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

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.
 ...
PMID:Free radical-induced contractile protein dysfunction in endotoxin-induced sepsis. 1115 56

Tumor necrosis factor-alpha (TNF-alpha), a crucial mediator in sepsis, elicits multiple biologic effects, including intravascular thrombosis and circulatory shock. TNF-alpha exerts its biologic effects through two distinct cell surface receptors, TNF-R1 and TNF-R2. The pathophysiologic interaction between TNF-alpha and nitric oxide (NO) in glomerular thrombosis caused by endotoxemia in rats and wild-type mice (C57BL6) as well as in knockout mice that are deficient in TNF-R1 (R1 -/-), TNF-R2 (R2 -/-), or both receptors (R1R2 -/-) was studied. Administration of lipopolysaccharide (LPS; Escherichia coli endotoxin) resulted in increased NO and TNF-alpha production but failed to induce glomerular thrombosis. Concomitant administration of LPS + NG-nitro-L-arginine methyl ester (L-NAME; an NO synthesis inhibitor) resulted in glomerular thrombosis in rats and in wild-type mice. Intraperitoneal administration of pentoxifylline before LPS inhibited TNF-alpha synthesis and prevented glomerular thrombosis in rats given LPS + L-NAME. In contrast to the results observed in rats and wild-type mice, administration of LPS + L-NAME did not result in glomerular thrombosis in knockout mice with either single or double TNF-alpha receptor deletion. Thus, during endotoxemia, (1) TNF-alpha fosters glomerular thrombosis if there is deficiency of NO synthesis and (2) both TNF-alpha receptors are necessary for TNF-alpha's prothrombogenic action. Clinically, these novel studies suggest that in gram-negative endotoxemia, inhibition of NO synthesis and selective blockade of TNF-alpha receptors may provide unique therapeutic approaches for mitigation of glomerular thrombosis and restitution of vascular tone.
 ...
PMID:Countervailing influence of tumor necrosis factor-alpha and nitric oxide in endotoxemia. 1137 43

Leukocyte accumulation has been shown to be increased in sepsis. Moreover, in inducible nitric oxide synthase (iNOS) knockout mice, a further increase in leukocyte accumulation has been observed during sepsis, suggesting that nitric oxide (NO) may affect leukocyte/endothelial interaction. Accelerated peroxynitrite formation also occurs during sepsis. In the present study, the effect of peroxynitrite or NO on leukocyte adhesion to nitric oxide synthase (NOS)-inhibited or endotoxin-treated endothelium was examined. Bovine aortic endothelial cells were treated with either L-NAME or lipopolysaccharide (LPS) and interferon-gamma for 4 hr and subsequent leukocyte adhesion was measured. Both L-NAME and LPS treatment resulted in increased leukocyte adhesion compared with control. Neither a peroxynitrite donor, SIN-1, nor a direct NO donor, DETA-NO, had any effect on leukocyte adhesion to untreated endothelium. However, when the L-NAME or LPS-treated endothelial cells were treated simultaneously with either SIN-1 or DETA-NO, there was a significant reduction in leukocyte adhesion. Moreover, at the concentrations used in the present study, neither peroxynitrite nor NO showed harmful effects on normal cultured endothelial cells. These data demonstrating inhibition of leukocyte adhesion to endotoxin-treated endothelium suggest that peroxynitrite or NO may exert a beneficial effect during sepsis.
 ...
PMID:Effects of nitric oxide and peroxynitrite on endotoxin-induced leukocyte adhesion to endothelium. 1147 60

Several natural flavonoids have been demonstrated to perform some beneficial biological activities, however, higher-effective concentrations and poor-absorptive efficacy in body of flavonoids blocked their practical applications. In the present study, we provided evidences to demonstrate that flavonoids rutin, quercetin, and its acetylated product quercetin pentaacetate were able to be used with nitric oxide synthase (NOS) inhibitors (N-nitro-L-arginine (NLA) or N-nitro-L-arginine methyl ester (L-NAME)) in treatment of lipopolysaccharide (LPS) induced nitric oxide (NO) and prostaglandin E2 (PGE2) productions, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) gene expressions in a mouse macrophage cell line (RAW 264.7). The results showed that rutin, quercetin, and quercetin pentaacetate-inhibited LPS-induced NO production in a concentration-dependent manner without obvious cytotoxic effect on cells by MTT assay using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide as an indicator. Decrease of NO production by flavonoids was consistent with the inhibition on LPS-induced iNOS gene expression by western blotting. However, these compounds were unable to block iNOS enzyme activity by direct and indirect measurement on iNOS enzyme activity. Quercetin pentaacetate showed the obvious inhibition on LPS-induced PGE2 production and COX-2 gene expression and the inhibition was not result of suppression on COX-2 enzyme activity. Previous study demonstrated that decrease of NO production by L-arginine analogs effectively stimulated LPS-induced iNOS gene expression, and proposed that stimulatory effects on iNOS protein by NOS inhibitors might be harmful in treating sepsis. In this study, NLA or L-NAME treatment stimulated significantly on LPS-induced iNOS (but not COX-2) protein in RAW 264.7 cells which was inhibited by these three compounds. Quercetin pentaacetate, but not quercetin and rutin, showed the strong inhibitory activity on PGE2 production and COX-2 protein expression in NLA/LPS or L-NAME/LPS co-treated RAW 264.7 cells. These results indicated that combinatorial treatment of L-arginine analogs and flavonoid derivates, such as quercetin pentaacetate, effectively inhibited LPS-induced NO and PGE2 productions, at the same time, inhibited enhanced expressions of iNOS and COX-2 genes.
 ...
PMID:Inhibition of nitric oxide synthase inhibitors and lipopolysaccharide induced inducible NOS and cyclooxygenase-2 gene expressions by rutin, quercetin, and quercetin pentaacetate in RAW 264.7 macrophages. 1150 Sep 31

The role of constitutive nitric oxide synthases (cNOS) in sepsis remains controversial. Part of the problem is that many of the studies have been performed in rats, which respond differently than larger animals. Our objective, therefore, was to determine whether cNOS, i.e. ecNOS (NOS-3) and nNOS (NOS-1) are still active in vessels of pigs treated with lipopolysaccharide (LPS) from Escherichia coli. We also characterized the dose-response relationship of the NOS inhibitor N(G)-nitro-L-arginine-methyl-ester (L-NAME) in the arterial, venous, and pulmonary circuits as a reflection of NO production. We anesthetized and ventilated 14 pigs, which were instrumented for hemodynamic measurements. We measured mean circulatory filling pressure and resistance to venous return by transiently arresting the circulation with a balloon in the right atrium. Animals were given 20 microg/kg of LPS (n = 8) or saline (n = 6) over 2 h. They were then given progressively increasing doses of L-NAME (0.5 to 16 microg/kg). We injected 20 microg boluses of norepinephrine at baseline, after 2 h, and after 0.5, 4, and 16 microg of L-NAME to test the pressor response. Tissue was obtained from six control animals followed for 2 h, eight animals treated with LPS for 2 h and then sacrificed, and four animals treated for 2 h and sacrificed after 2 more h. Cardiac output did not change, and the systemic vascular resistance fell in LPS animals. By Western analysis, ecNOS was increased in LPS animals at 2 and 4 h in the aorta and vena cava, and this was paralleled by changes in nNOS in the vena cava. In contrast, ecNOS decreased in the pulmonary artery and nNOS did not change. Calcium-dependent NOS activity increased with LPS in the aorta and vena cava but decreased in pulmonary artery at 4 h. The dose-response relationships to L-NAME for systemic vascular resistance, resistance to venous return, and cardiac output were shifted to the left after LPS in support of increased sensitivity supporting increased NO. The pressor response to norepinephrine was depressed after LPS and was partially restored with 4 mg/kg of L-NAME, but this dose produced 90% of the fall in cardiac output. In conclusion, in contrast to rats, cNOS activity is present in the systemic vessels of LPS-treated pigs and could play a role in the pathophysiology of sepsis.
 ...
PMID:Regional changes in constitutive nitric oxide synthase and the hemodynamic consequences of its inhibition in lipopolysaccharide-treated pigs. 1153 Oct 27

1. The influence of lipopolysaccharide (LPS)-induced sepsis on the various mast cell phenotypes of rat dura mater were examined both by immunohistochemical and biochemical methods. 2. Three different populations of mast cells were identified in control rats: connective tissue type mast cells (CTMC) which contain rat mast cell protease1 (RMCP1), histamine, serotonin and heparin, mucosal type mast cells (MMC) which contain RMCP2, histamine and serotonin, and intermediate type which contains both RMCP1 and RMCP2 and probably various proportions of amines and heparin. 3. LPS (25 mg kg(-1) i.p.) caused changes in the proportions of the various types of mast cells. The number of MMC and intermediate type mast cells significantly increased and the number of mast cells immunopositive for both heparin and serotonin significantly decreased. Biochemical analysis showed that the histamine concentration of dura increased while its serotonin concentration decreased. 4. While vasoactive intestinal peptide (VIP) (25 ng kg(-1) i.p.) appears to potentiate LPS effects on dura mater mast cells, non-selective inhibition of nitric oxide (NO) synthase by N(g)-nitro-L-arginine methyl ester (L-NAME) (30 mg kg(-1) i.p.) did not influence sepsis-induced mast cell changes. 5. These findings suggest that mast cells of dura mater may play a role in brain protection during sepsis.
 ...
PMID:Effects of sepsis on mast cells in rat dura mater: influence of L-NAME and VIP. 1172 41

Nitric oxide (NO) is postulated to play a key role in the pathophysiology of renal failure in sepsis. Whether the renal effects of increased NO are beneficial or harmful remains unclear. In a porcine model of lipopolysaccharide (LPS)-induced shock, we evaluated the effect of LPS on glomerular filtration rate (GFR) and renal blood flow (RBF). We then administered the nonselective nitric oxide synthase (NOS) inhibitor N(G)-L-arginine methyl ester (L-NAME), and compared its effects on GFR and RBF with those of S-methylisothiourea (SMT), a selective NOS inhibitor, and those of saline. We postulated that SMT, by maintaining constitutive NO, would be more beneficial than either L-NAME or saline. LPS infusion decreased mean arterial pressure (MAP), and increased cardiac output, RBF, and medullary NO content. The increased RBF was diverted to the medulla. There was no evidence of renal dysfunction in the saline-resuscitated group. Both NOS inhibitors increased MAP but decreased RBF, but only L-NAME reduced GFR and increased sodium excretion and renal oxygen extraction. We conclude that NO in endotoxemia is beneficial because it maintains RBF and GFR. Additionally, selective NOS inhibition did not offer any advantages over saline resuscitation.
 ...
PMID:Renal effects of nitric oxide in endotoxemia. 1173 42

Elevated levels of nitric oxide (NO) may be a primary cause of the vascular hyporeactivity (vasoplesia) and refractory hypotension in sepsis. This study was initiated to determine the efficacy of NO scavenging with acellular hemoglobin (Hb) solution in modulating sepsis-mediated vasoplesia. Male Sprague Dawley rats were subjected to sepsis by cecal ligation and puncture (CLP). Twenty-four hours post-CLP, the animals were randomly assigned to one of four groups (n = 5-6 each) and given an intravenous injection of 0.5 mL bovine serum albumin (BSA; 5 g/dL), 0.5 mL human Hb (7g/dL), 50 microL Nomega-nitro L-arginine methyl ester (NAME; 1 M), or both Hb and NAME. Blood pressure (BP), cardiac output, systemic vascular resistance, and vascular reactivity (VR) to norepinephrine (NE; 40 ng/Kg) were assessed before and after an experimental treatment. In some animals, inducible NO synthase (iNOS) mRNA expression was assessed in selected tissue samples harvested at the conclusion of experiment using a reverse transcription-polymerase chain reaction (RT-PCR) method. Treatment with Hb, NAME, or NAME + Hb elicited a significant improvement in mean BP and VR compared with the control (BSA) group (P < 0.05, analysis of variance and Neuman-Keuls tests). Tissue samples from 24-h CLP rats clearly exhibited iNOS gene expression; higher iNOS gene expression in the intestine compared with aorta suggests that the intestine may be a major source of the elevated NO level in this model. In conclusion, NO scavenging with Hb, alone, or in combination with NO synthesis inhibition, appears to be effective in modulating sepsis-mediated vascular hyporeactivity and may reduce complications associated with global NO synthesis inhibition.
 ...
PMID:Nitric oxide scavenging, alone or with nitric oxide synthesis inhibition, modulates vascular hyporeactivity in rats with intraperitoneal sepsis. 1202 65

Expression of P-450 (Cyp) enzymes is reduced in liver during the acute phase response, contributing to the decrease in bile acid levels and drug metabolism during infection. Nuclear hormone receptors CAR and PXR are key transactivators of Cyp2b and Cyp3a genes, respectively. Injection of bacterial lipopolysaccharide (LPS) induced the expected reduction in Cyp2b10 and Cyp3a mRNA levels in mouse liver. These decreases were associated with a marked reduction in CAR and PXR mRNA levels within 4 h following treatment. LPS-induced CAR and PXR repression were dose-dependent and sustained for at least 16 h. LPS treatment also reversed the up-regulation of Cyp3a in mice pre-treated with PXR ligand RU486. In addition, we observed a concomitant decrease in RXR (retinoid X receptor) mRNA levels, the obligatory partner of both CAR and PXR for high affinity binding to DNA. These findings represent one possible molecular mechanism underlying sepsis-induced repression of Cyp enzymes.
 ...
PMID:Reduction in cytochrome P-450 enzyme expression is associated with repression of CAR (constitutive androstane receptor) and PXR (pregnane X receptor) in mouse liver during the acute phase response. 1205 76

The increase in nitric oxide (NO) production in lipopolysaccharide (LPS)-induced sepsis is thought to contribute to the development of shock. However, NO could also play an antithrombotic role. Little is known about the modulating effect of NO on the endothelial overexpression and production of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) occurring in endotoxemia. We analyzed the effect of N(G)-nitro-L-arginine-methyl-ester (L-NAME), an inhibitor of NO synthases, and S-nitroso-N-acetyl-D,L-penicillamine (SNAP), a NO donor, on the expression and synthesis of TF and PAI-1 by LPS-challenged human umbilical vein endothelial cells (HUVEC): L-NAME enhanced the increase in TF mRNA and antigen levels (P <0.05) observed in LPS-treated HUVEC; SNAP down-regulated the LPS-induced TF increment (p <0.05). However, no effects of NO on regulation of the LPS-dependent increase in PAI-1 could be seen. Thus, NO could play an antithrombotic role in sepsis by down-regulating the endothelial overexpression and production of TF.
 ...
PMID:Regulation by nitric oxide of endotoxin-induced tissue factor and plasminogen activator inhibitor-1 in endothelial cells. 1252 60


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>