Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lipopolysaccharide (LPS)-regulated contractility in pericytes may play an important role in mediating pulmonary microvascular fluid hemodynamics during inflammation and sepsis. LPS has been shown to regulate inducible nitric oxide (NO) synthase (iNOS) in various cell types, leading to NO generation, which is associated with vasodilatation. The purpose of this study was to test the hypothesis that LPS can regulate relaxation in lung pericytes and to determine whether this relaxation is mediated through the iNOS pathway. As predicted, LPS stimulated NO synthesis and reduced basal tension by 49% (P < 0.001). However, the NO synthase inhibitors N (omega)-nitro-L-arginine methyl ester, aminoguanidine, and N (omega)-monomethyl-L-arginine did not block the relaxation produced by LPS. In fact, aminoguanidine and N (omega)-monomethyl-L-arginine potentiated the LPS response. The possibility that NO might mediate either contraction or relaxation of the pericyte was further investigated through the use of NO donor compounds; however, neither sodium nitroprusside nor S-nitroso-N-acetylpenicillamine had any significant effect on pericyte contraction. The inhibitory effect of aminoguanidine on LPS-stimulated NO production was confirmed. This ability of LPS to inhibit contractility independent of iNOS was also demonstrated in lung pericytes derived from iNOS-deficient mice. This suggests the presence of an iNOS-independent but as yet undetermined pathway by which lung pericyte contractility is regulated.
Am J Physiol Lung Cell Mol Physiol 2000 May
PMID:Lipopolysaccharide induces relaxation in lung pericytes by an iNOS-independent mechanism. 1078 17

Enhanced prostanoid generation has been implicated in vascular abnormalities occurring during endotoxemia and sepsis, and the lung is particularly prone to such events. Prostanoids are generated from arachidonic acid (AA) via cyclooxygenase (COX)-1 or -2, both isoenzymes recently demonstrated to be expressed in different lung cell types. Upregulation of COX may underlie the phenomenon that endotoxin [lipopolysaccharide (LPS)]-exposed lungs show markedly enhanced vasoconstrictor responses to secondarily applied stimuli (priming). Isolated rat lungs were perfused with a physiological salt buffer solution in the absence and presence of 1.5% rat plasma and exposed to different concentrations of LPS (1,000 or 10,000 ng/ml) during a 2-h priming period. No change in physiological variables was noted during this period, although enhanced baseline liberation of both thromboxane (Tx) A(2) and PGI(2) as well as of tumor necrosis factor (TNF)-alpha was evident compared with that in control lungs in the absence of LPS. LPS priming caused a significant elevation in AA-induced pulmonary arterial pressure, ventilation pressure, and lung weight gain. Concomitant increased levels of TxA(2) were found in the buffer perfusate. All changes were largely suppressed by three selective, structurally unrelated COX-2 inhibitors (NS-398, DUP-697, and SC-236) in both buffer- and buffer-plasma-perfused lungs. Anti-TNF-alpha neutralizing antibodies were ineffective under conditions of buffer perfusion. In the presence of plasma components, manyfold augmented TNF-alpha generation was noted, and anti-TNF-alpha antibodies significantly suppressed the increase in ventilation pressure but not in the vascular pressor response and lung edema formation. We conclude that the propensity of LPS-primed lungs to respond with enhanced vasoconstriction, edema formation, and bronchoconstriction to a secondarily applied stimulus proceeds nearly exclusively via COX-2 and increased Tx formation, with TNF-alpha generation being involved in the change in bronchomotor reactivity in the presence of plasma constituents. In context with recent immunohistological investigations, LPS-induced upregulation of the COX-2-thromboxane synthase axis in vascular and bronchial smooth muscle cells is suggested to underlie these events.
Am J Physiol Lung Cell Mol Physiol 2000 Jun
PMID:Endotoxin priming of the cyclooxygenase-2-thromboxane axis in isolated rat lungs. 1083 25

To study the mechanisms that link sepsis with ARDS, many animal models have been developed. In this chapter, a rabbit model of sepsis secondary to an intrapulmonary or intraabdominal infection has been described. One advantage of the rabbit model of sepsis is that this species produces the C-X-C chemokine, IL-8. In contrast, rodents, which are often used in studies of sepsis and ARDS, lack this important chemokine. A second advantage is the rabbit's size. This species is large enough so that the measurement of physiological parameters (e.g., mean arterial pressure, heart rate, etc.) is not difficult, but they are not so large that they require large quantities of precious reagents (e.g., recombinant proteins and MAbs). A disadvantage of the rabbit model is that there are fewer reagents (e.g., recombinant cytokines and MAbs) available for the study of inflammation in rabbits when compared to mice.
Methods Mol Biol 2000
PMID:Rabbit models of pneumonia, peritoneal sepsis, and lung injury. 1084 Jul 72

We examined gene expression of heat shock protein 70 (HSP70) and heme oxygenase-1 (HO-1), which is the rate limiting enzyme in heme catabolism and is also known as heat shock protein 32 (HSP32), in the rat brain using a sepsis model induced by bacterial lipopolysaccharide (LPS). Intraperitoneal injection of LPS (10 mg/kg) to rats caused the elevation of body temperature and white blood cell (WBC) counts as well as marked elevation of serum interleukin-6 (IL-6) level, showing the typical pathological characteristics of sepsis. In this model, HO-1 mRNA increased at 6 h after LPS administration and continued to rise until 30 h. In contrast, HSP70 mRNA increased only between 3 h and 6 h after LPS administration, returning completely to the control level by 12 h. HO-1 mRNA was expressed predominantly in the cortex and the medulla oblongata, while HSP70 mRNA was expressed mainly in the striatum. HO-1 and HSP70 mRNA levels thus showed distinctive time courses and tissue distribution in the brain, suggesting that gene expression of these heat shock proteins (HSPs) is separately regulated.
Res Commun Mol Pathol Pharmacol 1999
PMID:Differential induction of brain heme oxygenase-1 and heat shock protein 70 mRNA in sepsis. 1085 Mar 69

Escherichia coli hemolysin (HlyA) is a prototype of a large family of pore-forming proteinaceous exotoxins that have been implicated in the pathogenetic sequelae of severe infection and sepsis, including development of acute lung injury. In the present study in rabbit alveolar macrophages (AMs), subcytolytic concentrations of purified HlyA evoked rapid synthesis of platelet-activating factor, with quantities approaching those in response to maximum calcium ionophore challenge. In parallel, large quantities of leukotriene (LT) B(4) and 5-, 8-, 9-, 12-, and 15-hydroxyeicosatetraenoic acid (HETE) were liberated from HlyA-exposed AMs depending on exogenous arachidonic acid (AA) supply. Coadministration of eicosapentaenoic acid (EPA) dose dependently suppressed generation of the proinflammatory lipoxygenase products LTB(4) and 5-, 8-, 9-, and 12-HETE in parallel with the appearance of the corresponding EPA-derived metabolites LTB(5) and 5-, 8-, 9-, and 12-hydroxyeicosapentaenoic acid (HEPE). At equimolar concentrations, EPA turned out to be the preferred substrate over AA for these AM lipoxygenase pathways, with the sum of LTB(5) and 5-, 8-, 9-, and 12-HEPE surpassing the sum of LTB(4) and 5-, 8-, 9-, and 12-HETE by >80-fold. In contrast, coadminstration of EPA did not significantly reduce HlyA-elicited generation of the anti-inflammatory AA lipoxygenase product 15-HETE. We conclude that AMs are sensitive target cells for HlyA attack, resulting in marked proinflammatory lipid mediator synthesis. In the presence of EPA, lipoxygenase product formation is shifted from a pro- to an anti-inflammatory profile.
Am J Physiol Lung Cell Mol Physiol 2000 Jul
PMID:E. coli hemolysin-induced lipid mediator metabolism in alveolar macrophages: impact of eicosapentaenoic acid. 1089 8

Between December 1996 and September 1998, 13 patients with advanced recurrent malignant brain tumors (9 with glioblastoma multiforme, 1 with gliosarcoma, and 3 with anaplastic astrocytoma) were treated with a single intratumoral injection of 2 x 10(9), 2 x 10(10), 2 x 10(11), or 2 x 10(12) vector particles (VP) of a replication-defective adenoviral vector bearing the herpes simplex virus thymidine kinase gene driven by the Rous sarcoma virus promoter (Adv.RSVtk), followed by ganciclovir (GCV) treatment. The VP to infectious unit ratio was 20:1. Our primary objective was to determine the safety of this treatment. Injection of Adv.RSVtk in doses <==2 x 10(11) VP, followed by GCV, was safely tolerated. Patients treated with the highest dose, 2 x 10(12) VP, exhibited central nervous system toxicity with confusion, hyponatremia, and seizures. One patient is living and stable 29.2 months after treatment. Two patients survived >25 months before succumbing to tumor progression. Ten patients died within 10 months of treatment, 9 from tumor progression and 1 with sepsis and endocarditis. Neuropathologic examination of postmortem tissue demonstrated cavitation at the injection site, intratumoral foci of coagulative necrosis, and variable infiltration of the residual tumor with macrophages and lymphocytes.
Mol Ther 2000 Feb
PMID:Phase I study of adenoviral delivery of the HSV-tk gene and ganciclovir administration in patients with current malignant brain tumors. 1093 31

Group B streptococcal (GBS) infections are the most common cause of bacterial sepsis in the immediate newborn period. Apart from the capsule, the factors required for survival of GBS in the host are not well defined. In this study, signature-tagged transposon mutagenesis (STM) was used to identify genes required for growth and survival of GBS in a neonatal rat sepsis infection model. Approximately 1600 transposon mutants were screened in pools of 80 mutants, and approximately 120 mutants defective for survival in the animal host were identified. We successfully cloned and sequenced DNA flanking the transposon insertions from 92 of the mutants. Fifty per cent of the mutants had transposon insertions in genes with homologues in the public databases, whereas the remaining 50% had transposon insertions in genes with unknown function. A significant proportion of the avirulent mutants had transposon insertions in genes encoding transport-associated or regulatory proteins or in genes involved in cell surface metabolism, emphasizing the significance of these functions for in vivo survival of GBS. Overall, STM analysis revealed GBS genomic loci that encode a wide variety of functional gene classes, underscoring the diversity of bacterial processes required for the infection process. Currently, the function of the genes identified during the screening can only be inferred by homology to previously described genes. However, a number of the genes identified in this study have been shown to correlate with virulence in other pathogens. A virulence of a subset of mutants identified during the screening was confirmed by performing competitive index assays and lethal dose assays. This represents the first report of a genome-wide scan for virulence factors in GBS. The identified genes will further our understanding of the pathogenesis of GBS infections and may represent targets for intervention or lead to the development of novel therapies.
Mol Microbiol 2000 Sep
PMID:Identification of Streptococcus agalactiae virulence genes in the neonatal rat sepsis model using signature-tagged mutagenesis. 1099 75

Serotype III group B Streptococcus agalactiae (GBS) are the most common cause of neonatal sepsis and meningitis. We have classified type III GBS by restriction digest patterns of chromosomal DNA and demonstrated that a subgroup of genetically related strains (RDP type III-3) causes the majority of type III GBS neonatal infection. Genetic differences between type III GBS strains contribute significantly to differences in virulence and host immune responses. While 100% of less virulent RDP type III-1 and III-2 organisms express C5a-ase, an inhibitor of neutrophil chemotaxis, only 63% of virulent RDP type III-3 isolates have functional C5a-ase. Functional differences in type III GBS C5a-ase are attributable to a shared genetic polymorphism, supporting our genetic classification. The mean capsular sialic acid content of virulent RDP type III-3 strains is significantly higher than that of less virulent strains, suggesting that capsular sialylation is also genetically regulated. C5a-ase is not critical for all RDP type III-3 strains to be invasive because the higher capsular sialic acid content of III-3 strains limits complement activation. The identification of these and additional genetic differences between GBS strains has important implications for our understanding of the pathogenesis of these important human infections.
Mol Genet Metab
PMID:Bacterial genetics and human immunity to group B streptococci. 1100 39

We investigated the anti-inflammatory effects of aqueous extract from Lonicera japonica flower (AELJ), a traditional skin rash drug, in lipopolysaccharide (LPS)-induced rat liver sepsis. Immunoblot analysis showed that the level of nuclear factor (NF)-kappaBp65 was rapidly up-regulated and inhibitory (I)-kappaBalpha was down-regulated by LPS challenge. However, AELJ inhibited the increase of NF-kappaBp65 and degradation of I-kappaBalpha in the liver of LPS-challenged rats. Immunohistochemical analysis of rat hepatocytes showed that LPS-induced inflammatory responses, involving degradation of I-kappaBalpha and induction of NF-kappaBp65, tumor necrosis factor (TNF)-alpha and inducible nitric oxide synthase (iNOS), are partially inhibited by pretreatment with AELJ. These results suggest that AELJ may act as a therapeutic agent for inflammatory disease through a selective regulation of NF-kappaB activation.
Int J Mol Med 2001 Jan
PMID:Anti-inflammatory effect of the aqueous extract from Lonicera japonica flower is related to inhibition of NF-kappaB activation through reducing I-kappaBalpha degradation in rat liver. 1111 13

Recent studies have indicated that sepsis is associated with enhanced generation of several free-radical species (nitric oxide [NO], superoxide, hydrogen peroxide) in skeletal muscle. It is also known that this enhanced free-radical generation results in reductions in skeletal muscle force-generating capacity, but the precise mechanism(s) by which free radicals exert this effect in sepsis has not been determined. We postulated that free radicals might react directly with the contractile proteins in this condition, altering contractile protein force-generating capacity. To test this theory, we compared the force generation of single Triton-skinned diaphragmatic fibers (Triton skinning exposes the contractile apparatus, permitting direct assessment of contractile protein function) from the following groups of rats: (1) control animals; (2) endotoxin-treated animal; (3) animals given endotoxin plus polyethylene glycol- superoxide dismutase (PEG-SOD), a superoxide scavenger; (4) animals given endotoxin plus N(omega)-nitro-L-arginine methylester (L-NAME), a NO synthase inhibitor; (5 ) animals given only PEG-SOD or L-NAME; and (6 ) animals given endotoxin plus denatured PEG-SOD. We found that endotoxin administration produced both a reduction in the maximum force-generating capacity (Fmax) (i.e., a decrease in Fmax) of muscle fibers and a reduction in fiber calcium sensitivity (i.e., an increase in the Ca2+ concentration required to produce half-maximal activation [Ca50]). L-NAME and PEG-SOD administration preserved Fmax and Ca50 in endotoxin-treated animals; neither drug affected these parameters in non-endotoxin treated animals. Denatured PEG-SOD failed to inhibit endotoxin-related alterations in contractile protein function. Sodium dodecyl sulfate polyacrylamide gel electrophoresis of skinned fibers from endotoxin-treated animals revealed a selective depletion of several proteins; administration of L-NAME or PEG-SOD to endotoxin-treated animals prevented this protein depletion, paralleling the effect of these two agents to prevent a reduction in contractile protein force-generating capacity. These data indicate that free radicals (superoxide, NO, or daughter species of these radicals) play a central role in altering skeletal muscle contractile protein force-generating capacity in endotoxin-induced sepsis.
Am J Respir Cell Mol Biol 2001 Feb
PMID:Free radical-induced contractile protein dysfunction in endotoxin-induced sepsis. 1115 56


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