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)

Endotoxin is one of the major factors causing myocardial depression and death during sepsis in humans. Recently, it was reported that endotoxin may induce cardiomyocyte apoptosis. Also, multiple caspase activation has been implicated in endotoxin-induced apoptosis in several organ systems. In this study, we investigated whether endotoxin would increase myocardial caspase activities and evaluated the effects of in vivo administration (3 mg/kg) of the broad-spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone(z-VAD.fmk), the caspase-3-like inhibitor benzyloxycarbonyl-Asp-Glu-Val-Asp-chloromethylketone (z-DEVD.cmk), and the caspase-1-like inhibitor acetyl-Tyr-Val-Ala-Asp-chloromethylketone (Ac-YVAD. fmk), on endotoxin-induced myocardial dysfunction and apoptosis. Endotoxin administration (10 mg/kg iv) induced myocardial contractile dysfunction that was associated with caspase activity increases and nuclear apoptosis. Broad-spectrum z-VAD.fmk and z-DEVD.cmk improved endotoxin-induced myocardial dysfunction and reduced caspase activation and nuclear apoptosis when given immediately and 2 h after endotoxin. In contrast, no effects of Ac-YVAD.fmk were observed on myocardial function and caspase-induced apoptosis. Administration of caspase inhibitors 4 h after endotoxin treatment was not able to protect the rat heart from myocardial dysfunction and nuclear apoptosis. These observations provide evidence that in our model, caspase activation plays a role in endotoxin-induced myocardial apoptosis. Caspase inhibition strategy may represent a therapeutic approach to endotoxin-induced myocardial dysfunction.
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PMID:Differential effects of caspase inhibitors on endotoxin-induced myocardial dysfunction and heart apoptosis. 1124 71

The tyrosine nitration of proteins has been observed in diverse inflammatory conditions and has been linked to the presence of reactive nitrogen species. From many in vitro experiments, it is apparent that tyrosine nitration may alter the function of proteins. A limited number of experiments under in vivo conditions also demonstrate that protein nitration is associated with altered cellular processes. To understand the association of protein nitration with the pathogenic mechanism of the disease, it is essential to identify specific protein targets of nitration with in vivo or intact tissue models. Using anti-nitrotyrosine antibodies, we demonstrated the accumulation of nitrotyrosine in a 52-kDa protein in rat kidney after lipopolysaccharide treatment. The 52-kDa protein was purified and identified with partial sequence as succinyl-CoA:3-oxoacid CoA-transferase (SCOT; EC ). Western blot analysis revealed that the nitration of this mitochondrial enzyme increased in the kidneys and hearts of lipopolysaccharide-treated rats, whereas its catalytic activity decreased. These data suggest that tyrosine nitration may be a mechanism for the inhibition of SCOT activity in inflammatory conditions. SCOT is a key enzyme for ketone body utilization. Thus, tyrosine nitration of the enzyme with sepsis or inflammation may explain the altered metabolism of ketone bodies present in these disorders.
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PMID:Nitration of succinyl-CoA:3-oxoacid CoA-transferase in rats after endotoxin administration. 1141 99

The administration of bacterial lipopolysaccharide (LPS; endotoxin) can stimulate the development of the systemic inflammatory response syndrome, which can compromise the function of many organ systems, resulting in multiple organ failure. Activation of macrophages and cytokines by endotoxin and the subsequent formation of reactive oxygen and nitrogen species are of central pathogenic importance in various inflammatory diseases including sepsis. However, whether different tissues behave the same in pathological changes produced by LPS and what factors may affect pathological processes and protein tyrosine nitration in different organs, still remain to be evaluated. In the present study, we investigated the distribution of nitrotyrosine and other pathological changes induced by LPS in rat liver, spleen, and lung, all of which are rich in macrophages and endothelial cells. Our study revealed two important findings: first, a denitration activity in spleen white pulp might play a key role to protect the areas from nitration. Similar activity might also exist in endothelial cells of sinusoids and capillaries. Second, protein nitration might not induce significant tissue damage as shown in liver and spleen. However, inflammatory infiltration with increased formation NO* and other reactive species may result in severe tissue injury, as demonstrated in lung after LPS administration.
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PMID:Diversity of endotoxin-induced nitrotyrosine formation in macrophage-endothelium-rich organs. 1149 75

Because activation of the coagulation cascade and the generation of thrombin coexist with sepsis and the release of tumor necrosis factor (TNF)-alpha, we determined the effects of TNF-alpha on the mechanism of thrombin-induced increase in endothelial permeability. We assessed Ca(2+) signaling in human umbilical vein endothelial cells. In human umbilical vein endothelial cells exposed to TNF-alpha for 2 h, thrombin produced a rise in the intracellular Ca(2+) concentration ([Ca(2+)](i)) lasting up to 10 min. In contrast, thrombin alone produced a rise in [Ca(2+)](i) lasting for 3 min, whereas TNF-alpha alone had no effect on [Ca(2+)](i.) Thrombin-induced inositol 1,4,5-trisphosphate generation was not different between control and TNF-alpha-exposed cells. In the absence of extracellular Ca(2+), thrombin produced similar increases in [Ca(2+)](i) in both control and TNF-alpha-exposed cells. In TNF-alpha-exposed cells, the thrombin-induced Ca(2+) influx after intracellular Ca(2+) store depletion was significantly greater and prolonged compared with control cells. Increased Ca(2+) entry was associated with an approximately fourfold increase in Src activity and was sensitive to the Src kinase inhibitor PP1. After TNF-alpha exposure, thrombin caused increased tyrosine phosphorylation of junctional proteins and actin stress fiber formation as well as augmented endothelial permeability. These results suggest that TNF-alpha stimulation of endothelial cells results in amplification of the thrombin-induced Ca(2+) influx by an Src-dependent mechanism, thereby promoting loss of endothelial barrier function.
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PMID:Synergistic effects of tumor necrosis factor-alpha and thrombin in increasing endothelial permeability. 1155

Inflammation in asthma, sepsis, transplant rejection, and many neurodegenerative diseases associates an up-regulation of NO synthesis with increased protein nitration at tyrosine. Nitration can cause protein dysfunction and is implicated in pathogenesis, but few proteins that appear nitrated in vivo have been identified. To understand how this modification impacts physiology and disease, we used a proteomic approach toward targets of protein nitration in both in vivo and cell culture inflammatory disease models. This approach identified more than 40 nitrotyrosine-immunopositive proteins, including 30 not previously identified, that became modified as a consequence of the inflammatory response. These targets include proteins involved in oxidative stress, apoptosis, ATP production, and other metabolic functions. Our approach provides a means toward obtaining a comprehensive view of the nitroproteome and promises to broaden understanding of how NO regulates cellular processes.
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PMID:Proteomic method identifies proteins nitrated in vivo during inflammatory challenge. 1159 16

Modification of tyrosine residues and formation of 3-nitrotyrosine is one of the most commonly identified effects of reactive nitrogen species on proteins. In this study we evaluated the presence and localization of tyrosine nitration in various ventilatory and limb muscles. We also assessed the contribution of the neuronal (nNOS), the endothelial (eNOS), and the inducible (iNOS) isoforms of nitric oxide synthase (NOS) to tyrosine nitration in skeletal muscles both under normal conditions and in response to severe sepsis. In normal rats and mice, muscle tyrosine nitration was detected at 52, 48, 40, 30, 18, and 10 kD protein bands. Tyrosine nitration of the majority of these protein bands was significantly reduced within 1 h of in vivo NOS inhibition in rats. Diaphragmatic protein tyrosine nitration in mice deficient in the inducible NOS (iNOS-/-) averaged ~ 50% of that detected in wild-type (iNOS+/+) mice. Injection of bacterial lipopolysaccharides (LPS) in rats produced a significant rise in protein tyrosine nitration in the mitochondrial and membrane fractions but not in the cytosol of ventilatory muscles. Absence of iNOS expression (iNOS-/-), but not nNOS (nNOS-/-) or eNOS (eNOS-/-), in genetically altered mice resulted in a significant reduction in LPS-mediated rise in diaphragmatic nitrotyrosine. We conclude that tyrosine nitration of proteins occurs in normal muscle fibers and is dependent mainly on the activity of the iNOS isoform. Sepsis-mediated increase in protein tyrosine nitration is limited to the mitochondria and cell membrane and is highly dependent on the activity of the iNOS but not the nNOS or eNOS isoforms.
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PMID:Protein tyrosine nitration in the ventilatory muscles: role of nitric oxide synthases. 1191 80

Myocellular creatine (Cr) uptake is predominantly governed by a sodium-dependent Cr transporter (CreaT) and plays a pivotal role in skeletal muscle energy metabolism. The CreaT belongs to a neurotransmitter transporter family that can be functionally regulated by protein tyrosine kinase-induced tyrosine phosphorylation. The association between myocellular Cr and c-Src-related tyrosine phosphorylation of the CreaT and the influence of oral Cr supplementation on this association were investigated during sepsis. Animals were randomized to receive standard rat chow or standard rat chow with oral Cr supplementation for 4 days followed by cecal ligation and puncture (CLP) or sham operation. Fast-twitch gastrocnemius muscles were harvested 24 h after operation. Myocellular free Cr levels were 70% higher after CLP. Western blotting of the immunoprecipitated CreaT with an anti-phosphotyrosine or anti-phospho-c-Src (Y-416) antibody revealed that tyrosine phosphorylation of the CreaT and tyrosine-phosphorylated c-Src (Tyr(416)) expression in the CreaT-c-Src complex were significantly increased after CLP compared with sham operation. These changes were observed in homogenates and plasma membrane fractions of gastrocnemius muscles. Although oral Cr supplementation increased myocellular free Cr levels equivalently in CLP and sham-operated animals, c-Src-related tyrosine phosphorylation of the CreaT in homogenates and plasma membrane fractions of gastrocnemius muscles was, however, downregulated in Cr-supplemented CLP animals compared with Cr-supplemented sham-operated rats. During sepsis, increased myocellular free Cr levels are associated with enhanced tyrosine phosphorylation of the CreaT, which is likely induced by active c-Src. Oral Cr supplementation downregulates c-Src-related tyrosine phosphorylation of the CreaT. The data suggest that myocellular Cr homeostasis and CreaT activity are tightly regulated and closely related during sepsis.
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PMID:Cr supplementation decreases tyrosine phosphorylation of the CreaT in skeletal muscle during sepsis. 1193 69

Nitric oxide (NO) plays an important regulatory/modulatory role in a variety of inflammatory conditions. NO is a small, short-lived molecule that is released from a variety of cells in response to homeostatic and pathologic stimuli. It may act as a vasodilator and a platelet inhibitor and may interfere with adhesion molecules to prevent neutrophil adhesion. NO release may also lead to the formation of highly reactive species such as peroxynitrite and stable nitrosothiols and may cause mitochondrial damage and nitration of protein tyrosine residues. In addition, NO inhibits cell proliferation via inhibition of polyamine synthesis and cell uptake and may well act as a 'brake' on the proliferative response following cytokine exposure. All three isoforms of nitric oxide synthases are found in the kidney during inflammation. The site of NO release impacts significantly on its net function and structural impact. NO plays a protective role in many forms of immune injury, such as nephrotoxic serum-induced glomerulonephritis, autoimmune tubular interstitital nephritis, and experimental allergic encephalomyelitis. NO overproduction in sepsis, after cytokine exposure, inducible NO synthase transcription, and local inflammation can autoinhibit endothelial NO synthase, leading to selective renal and mesenteric vasoconstriction.
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PMID:Role of nitric oxide in inflammatory conditions. 1196 94

Our hypothesis is that nitrogen loss in septic neonates is caused by increased muscle proteolysis. Sprague-Dawley rat pups (P7) were injected intraperitoneally with NaCl or 4 mg/kg/BW lipopolysaccharide (LPS) and then sacrificed at 2, 4, 24, and 48 hr. Sepsis syndrome was confirmed by elevated serum tumor necrosis factor (24.6 ng/mL +/- 18.4 [LPS] and < 1.0 ng/mL [controls]; p < .05). Proteolysis in gastrocnemius/soleus muscle was analyzed by quantitation of tissue tyrosine loss. The neonatal rats injected with LPS had significant media tyrosine release at 24 hr compared to the controls (0.39 +/- 0.14 versus 0.25 +/- 0.11 micromol tyrosine/g muscle; p < .05). At 48 hr, LPS-induced muscle tyrosine release ceased (0.24 +/- 0.04 [control] versus 0.23 +/- 0.03 micromol tyrosine/g muscle [LPS]). After 48 hr, gastrocnemius/soleus weight was less in the LPS-injected rats (50.5 +/- 4.8 to 31.2 +/- 4.0 g; p < .0001). Similar changes were not seen in the extensor digitorum longus, suggesting that some muscles were relatively preserved. Also, LPS resulted in significant weight loss. We conclude that selective muscle proteolysis contributes to nitrogen loss in neonatal sepsis. Although proteolysis abates by 48 hr, short-term injury results in significant muscle-mass deficit.
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PMID:Muscle proteolysis and weight loss in a neonatal rat model of sepsis syndrome. 1198 93

Reduction of neutrophil apoptosis represents a major cause for granulocytosis and increases the destructive potential of theses cells during systemic inflammatory response syndrome (SIRS) and sepsis. In this light, the role of protein kinases for the regulation of altered neutrophil apoptosis under infectious conditions was investigated. Neutrophils, obtained from patients with severe sepsis (n = 18), were incubated ex vivowith either LPS (1 microg/mL) or interferon-gamma (IFN-gamma; 10 ng/mL) for 16 h. Apoptosis was determined by propidium iodine (PI) staining of DNA fragments and was compared with the rate of spontaneous apoptosis. Tyrosine kinases were inhibited by herbimycin (1 microM), the mitogen-activated protein (MAP) kinase ERK was inhibited with PD98059 (50 microM), and p38 MAP kinase was inhibited with SB203580 (5 microM). Herbimycin reconstituted LPS-reduced apoptosis in neutrophils from controls (39.9 +/- 3.8%) and patients (20.8 +/- 2.8%) to levels seen in spontaneous apoptosis (70.9 +/- 2.8% and 40.7 +/- 3.7%, respectively). Inhibition of the ERK kinase yielded similar results, whereas SB203580 had no effect on LPS-reduced apoptosis. However, inhibition of p38 partially reconstituted IFN-gamma-reduced apoptosis (51.3 +/- 7.7% and 25.6 +/- 5.8%) and increased spontaneous apoptosis (82.4 +/- 3.3% and 42.0 +/- 5.8%) in controls and patients, respectively. Western blot analysis revealed phosphorylation of both MAP kinases by LPS, but not by IFN-gamma. Inhibition of MAP kinases did not augment neutrophil apoptosis in patients to the level seen in controls, indicating that other mechanisms must be involved in the regulation of neutrophil apoptosis. Although the ERK kinase regulates LPS-induced reduction of apoptosis, the p38 MAP kinase might be involved in IFN-gamma signaling and the feedback regulation of neutrophil apoptosis.
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PMID:Activation of mitogen-activated protein kinases during granulocyte apoptosis in patients with severe sepsis. 1241 17


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