UMLS:C0243026 - FACTA Search

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Query: UMLS:C0243026 (sepsis)
52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Ethyl pyruvate (EP), a simple aliphatic ester of pyruvic acid, has been shown to improve survival and ameliorate organ damage in animal models of sepsis, ischemia/reperfusion injury and hemorrhagic shock. Incubating IL3-dependent mouse hematopoietic progenitor cell 32Dcl3 cells before or after irradiation with 10 mM EP increased resistance to radiation as assessed by clonogenic radiation survival curves, decreased release of mitochondrial cytochrome C into the cytoplasm, and decreased apoptosis. EP inhibited radiation-induced caspase 3 activation and poly(ADP-ribose) polymerase (PARP) cleavage in 32Dcl3 cells in a concentration-dependent fashion. EP was given i.p. to C57BL/6NHsd mice irradiated with 9.75 Gy total-body irradiation (TBI). This treatment significantly improved survival. The survival benefit was apparent irrespective of whether treatment with EP was started 1 h before TBI and continued for 5 consecutive days after TBI or the compound was injected only 1 h before or only for 5 days after TBI. In all of the in vitro and in vivo experiments, ethyl lactate, an inactive analogue of EP, had no detectable radioprotective or mitigating effects. EP may be an effective radioprotector and mitigator of the hematopoietic syndrome induced by TBI.
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PMID:Ethyl pyruvate, a potentially effective mitigator of damage after total-body irradiation. 1797 49

Muscle wasting in chronic kidney disease (CKD) and other catabolic diseases (e.g. sepsis, diabetes, cancer) can occur despite adequate nutritional intake. It is now known that complications of these various disorders, including acidosis, insulin resistance, inflammation, and increased glucocorticoid and angiotensin II production, all activate the ubiquitin-proteasome system (UPS) to degrade muscle proteins. The initial step in this process is activation of caspase-3 to cleave the myofibril into its components (actin, myosin, troponin, and tropomyosin). Caspase-3 is required because the UPS minimally degrades the myofibril but rapidly degrades its component proteins. Caspase-3 activity is easily detected because it leaves a characteristic 14kD actin fragment in muscle samples. Preliminary evidence from several experimental models of catabolic diseases, as well as from studies in patients, indicates that this fragment could be a useful biomarker because it correlates well with the degree of muscle degradation in dialysis patients and in other catabolic conditions.
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PMID:Muscle wasting in chronic kidney disease: the role of the ubiquitin proteasome system and its clinical impact. 1798 22

The mechanisms responsible for myocardial dysfunction in the setting of sepsis remain undefined. Fas ligation with its cognate ligand (FasL) induces apoptosis and activates cellular inflammatory responses associated with tissue injury. We determined whether interruption of Fas/FasL interaction by cardiac-specific expression of soluble Fas (sFas), a competitive inhibitor of FasL, would improve myocardial dysfunction and inflammation in a lipopolysaccharide (LPS)-induced mouse model of sepsis. Wild-type (WT) and sFas transgenic mice were injected intraperitoneally with 10 mg/kg LPS or with an equivalent volume of saline. At 18 h after LPS administration, echocardiographic evaluation revealed a significant decrease in left ventricular fractional shortening in the WT mice, whereas the fractional shortening was preserved in the sFas mice. Activation of nuclear factor-kappa B (NF-kappaB) and the increase in the transcript levels of proinflammatory cytokines, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 resulting from LPS treatment were attenuated in the myocardium of sFas mice. sFas expression also inhibited LPS-induced upregulation of Toll-like receptor 4 (TLR-4) and inducible nitric oxide synthase (iNOS), and formation of peroxynitrite in the myocardium. LPS-induced increase in caspase-3/7 activity and apoptotic cell death were suppressed in sFas mice compared with WT mice. LPS-induced lung injury and increase in lung water content were also significantly reduced in sFas mice. These data indicate that neutralization of FasL by expression of sFas significantly preserves cardiac function and reduces inflammatory responses in the heart, suggesting that Fas/FasL signaling pathway is important in mediating the deleterious effects of LPS on myocardial function.
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PMID:Protection against lipopolysaccharide-induced myocardial dysfunction in mice by cardiac-specific expression of soluble Fas. 1799 50

Sepsis induces widespread lymphocyte apoptosis, resulting in impaired immune defenses and increased morbidity and mortality. There are multiple potential triggers or signaling molecules involved in mediating death signals. Elucidating the specific signaling pathways that are involved in mediating lymphocyte apoptosis may lead to improved therapies of this lethal disorder. We investigated a number of key cellular receptors and intracellular signaling pathways that may be responsible for apoptotic cell death. Specifically, we investigated the role of pathogen-associated molecular patterns (TLR2, TLR4, and IL-1R), intracellular signaling proteins (MyD88 and TRIF), cytoplasmic transcription factors (STAT1 and STAT4), and the MAPK pathway (JNK1) in sepsis-induced lymphocyte apoptosis. Studies were performed in the cecal ligation and puncture (CLP) model of sepsis using specific gene-targeted deletions. CLP-induced lymphocyte apoptosis was evaluated 20 h post-operation by active caspase-3 and TUNEL staining. Surprisingly, the only genetic construct that ameliorated T and B lymphocyte sepsis-induced apoptosis ( approximately 80% and 85%, respectively) occurred in MyD88(-/-) mice. Despite the marked decrease in sepsis-induced apoptosis, MyD88(-/-) mice had a worsened survival. In conclusion, lymphocyte death in sepsis likely involves multiple pathogen-sensing receptors and redundant signaling pathways. MyD88 was effective in blocking apoptosis, as it is essential in mediating most pathogen recognition pathways; however, MyD88 is also critical for host survival in a model of severe peritonitis.
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PMID:Deletion of MyD88 markedly attenuates sepsis-induced T and B lymphocyte apoptosis but worsens survival. 1821 65

Ischemic gut contributes to the development of sepsis and organ failure in critically ill patients. Toll-like receptors (TLRs) have been reported to mediate the pathophysiology of organ damage following ischemia/reperfusion (I/R) injury. We hypothesize that LPS, a ligand for TLR4, decreases mesenteric I/R injury-induced gut damage through tumor necrosis factor alpha (TNF-alpha) signaling. First, wild-type (WT) mice were fed with oral antibiotics for 4 weeks to deplete the intestinal commensal microflora. At week 3, drinking water was supplemented with LPS (10 microg/microL) to trigger TLRs. The intestinal mucosa was harvested for TLR4 protein, caspase 3 activity, and terminal deoxynucleotide transferase labeling assay. Second, WT and Tnfrsf1a mice received 30-min ischemia and 30-min reperfusion (30I-30R) or 30I-180R of the intestine; intestinal permeability and lipid peroxidation of the intestine were examined. Third, WT and Tnfrsf1a mice were fed with oral antibiotics with or without LPS and received 30I-180R of the intestine. The intestinal mucosa was harvested for lipid peroxidation; glutathione (GSH) level; nuclear factor kappaB (NF-kappaB) and AP-1 DNA-binding activity; Bcl-w, TNF-alpha, and CXCR2 mRNA expression; and HSP70 protein assay. Commensal depletion increased caspase 3 activity as well as villi apoptosis and decreased TLR4 expression of the intestinal mucosa. LPS increased TLR4 expression and decreased villi apoptosis. Commensal depletion augmented 30I-180R-induced intestine permeability as well as lipid peroxidation and decreased GSH level in WT mice but not in Tnfrsf1a mice. LPS decreased 30I-180R-induced intestinal permeability as well as lipid peroxidation and increased GSH level of the intestinal mucosa in WT mice but not in Tnfrsf1a mice. Commensal depletion with 30I-180R increased NF-kappaB and AP-1 DNA-binding activity, HSP70 protein expression, and decreased Bcl-w and TNF-alpha mRNA expression of the intestinal mucosa in WT mice but not in Tnfrsf1a mice. Collectively, commensal microflora induces TLR4 expression and decreases apoptosis of the intestinal mucosa. Commensal depletion enhances I/R-induced gut damage. LPS prevents I/R-induced intestinal permeability, lipid peroxidation, and decrease in GSH level. Given that the preventive effect of LPS on I/R-induced gut damage and NF-kappaB activity of the intestine is abolished in Tnfrsf1a mice, we conclude that TLR ligand decreases mesenteric I/R injury-induced gut damage through TNF-alpha signaling.
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PMID:TLR ligand decreases mesenteric ischemia and reperfusion injury-induced gut damage through TNF-alpha signaling. 1831 7

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that causes cardiac contractile dysfunction, whereas inactivation of MIF improves cardiac function in experimental animal models of sepsis. We used cultured cardiomyocytes to determine whether MIF-induced contractile dysfunction was mediated in part by myocyte apoptosis and to identify MIF-activated intracellular signaling pathways in this process. MIF treatment significantly increased myocyte apoptosis in a dose-dependent manner to 15.5+/-3.9% and 26.0+/-7.1% TUNEL positive nuclei (20 and 30 ng/ml MIF for 24h) vs control (3.7+/-0.9%). This effect was attenuated by inactivation of MIF with the chemical inhibitor, ISO-1. MIF-induced cleavage of caspase 3 and reduction of Bcl-xL/Bax were similarly attenuated by ISO-1 pre-treatment. MIF stimulated the rapid, transient phosphorylation of stress kinases, p38MAPK and JNK. Thus, MIF induces cardiomyocyte apoptosis by activating stress kinases and mitochondria-associated apoptotic mechanisms, whereas inactivation of MIF pro-inflammatory activity improves cardiomyocyte survival.
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PMID:Macrophage migration inhibitory factor induces cardiomyocyte apoptosis. 1843 9

Sepsis is the leading cause of death in intensive care units, which reflects detrimental host response to infection where lipopolysaccharide (LPS) shared by Gram-negative bacteria acts as a potent activator of immune cells via Toll-like receptor 4 (TLR4). Recently it was found that TLR4 downstream signalling leads to the accumulation of hypoxia-inducible factor 1 alpha (HIF-1alpha), which is important for TLR4-dependent expression of pro-inflammatory cytokines, however, basic biochemical mechanisms of involvement of this protein in TLR4 downstream signalling remains unclear. Here we found that knockdown of the expression of HIF-1alpha protein by siRNA led to the depletion of ATP, which corresponded to the constant increase in the activity of apoptosis signal-regulating kinase 1 (ASK1) and therefore apoptosis as estimated based on the increase in the activity of caspase 3. On the other hand, LPS-dependent production of IL-6 was attenuated. Treatment of HIF-1alpha knockdown cells with extracellular ATP in combination with LPS preserved the IL-6 expression but not the activity of ASK1 on the level observed in LPS-stimulated control cells. We therefore suggested that HIF-1alpha protein supports LPS-dependent expression of IL-6 by preventing depletion of ATP. On the other hand HIF-1alpha protein is selectively required for down-regulation of ASK1 activated during LPS-induced TLR4 downstream signalling.
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PMID:HIF-1alpha protein is an essential factor for protection of myeloid cells against LPS-induced depletion of ATP and apoptosis that supports Toll-like receptor 4-mediated production of IL-6. 1846 99

The use of glucocorticoids for treatment of sepsis has waxed and waned during the past several decades, and recent randomized controlled trials have evoked a reassessment of this therapy. Most glucocorticoid actions are mediated by its specific intracellular receptors (GRs). Thus we initially evaluated whether sepsis and high-dose corticosteroid therapy can regulate guinea pig pulmonary expression of GRs: active receptor, GRalpha, and dominant negative receptor, GRbeta. Sepsis induction by LPS injection (300 mug/kg ip) decreased mRNA and protein levels of GRalpha and increased protein expression of GRbeta in lungs. High-dose methylprednisolone (40 mg/kg ip), administered simultaneously with LPS, markedly potentiated the decrease in GRalpha expression but slightly affected the increase in GRbeta expression. Consequently, this led to a significant reduction in GRalpha nuclear translocation. Nevertheless, methylprednisolone treatment strongly eliminated LPS induction of NF-kappaB activity, as determined by NF-kappaB nuclear translocation and by gel mobility shift assays. Furthermore, the LPS-induced increase in inflammatory cells in bronchoalveolar lavage fluid was blunted by administration of the corticosteroid. On the other hand, immunofluorescent staining for cleaved caspase-3 showed a marked increase in this proapoptotic marker in lung sections, and terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling (TUNEL) represented an enhanced appearance of cell apoptosis in lungs and spleen when methylprednisolone was given together with LPS. Cell apoptosis is now considered to play a role in the pathogenesis of septic syndrome. We thus suggest that the action of glucocorticoids at high doses to accelerate sepsis-induced cell apoptosis may overwhelm their therapeutic advantages in septic shock.
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PMID:Modulation of glucocorticoid receptor expression, inflammation, and cell apoptosis in septic guinea pig lungs using methylprednisolone. 1883 31

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