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

Caspase-9 is believed to play an essential role in sepsis-induced lymphocyte apoptosis. The aim of this study was therefore to evaluate its contribution within the caspase-dependent apoptosis pathway in a murine model of polymicrobial sepsis. Local injections of Z-LEHD-fmk, a specific caspase-9 inhibitor, into thymi of septic mice led to the complete inhibition of caspase-9, decreased apoptosis of resident tissue cells, and, in addition, reduced further downstream caspase-3 activity. In contrast to its systemic administration, only local injections improved the overall survival of septic mice. However, local injections of a pancaspase inhibitor (Z-VAD-fmk) did not improve survival, although caspase-3 activity was reduced to a similar degree as by the administration of Z-LEHD-fmk. These results indicate that local apoptosis of lymphatic tissue in polymicrobial sepsis is processed dependent of caspase-9 and suggests alternative caspase-dependent beneficial effects, which may determine a positive outcome.
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PMID:Local thymic caspase-9 inhibition improves survival during polymicrobial sepsis in mice. 1645 49

Sepsis induced by exposure to lipopolysaccharide (LPS) can be life-threatening and lead to multiple-organ dysfunction. Sepsis-associated cardiac dysfunction is a primary cause of mortality. The response of isolated cardiac myocytes to LPS exposure is poorly understood. Cultured neonatal rat ventricular cardiomyocytes were used to evaluate the response to LPS exposure. Other authors have reported that LPS exposure at doses sufficient to induce tumor necrosis factor alpha (TNF-alpha) production and apoptosis in adult cardiomyocytes do not induce apoptosis in neonatal cardiomyocytes. We therefore hypothesized that neonatal cardiomyocytes have innate protective mechanisms that protect from septic damage. Cultured neonatal rat ventricular cardiomyocytes were stimulated by exposure to LPS for varying lengths of time. NFkappaB signaling pathways, TNF-alpha production, and Akt activation were monitored. We also assessed the induction of apoptosis in these cells by monitoring caspase-3 activity. LPS rapidly stimulates nuclear translocation of NFkappaB and Akt activation. TNF-alpha production is also stimulated. However, high doses of LPS are unable to induce apoptosis in these cells, and protection is not a function of Akt activation. LPS treatment also stimulated the levels of cyclooxygenase-2 and the production of downstream metabolites, specifically PGE2 and 15deoxyDelta12-14PGJ2 (15dPGJ2). Specific inhibition of cyclooxygenase-2 activity induced apoptosis in the presence of LPS, whereas direct exposure to 15dPGJ2 at pharmacological levels induced apoptosis. Neonatal rat ventricular cardiomyocytes have innate protective mechanisms that prevent apoptotic cell death after LPS exposure. Metabolic products of arachidonic acid metabolized by the cyclooxygenase pathway can be potentially apoptotic or antiapoptotic. The balance of these products within these cells may define the cellular response to LPS exposure.
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PMID:The response of neonatal rat ventricular myocytes to lipopolysaccharide-induced stress. 1668 21

Conditions such as acidosis, uremia, and sepsis are characterized by insulin resistance and muscle wasting, but whether the insulin resistance associated with these disorders contributes to muscle atrophy is unclear. We examined this question in db/db mice with increased blood glucose despite high levels of plasma insulin. Compared with control littermate mice, the weights of different muscles in db/db mice and the cross-sectional areas of muscles were smaller. In muscle of db/db mice, protein degradation and activities of the major proteolytic systems, caspase-3 and the proteasome, were increased. We examined signals that could activate muscle proteolysis and found low values of both phosphatidylinositol 3 kinase (PI3K) activity and phosphorylated Akt that were related to phosphorylation of serine 307 of insulin receptor substrate-1. To assess how changes in circulating insulin and glucose affect muscle protein, we treated db/db mice with rosiglitazone. Rosiglitazone improved indices of insulin resistance and abnormalities in PI3K/Akt signaling and decreased activities of caspase-3 and the proteasome in muscle leading to suppression of proteolysis. Underlying mechanisms of proteolysis include increased glucocorticoid production, decreased circulating adiponectin, and phosphorylation of the forkhead transcription factor associated with increased expression of the E3 ubiquitin-conjugating enzymes atrogin-1/MAFbx and MuRF1. These abnormalities were also corrected by rosiglitazone. Thus, insulin resistance causes muscle wasting by mechanisms that involve suppression of PI3K/Akt signaling leading to activation of caspase-3 and the ubiquitin-proteasome proteolytic pathway causing muscle protein degradation.
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PMID:Insulin resistance accelerates muscle protein degradation: Activation of the ubiquitin-proteasome pathway by defects in muscle cell signaling. 1677 75

Circulating soluble E-selectin is increased in diseases associated with endothelial apoptosis such as sepsis and acute respiratory distress syndrome. We investigated the mechanism by which endothelial cell (EC) apoptosis may promote soluble E-selectin release. We found that serum deprivation of EC caused apoptosis, yet it did not induce E-selectin EC surface expression. Tumor necrosis factor-alpha (TNFalpha) significantly increased EC E-selectin surface expression. Soluble E-selectin was noted, however, only in the medium of TNFalpha-activated, apoptotic EC. Preincubation of the EC with the caspase inhibitor z-VAD-fmk significantly attenuated soluble E-selectin levels in the culture medium of TNFalpha-activated, apoptotic EC, but it had no effect on E-selectin surface expression. These results indicate that TNFalpha activation, but not apoptosis, is necessary for E-selectin surface expression in EC. Furthermore, E-selectin release from EC requires caspase-3 activation. Thus, increased concentrations of circulating E-selectin in serum may serve as a marker for endothelial apoptosis in certain disease states.
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PMID:Release of soluble E-selectin from activated endothelial cells upon apoptosis. 1723 25

Protein C (PC) plays an important role in vascular function, and acquired deficiency during sepsis is associated with increased mortality in both animal models and in clinical studies. This study explored the consequences of PC suppression on the kidney in a cecal ligation and puncture model of polymicrobial sepsis. This study shows that a rapid drop in PC after sepsis is strongly associated with an increase in blood urea nitrogen, renal pathology, and expression of known markers of renal injury, including neutrophil gelatinase-associated lipocalin, CXCL1, and CXCL2. The endothelial PC receptor, which is required for the anti-inflammatory and antiapoptotic activity of activated PC (APC), was significantly increased after cecal ligation and puncture as well as in the microvasculature of human kidneys after injury. Treatment of septic animals with APC reduced blood urea nitrogen, renal pathology, and chemokine expression and dramatically reduced the induction of inducible nitric oxide synthase and caspase-3 activation in the kidney. The data demonstrate a clear link between acquired PC deficiency and renal dysfunction in sepsis and suggest a compensatory upregulation of the signaling receptor. Moreover, these data suggest that APC treatment may be effective in reducing inflammatory and apoptotic insult during sepsis-induced acute renal failure.
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PMID:Role of protein C in renal dysfunction after polymicrobial sepsis. 1730 Nov 89

The current comparative investigation analyses markers of inflammation and apoptosis in peripheral blood of intensive care unit (ICU) patients with postoperative/posttraumatic SIRS (systemic inflammatory response syndrome), sepsis, severe sepsis, or septic shock. Inflammatory markers (C-reactive protein [CRP], cytokines, metalloproteinases [MMPs]) and soluble FAS-Ligand (sCD178) were determined in plasma, and apoptosis-relevant antigens such as active caspase-3, Bcl-2, and sCD178 were quantified in whole-blood cell lysates. These parameters were analyzed daily in 20 postoperative/posttraumatic patients: 2 patients had SIRS, 5 suffered from sepsis (2 died), and 13 had septic shock (5 died). Active caspase-3, Bcl-2, and sCD178 were determined by ELISA and by fluorescence-activated cell sorting (FACS)-array kits using bead-assisted flow cytometry. Cytokines and MMPs were quantified by Luminex-assisted Beadlyte assays. Active caspase-3 was identified in defined samples of whole-blood lysates covering, for example, 5/7, 8/18, and 6/11 consecutive days during the patients' stay on the ICU. Also, sCD178 was detected on successive days. Peaks of active caspase-3 antigen contents in whole blood occurred independently of CRP and inflammatory cytokines such as tumor necrosis factor (TNF)-alpha and IL-6. In addition, high MMPs 1-3, 7-10, and 13 concentrations were detected. Interestingly, active caspase-3 and cell-associated sCD178 were either elevated simultaneously or in a close time window. The same was true for Bcl-2. In conclusion, activation of apoptosis can be determined in whole blood of postoperative/posttraumatic patients by active caspase-3 and by Bcl-2. Pro- and antiapoptotic effects during sepsis may occur independently of peaks in inflammatory markers. Apoptosis could explain modeling and remodeling of leukocyte subpopulations.
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PMID:Caspase-3 activation, Bcl-2 contents, and soluble FAS-ligand are not related to the inflammatory marker profile in patients with sepsis and septic shock. 1738 59

Trauma causes immediate cytokine release and the systemic inflammatory response syndrome (SIRS), often preceding sepsis and septic shock. Mechanisms may involve P2X7 ion channel activation via adenosine 5'-triphosphate (ATP) released from surrounding tissue and platelets. A number of single nucleotide polymorphisms (SNPs) influence the nature and magnitude of P2X7-stimulated cytokine release and apoptosis. In whole blood and isolated mononuclear blood cells (PBMCs) of donors with wild-type and heterozygous mutated genotypes, we found downregulated IL-8 and caspase-3 activation but no reproducible effect on tumor necrosis factor (TNF)-alpha and IL-1beta release. IL-8 and caspase-3 activation were both influenced by paxilline, an inhibitor of calcium-activated potassium channels. Confocal laser scanning microscopy demonstrated that calcium signaling is affected by paxilline as well. We propose that blockade of potassium channels may be relevant to attenuate ATP-induced cytokine responses and apoptosis. The presence of functional SNPs in heterozygous genotypes appears to play a role.
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PMID:Role of ATP in trauma-associated cytokine release and apoptosis by P2X7 ion channel stimulation. 1738 68

Apoptosis of blood monocytes was studied in experimental sepsis by multi-drug-resistant Pseudomonas aeruginosa. Thirty-six rabbits were used, divided into the following groups: A (n = 6), sham; B (n = 6), administered anaesthetics; and C (n = 24), acute pyelonephritis induced after inoculation of the test isolate in the renal pelvis. Blood was sampled at standard time intervals for estimation of tumour necrosis factor (TNF)-alpha and isolation of monocytes. Half the monocytes were incubated and the other half was lysed for estimation of the cytoplasmic activity of caspase-3 by a kinetic chromogenic assay. No animal in groups A and B died; those in group C were divided into two subgroups, CI (n = 8) with present activity of caspase-3 of blood monocytes at 3.5 h and CII (n = 16) with absent activity. Their median survival was 2.0 and 3.5 days, respectively (P = 0.0089). Ex vivo secretion of TNF-alpha from monocytes was higher by monocytes of subgroup CII than subgroup CI at 3.5 h (P = 0.039) and of group A than CII at 48 h (P = 0.010). Median change of caspase-3 activity between 3.5 and 24 h of sampling was 56.1 and -5.8 pmol/min per 10(4) cells for subgroups CI and CII (P = 0.040), respectively. Respective changes between 3.5 and 48 h were 28 981.0 and 0 pmol/min per 10(4) cells (P = 0.036). Early induction of apoptosis in blood monocytes is of prime importance for the survival of the septic host and might be connected to changes of monocyte potential for the secretion of TNF-alpha.
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PMID:Early apoptosis of blood monocytes is a determinant of survival in experimental sepsis by multi-drug-resistant Pseudomonas aeruginosa. 1748 99

Although studies blocking the Fas pathway indicate it can decrease organ damage while improving septic (cecal ligation and puncture, CLP) mouse survival, little is known about how Fas-Fas ligand (FasL) interactions mediate this protection at the tissue level. Here, we report that although Fas expression on splenocytes and hepatocytes is up-regulated by CLP and is inhibited by in vivo short interfering RNA, FasL as well as the frequency of CD8(+) T cells are differentially altered by sepsis in the spleen (no change in FasL, decreased percentage of CD8(+) and CD4(+) T cells) versus the liver (increased FasL expression on CD8(+) T cells and increase in percentage/number). Adoptive transfer of CLP FasL(+/+) versus FasL(-/-) mouse liver CD8(+) T cells to severe combined immunodeficient or RAG1(-/-) recipient mice indicated that these cells could induce inflammation. The FasL-mediated cytotoxic capacity of these septic mouse liver CD8(+) T cells was shown by their ability to damage directly cultured hepatocytes. Finally, although CD8(-/-) mice exhibited a reduction in both CLP-induced liver active caspase-3 staining and blood interleukin-6 levels, only FasL(-/-) (but not CD8(-/-)) protected the septic mouse spleen from increasing apoptosis. Thus, although truncating Fas-FasL signaling ameliorates many untoward effects of sepsis, the pathological mode of action is distinct at the tissue level.
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PMID:CD8+ T cells promote inflammation and apoptosis in the liver after sepsis: role of Fas-FasL. 1759 56

We hypothesized that progressive decline in myocardial performance would correlate with upregulation of markers for apoptotic mechanisms following increased duration of polymicrobial sepsis in the rat. Male Sprague-Dawley rats (350-400 g) were randomized into sham, 1-, 3- and 7-day sepsis groups. Each septic rat received 200 mg/kg cecal inoculum intraperitoneally (i.p). The post-mortem analysis showed a severely inflamed peritoneum with the presence of pus in all septic animals that was directly proportional to the duration of sepsis. We observed 10, 33 and 42% mortality in the 1-, 3- and 7-day sepsis groups, respectively. Septic animals at 3 and 7 days exhibited an increased wet lung/total body weight and heart weight/total body weight. A significant increase in total cardiac troponin I (cTnI) and C Reactive Protein (CRP) and endothelin-1 (ET-1) was also observed with an increased duration of sepsis. Myocardial ET-1 concentration in the 7-day post-sepsis group was significantly elevated compared to the sham and 1-day post-sepsis groups. Sepsis also produced a significant decrease in the mean arterial pressure in the 7-day post-sepsis group and tachycardia in the 1-, 3-, and 7-day post-sepsis groups compared to the sham group. A significant prolongation of the left ventricular isovolumic relaxation rate constant, tau, and left ventricular end-diastolic pressure in the 1-, 3- and 7-day post-sepsis groups compared to the sham group was observed. In addition, a significant decrease in the rates of left ventricular relaxation (-dP/dt) and contraction (+dP/dt) in the 3- and 7-day post-sepsis groups compared to the sham and 1-day post-sepsis group was observed. Sepsis produced a significant upregulation in the expression of myocardial TRADD, cytosolic active caspase-3, the Bax/Bcl(2) ratio, and the mitochondrial release of cytochrome C in the 3- and 7-day post-sepsis groups. We observed a progressive increase in the number of TUNEL positive nuclei, cytosolic caspase-3 activation and co-localization of PARP in the nuclei at 1, 3 and 7 days post-sepsis. These data suggest that the progression of sepsis from 1 day to 3-7 days produce distinct cardiodynamic characteristics with a more profound effect during later stages. The sepsis-induced decline in myocardial performance correlates with the induction of myocardial apoptosis.
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PMID:Distinct cardiodynamic and molecular characteristics during early and late stages of sepsis-induced myocardial dysfunction. 1761 71


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