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)

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

During Vibrio vulnificus infection, V. vulnificus reaches the intestine and then invades the bloodstream by crossing the intestinal mucosal barrier of the host, which results in systemic septicemia. Previously, we reported that the RtxA toxin secreted through the RtxE transporter contributes to the cytotoxicity of V. vulnificus against intestinal epithelial cells. Here, we used gene mutants of rtxE and rtxA to determine the role that V. vulnificus RtxA toxin plays in the apoptotic death of human intestinal epithelial cells. The levels of DNA fragmentation were lower in human epithelial cells infected with an rtxE mutant of V. vulnificus than in those that were infected with the wild type. In addition, the rtxE mutant was found to induce lower levels of TUNEL positive cells and cell cycle arrest at the subG(1) than the wild type V. vulnificus. Furthermore, the decreased levels of DNA fragmentation, TUNEL positive cells and subG(1) arrest by the rtxE gene mutation were restored by the complementation of an rtxE gene into the rtxE mutant V. vulnificus. Finally, the rtxA mutant induced significantly lower levels of apoptotic cell death than the wild type. The levels of the PARP, cytochrome c, caspase-3, and mitochondrial membrane depolarization were lower in human epithelial cells infected with the rtxE and rtxA mutants, compared with the wild type and rtxE gene-complemented strains of V. vulnificus. Taken together, these results indicate that V. vulnificus RtxA toxin induces the apoptotic death through a mitochondria-dependent pathway in human intestinal epithelial cells exposed to V. vulnificus.
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PMID:Vibrio vulnificus RTX toxin plays an important role in the apoptotic death of human intestinal epithelial cells exposed to Vibrio vulnificus. 1884 6

Recent studies have shown that increased lymphocyte apoptosis contributes to sepsis-induced mortality. Furthermore, studies have demonstrated that IL-10 can suppress lymphocyte apoptosis, in part, by upregulating Bcl-2 expression and interfering with activation induced cell death. We have previously shown that intrathymic delivery of IL-10 with an adenoviral vector in wild-type mice significantly improves outcome to sepsis. Presently, we investigated the role of endogenous IL-10 expression on thymocyte apoptosis and outcome in IL-10 null mice subject to induction of generalized polymicrobial peritonitis via cecal ligation and puncture. Compared to wild-type C57BL/6 mice, IL-10 null mice demonstrated increased mortality and enhanced lymphocyte apoptosis. Intrathymic injection with an adenoviral vector expressing human IL-10 prior to cecal ligation and puncture in IL-10 null mice significantly improved outcome and decreased thymic caspase-3 activity. Furthermore, plasma concentrations of IL-6 were also significantly reduced in IL-10 null mice treated with the IL-10 expressing adenovirus. In contrast, injection of a control adenovirus did not improve outcome in IL-10 null mice, nor was caspase-3 activity reduced. Thus, local thymic expression of IL-10 not only improves outcome but also reduces local tissue apoptosis and caspase-3 activity, and appears to attenuate the systemic proinflammatory cytokine response.
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PMID:Endogenous IL-10 regulates sepsis-induced thymic apoptosis and improves survival in septic IL-10 null mice. 1895 26

The need for identification of specific modes of cell death, like apoptosis and necrosis, is driven by their detrimental or beneficial effect in different forms of disease, and the need in many instances of disease to modulate their levels. Apoptosis, an organized, gene-driven, and often energy-dependent mode of cell death, may be identified in tissue sections by its distinct morphological features, DNA degradation that is executed by endonucleases, and by presence of certain proteins, like the activated caspases. In the kidney, apoptosis is central to the development of a normal healthy kidney and it has been noted in glomeruli, the tubulo-interstitium, and renal vasculature in renal diseases or syndromes as diverse as acute kidney injury and chronic kidney disease of various causes, renal complications of diabetes and hypertension, sepsis, immune disorders and inflammation, nephrotoxicity, and in the development, progression, and treatment of renal cancers. Many research articles analyze apoptosis in tissue sections using the TUNEL assay that detects DNA strand breaks in situ in tissue sections. This method has been criticized because of false-positive or false-negative findings, and in situ analysis of activated caspase-3, thought to be the "executioner" caspase in the apoptotic pathway, may be a good alternative for quantifying apoptosis by light microscopy. The morphology of apoptosis, however, remains a standard that should not be ignored. This chapter reviews current methods of identifying apoptosis in tissue sections, with an emphasis on identification and quantification in the kidney using molecular methods.
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PMID:Identification of apoptosis in kidney tissue sections. 1914 10

Despite the widespread use of antenatal glucocorticosteroids (GCs), the possibility of adverse effects on the immune response in preterm neonates remains a major concern. GCs stimulate lymphocyte apoptosis, resulting in lymphopenia and functional disorders, which have been associated with sepsis-related death in critically ill neonates. We sought to assess the effect of antenatal betamethasone (BM) on lymphocyte apoptosis in preterm neonates. Fifty preterm neonates exposed to antenatal BM and 50 controls were studied prospectively. Lymphocyte apoptosis was assessed using the annexin-V/propidium iodide (PI) assay, analysis of cell cycle after staining with PI, and intracellular caspase-3 activity. The two groups did not differ significantly as regards absolute lymphocyte counts and the percentage of lymphocytes being annexin-V (+)/PI (-) (early apoptotic) or lymphocytes in the subG1 peak after staining with PI and those with intracellular caspase-3 activation. The lymphocyte number and apoptosis were not associated with the time elapsed between antenatal BM administration and delivery. A single course of antenatal BM does not influence apoptosis of neonatal lymphocytes. This is of significant importance with respect to the preservation of lymphocyte-associated immune response in preterm neonates.
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PMID:Antenatal betamethasone does not influence lymphocyte apoptosis in preterm neonates. 1926 38

Activated Protein C renders anti-apoptotic properties in neurons and endothelial cells. The aim of the present study was to evaluate the in vivo cytoprotective role of Protein C zymogen (PC) administration in septic rat brain. Male Wistar rats (n=60) were subjected to sepsis via Cecal Ligation and Puncture (CLP). Animals were randomly divided either to receive 100 IU/kg human PC concentrate at 1, 7 and 13 h post CLP (CLP+PC group) or placebo treatment (CLP group). At pre-specified time points (6, 12, 24, 36, 48 and 60 h post CLP) five animals from either group were euthanized and the brain tissue was removed. Apoptosis in both neurons (Neu-N+) and astroglia (GFAP+) was assessed by flow cytometry using 7-aminoactinomycin D (7AAD). Immunohistochemical detection of cleaved caspase 3, bax, bcl-2, cytochrome c and caspase 8 was also performed. PC treated animals had significantly reduced apoptosis in neurons at 6 and 24 h post CLP (p=0.04 and p=0.016 respectively) and necrosis at 6, 12 and 60 h post CLP (p=0.008, p=0.012 and p=0.032 respectively). Astrocyte necrosis was also decreased in septic rats receiving PC (6, 12 and 60 h post CLP p=0.008, p=0.016 and p=0.008 respectively). In addition, active caspase 3, bax, cytochrome c and caspase 8 expression was significantly decreased during early sepsis (6-36 h) while bcl-2 expression was increased (24 h p=0.001 and 60 h p=0.001) in the PC treated animals compared to placebo. PC concentrate administration in experimental sepsis produced a time dependent inhibition of apoptosis in rat neurons and astrocytes. The inhibition of sepsis related apoptosis concerned both the mitochondrial and caspase 8 dependent pathways.
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PMID:Administration of Human Protein-C concentrate prevents apoptotic brain cell death after experimental sepsis. 1936 19

Infections produce severe respiratory muscle dysfunction. It is known that the proteasome proteolytic system is activated in skeletal muscle in sepsis, and it has been postulated that this degradative pathway is responsible for inducing skeletal muscle weakness and wasting. The objective of this study was to determine if administration of proteasomal inhibitors (MG132, epoxomicin, bortezomib) can prevent sepsis-induced diaphragm weakness. Rats were given either 1) saline (0.5 ml ip), 2) endotoxin (12 mg/kg ip), 3) endotoxin plus MG132 (2.5 mg/kg), 4) endotoxin plus epoxomicin (1 micromol/kg), or 5) endotoxin plus bortezomib (0.05 mg/kg). Animals were killed either 48 or 96 h after injections, and assessments were made of diaphragm proteolysis, force-frequency relationships, mass, protein content, and caspase activation. Endotoxin increased proteolysis (P <0.001). MG132, epoxomicin, and bortezomib each prevented the endotoxin-induced increase in proteolysis (P <0.01). Endotoxin induced severe reductions in diaphragm force generation by 48 h (P <0.01); none of the proteasomal inhibitors prevented loss of force. Endotoxin induced significant reductions in diaphragm mass and protein content by 96 h (P <0.01); neither MG132 nor epoxomicin prevented loss of mass or protein, but bortezomib attenuated the reduction in protein content (P <0.05). Endotoxin increased diaphragm caspase-3 activity (P <0.01); caspase-3 activity remained high when either MG132, epoxomicin, or bortezomib were given. These data suggest proteasomal inhibitors are not an adequate treatment to prevent endotoxin-induced diaphragmatic dysfunction.
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PMID:Effect of proteasome inhibitors on endotoxin-induced diaphragm dysfunction. 1937 88


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