

Gut fuel utilisation has several unique features. Arterial and luminal fuels provide nutrition for the enterocyte, the former being of more importance. This factor, and the heterogeneity of cell types within the gut makes it difficult to define its fuel utilisation. Metabolic control logic suggests that modulation of the maximal activity of any pathway resides in those enzymes that operate in vivo at rates far below their maximal capacity and that catalyse non-equilibrium reactions. On this basis, although enterocyte hexokinase activity is much higher than in other 'glycolytic' cells (for example, brain), potentially high rates of glucose utilisation are modulated by substrate cycling of glucose 6-phosphate back to glucose through glucose 6-phosphatase. Glutamine metabolism proceeds by glutaminase to produce glutamate, which may then be transaminated (aspartate-aminotransferase and alanine-amino transferase) to produce alpha-ketoglutarate, alanine, and aspartate. The end products of glutamine metabolism by incubated gut preparations in vitro (mainly alanine), suggests that enterocytes, not immune cells, are responsible for most gut glutamine metabolism. High flux rates of glucose and glutamine metabolism in the enterocyte may result from the need for de novo synthesis of purines and pyrimidines and ribose sugars for nucleic acid synthesis. Sepsis reduces rates of glucose and glutamine metabolism, perhaps to preserve the increased consumption of these fuels by activated lymphocytes and macrophages in the gut wall.
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PMID:Quantitative aspects of glucose and glutamine metabolism by intestinal cells. 812 83

During the last decade, a multitude of experimental arguments have led to the concept that EDRF is nitric oxide (NO), a messenger not only involved in the control of vasomotor tone but also in vascular homeostasis, neuronal and immunological functions. Regardless of its origin, endogenous NO is produced through the conversion of L-arginine to L-citrulline by NO-synthase (NOS) from which several isoforms have recently been isolated, purified and cloned. NOS-type I (isolated from brain) and type III (isolated from endothelial cells) are termed "constitutive-NOS" and produce picomolar levels of NO from which only a small fraction elicits physiological responses. These isoforms are regulated by Ca(2+)-calmodulin with NADPH, FAD/FMN and tetrahydrobiopterin as co-factors and reveal a high degree of homology with the amino-acid sequence of cytochrome P450 reductase within the C-terminal domain. Functionally, neuronal-NOS type I is important in neurotransmission (modulation of NMDA receptor), the central control of vascular homeostasis and possibly learning and memory. In the peripheral nervous system, NOS appears to be linked to nonadrenergic noncholinergic (NANC) neuronal pathways. Endothelial-NOS type III is essential for the control of vascular tone in response to the release of endogenous mediators, although shear stress is the major trigger of endothelial-NOS activity under physiological conditions. NOS-type III also contributes to the prevention of abnormal platelet aggregation. NOS-types II and IV (isolated from macrophages) are Ca(2+)-calmodulin independent and are termed "inducible-NOS" since their activation is only promoted under pathophysiological situations where macrophages exert cytotoxic effects in response to cytokines. In contrast with NOS-types I and III, activation of NOS-type II in these cells induces the formation of nanomolar levels of NO which act as a defense mechanism of the immune system. Dysfunctions of the L-arginine-NO pathway have been characterized in multiple diseases (atherosclerosis, hypertension, diabetes, sepsis, cerebral ischemia, etc) and the design of more selective activators/inhibitors of NOS isoforms is a new challenge for the understanding of their pathophysiology and treatment.
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PMID:Nitric oxide: an ubiquitous messenger. 829 80

A 2-year-old girl admitted with third degree burns (35% TBSA) received 7 weeks poly-antibiotic therapy combined with heparin for a severe Methicillin-resistant Staphylococcus aureus sepsis with multiple metastatic abscesses (lung, skin, brain), from a suppurative thrombophlebitis of the right jugularis interna, extended to the axillary and cava superior veins. Surgical treatment was contraindicated by the local extension. The child was discharged without major neurological sequelae 3 months after admission.
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PMID:Medical treatment of a central vein suppurative thrombosis with cerebral metastatic abscesses in a burned child. 1152 66

Vasopressin (antidiuretic hormone) is emerging as a potentially major advance in the treatment of a variety of shock states. Increasing interest in the clinical use of vasopressin has resulted from the recognition of its importance in the endogenous response to shock and from advances in understanding of its mechanism of action. From animal models of shock, vasopressin has been shown to produce greater blood flow diversion from non-vital to vital organ beds (particularly the brain) than does adrenaline. Although vasopressin has similar direct actions to the catecholamines, it may uniquely also inhibit some of the pathologic vasodilator processes that occur in shock states. There is current interest in the use of vasopressin in the treatment of shock due to ventricular fibrillation, hypovolaemia, sepsis and cardiopulmonary bypass. This article reviews the physiology and pharmacology of vasopressin and all of the relevant animal and human clinical literature on its use in the treatment of shock following a MEDLINE (1966-2000) search.
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PMID:Vasopressin and shock. 1193 28

OBJECTIVE: Life-threatening conditions cause severe changes in the organization and conformation of macromolecules, creating urgent requirements for protein repair to ensure survival. As molecular chaperones, heat shock proteins (HSP) that have specialized functions in protein folding are now well established to restore homeostasis in cells and organisms. Augmentation of HSP synthesis is tightly regulated by stress-inducible heat shock factors (HSF), which are part of a transcriptional signaling cascade with both positive (e.g., HSP) and negative (e.g., proinflammatory cytokines) properties. In this review, we discuss the biological roles and mechanisms of HSP-mediated protection in pathophysiologic conditions (ischemia, sepsis, and preeclampsia) and the regulation for stress-dependent HSP synthesis and speculate about future applications for harnessing HSF and HSP partners as cytoprotective agents. DATA SOURCES: Reactive oxygen species are major pathogenic factors in cell death pathways (e.g., necrosis, apoptosis), in part, because of proteotoxic effects. In intact organisms, forced overexpression of HSP per se affords effective counterbalance against ischemia challenges (e.g., heart and brain) and systemic conditions (e.g., sepsis). Besides stressful conditions, gene-targeting studies have uncovered new functions for heat shock transcription factors (e.g., maintenance of intrauterine pregnancy) in mammals. In parallel, pharmacologic studies using small molecules are paving the way for future prospects to exploit the beneficial properties of HSP, albeit an important but presently elusive goal. CONCLUSIONS: Together, HSF and HSP partners are attractive targets in therapeutic strategies designed to stimulate endogenous protective mechanisms against deleterious consequences of oxidative stress. With further technological advances, it is anticipated that the spotlight on HSP, alone or in combination with other stress response pathways, could, ultimately, reduce injury and accelerate functional recovery of susceptible organs in living organisms including humans.
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PMID:Heat shock factor 1 and heat shock proteins: Critical partners in protection against acute cell injury. 1183 44

The detection of neurodegenerative and neurometabolic diseases in children relies on a high index of suspicion as most will present as common paediatric problems such as recurrent vomiting, feeding problem, failure to thrive, sepsis, or developmental delay. Alternatively, children may present with an acute encephalopathy or with a chronic progressive encephalopathy. Clinical clues suggestive of neurometabolic disorders include encephalopathic features such as microcephaly, macrocephaly, developmental regression, developmental arrest, change in sensorium, seizures, hypotonia, hypertonia, abnormal eye signs; also extrapyramidal or cerebellar signs and systemic features like abnormal respiration, hepatosplenomegaly, abnormal hair, liver dysfunction, renal tubular dysfunction, cardiomyopathy, and feeding difficulties or growth problems. Initial screening include tests for acidosis, ketosis, hyperlacticemia, and hyperammonemia. Further investigations should amino acid chromatography, assays of organic acids, specific enzyme assay of white cell or fibroblast culture, and histopatholgy of cell and tissue biopsy (white blood cell, skin, muscle, conjunctiva, bone marrow, liver, rectum, or brain). The correct diagnosis holds implications for targeted therapeutic intervention, genetic counselling, and possibly, prenatal diagnosis.
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PMID:Neurodegenerative diseases in children. 1184 61

An excessive production of nitric oxide (NO) by NO synthase (NOS) is considered to contribute to circulatory disturbance, tissue damage, and refractory hypotention, which are often observed in septic disorders. It is anticipated that a selective inducible NOS (iNOS) inhibitor with excellent pharmacokinetics may be potentially effective as a novel and potent therapeutic intervention in sepsis. We examined whether or not a selective iNOS inhibitor shows iNOS selectivity at the tissue level, when administered systemically. The effects of four NOS inhibitors on plasma nitrite/nitrate (NOx) and tissue NOS levels were compared in major organs (lungs, liver, heart, kidneys, and brain) 6 hr after the injection of E. coli lipopolysaccharide (LPS) into male Wistar-King rats. The rats treated with the three iNOS inhibitors (N-(3-(aminomethyl)benzyl)acetamidine (1400W), (1 S, 5 S, 6 R, 7 R )-2-aza-7-chloro-3-imino-5-methylbicyclo [4.1.0] heptane hydrochloride (ONO-1714), and aminoguanidine) administered 1 hr after LPS injection, showed dose-dependent decreases in plasma NOx levels and NOS activity in the lungs. The non-selective NOS inhibitor (N(G)-methyl-L-arginine (L-NMMA)) had an effect only at the maximum dose. The differences in in vitro iNOS selectivity among these drugs did not correlate with iNOS selectivity at the tissue level. The relationship between plasma NOx levels and NOS activity in the lungs showed a linear relationship with or without the NOS inhibitors. In conclusion, the iNOS selectivity of these drugs does not seem to differ at the tissue level. Plasma NOx levels may be a useful indicator of lung NOS activity.
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PMID:Comparison of effects of nitric oxide synthase (NOS) inhibitors on plasma nitrite/nitrate levels and tissue NOS activity in septic organs. 1572 99

Broadly speaking, C1 inhibitor plays important roles in the regulation of vascular permeability and in the suppression of inflammation. Vascular permeability control is exerted largely through inhibition of two of the proteases involved in the generation of bradykinin, factor XIIa and plasma kallikrein (the plasma kallikrein-kinin system). Anti-inflammatory functions, however, are exerted via several activities including inhibition of complement system proteases (C1r, C1s, MASP2) and the plasma kallikrein-kinin system proteases, in addition to interactions with a number of different proteins, cells and infectious agents. These more recently described, as yet incompletely characterized, activities serve several potential functions, including concentration of C1 inhibitor at sites of inflammation, inhibition of alternative complement pathway activation, inhibition of the biologic activities of gram negative endotoxin, enhancement of bacterial phagocytosis and killing, and suppression of the influx of leukocytes into a site of inflammation. C1 inhibitor has been shown to be therapeutically useful in a variety of animal models of inflammatory diseases, including gram negative bacterial sepsis and endotoxin shock, suppression of hyperacute transplant rejection, and treatment of a variety of ischemia-reperfusion injuries (heart, intestine, skeletal muscle, liver, brain). In humans, early data appear particularly promising in myocardial reperfusion injury. The mechanism (or mechanisms) of the effect of C1 inhibitor in these conditions is (are) not completely clear, but involve inhibition of complement and contact system activation, in addition to variable contributions from other C1 inhibitor activities that do not involve protease inhibition.
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PMID:Biological activities of C1 inhibitor. 1867 18


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