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)

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

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

This study was to investigate the role of calpain in the apoptosis of pulmonary microvascular endothelial cells (PMEC) during septic plasma stimulation. Septic plasma was collected from endotoxemic mice. In cultured PMEC, incubation with septic plasma stimulated calpain activation, increased caspase-3 activity and induced apoptotic cell death. These effects of septic plasma were abrogated by knockdown of calpain-1 but not calpain-2 using specific siRNA. Consistently, treatment with calpain inhibitor-III, or over-expression of calpastatin, an endogenous calpain inhibitor significantly decreased apoptosis induced by septic plasma. Septic plasma also induced NADPH oxidase activation and reactive oxygen species (ROS) production. Inhibiting NADPH oxidase or scavenging ROS attenuated calpain activity and decreased apoptosis in PMEC during septic plasma stimulation. In summary, our study demonstrates that ROS produced from NADPH oxidase stimulates calpain-1 activation, which induces apoptosis under septic conditions. Thus, targeting calpain-1/calpastatin may represent a potential strategy to protect against endothelial injury in sepsis.
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PMID:Calpain-1 induces apoptosis in pulmonary microvascular endothelial cells under septic conditions. 1937 62

Sepsis accounts for 50% of intensive care unit deaths due to cardiac dysfunction. The cellular mechanisms following norepinephrine (NE) during sepsis are undefined. Using a septic adult rat ventricular myocyte (ARVM) paradigm, we examined the molecular mechanism responsible for the blunted contractile response of NE. We tested the hypothesis that NE-induced increases in active caspase-3 contribute to sepsis-induced ARVM contractile dysfunction. Single ARVMs were isolated from hearts harvested from sham and septic male rats. The contractile properties and expression of caspase-3 cascade proteins were determined in ARVMs treated with NE with and without QVD-OPH, prazosin and atenolol to characterize the effect of NE on their mechanical properties. Septic ARVMs exhibited a significant decrease in peak shortening (PS) compared to sham ARVMs. The effect of NE on the PS of the sham ARVMs was more pronounced compared to the septic ARVMs, suggesting a blunted contractile response of NE. NE in the presence of QVD-OPH ameliorated the sepsis-induced decrease in PS at 18h but not at 1h, while the effect of NE on sepsis-induced contractile response remained unaffected at 18h by prazosin and atenolol. An up-regulated expression of caspase-3 in NE-treated septic ARVMs was reversed by QVD-OPH, as seen by the increased number of septic ARVMs exhibiting caspase-3 fluorescence. Transfection of ARVMs using caspase-3 siRNA blocked sepsis-induced up-regulation of caspase-3 and increased PS following NE treatment. These data suggest that caspase-3 inhibition ameliorated sepsis-induced decreased ARVM contractility and blocked the blunted contractile response of NE.
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PMID:Contractile response of norepinephrine is modulated by caspase-3 in adult rat ventricular myocytes isolated from septic rat heart. 1939 24

Recent reports that hyperbaric oxygenation (HBO2) induced apoptosis in T-cell lines raised concern about a possible immunosuppressive effect of HBO2. Nucleosomes, DNA fragments wrapped around a histone core, have been observed in the circulation in diseases with increased cell death such as sepsis. Our aim was to investigate, whether HBO2 increases circulating nucleosomes as a marker of cell death and induces apoptosis of peripheral blood mononuclear cells in vivo. After informed consent 29 healthy volunteers were exposed to a 30 minute dive at 2.8 atmospheres absolute in a pressure chamber under resting conditions, while breathing 100% oxygen. Samples were obtained before and 24 hours after exposure. Circulating nucleosomes were measured in serum. Caspase-3 activation, Bcl-2 expression and mRNA of Bcl-2, Bcl-xl and Bax were analyzed in mononuclear cell extracts. Nucleosomes were elevated markedly 24h after exposure (p<0.01), while caspase-3 was not activated significantly. mRNA levels of Bcl-2, Bcl-xl and Bax were not altered. In conclusion, while evidence of elevated levels of circulating nucleosomes was found, mononuclear cell apoptosis was not affected by a single exposure to hyperbaric oxygen.
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PMID:A single exposure to hyperbaric oxygen increases levels of circulating nucleosomes but does not induce mononuclear cell apoptosis in divers. 1946 51

Endothelial cell injury/dysfunction is considered to play a critical role in the pathogenesis of severe sepsis and septic shock. Although it is considered that endothelial cell apoptosis is involved in endothelial injury/dysfunction, physiological involvement remains ambiguous since the induction of apoptosis requires the inhibition of endogenous apoptosis inhibitors. Here we show that caspase-3 activation, a biological indicator of apoptosis, is observed in response to lipopolysaccharide (LPS) stimulation even under the influence of endogenous apoptosis inhibitors, and that activated caspase-3 is rapidly released from human umbilical vein endothelial cells (HUVEC). In the presence of cycloheximide (CHX), an increase in intracellular caspase-3/7 activity in response to LPS was not detected in HUVEC up to 24 h following stimulation even in the presence of LPS-binding protein (LBP), soluble CD14 and soluble MD-2, whereas the decrease in cell viability and increase in release of the cellular enzyme lactate dehydrogenase (LDH) were observed in a soluble CD14/LBP-dependent manner. On the other hand, even in the absence of CHX, a significant increase in caspase-3/7 activity and a cleaved caspase-3 fragment with a slight increase in LDH release was observed in culture supernatants in response to LPS. This increase in caspase-3/7 activity was observed even when LDH release was undetected. These results indicate that caspase-3 is activated by LPS under physiological conditions and suggest that HUVEC escape from cell death by rapidly releasing activated caspase-3 into extracellular space. Failure of this escape mechanism may result in endothelial injury/dysfunction.
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PMID:Caspase-3 is activated and rapidly released from human umbilical vein endothelial cells in response to lipopolysaccharide. 1955 90

The cecal ligation perforation (CLP) model of sepsis is known to induce severe diaphragm dysfunction, but the cellular mechanisms by which this occurs remain unknown. We hypothesized that CLP induces diaphragm caspase-3 and calpain activation, and that these two enzymes act at the level of the contractile proteins to reduce muscle force generation. Rats (n = 4/group) were subjected to 1) sham surgery plus saline (intraperitoneal); 2) CLP; 3) CLP plus administration of calpain inhibitor peptide III (12 mg/kg ip); or 4) CLP plus administration of a caspase inhibitor, zVAD-fmk (3 mg/kg). At 24 h, diaphragms were removed, and the following were determined: 1) calpain and caspase-3 activities by fluorogenic assay; 2) caspase-3 and calpain I protein levels; 3) the intact diaphragm force-frequency relationship; and 4) the force generated by contractile proteins of single, permeabilized diaphragm fibers in response to exogenous calcium. CLP significantly increased diaphragm calpain activity (P < 0.02), caspase-3 activity (P < 0.02), active calpain I protein levels (P < 0.02), and active caspase-3 protein (P < 0.02). CLP also reduced the force generated by intact diaphragm muscle (P < 0.001) and the force generated by single-fiber contractile proteins (P < 0.001). Administration of either calpain inhibitor III or zVAD-fmk markedly improved force generation of both intact diaphragm muscle (P < 0.01) and single-fiber contractile proteins (P < 0.001). CLP induces significant reductions in diaphragm contractile protein force-generating capacity. This force reduction is mediated by the combined effects of activated caspase and calpain. Inhibition of these pathways may prevent diaphragm weakness in infected patients.
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PMID:Caspase and calpain activation both contribute to sepsis-induced diaphragmatic weakness. 1971 28

Recent evidence suggests that apoptotic cell death plays an important role in the pathophysiology of sepsis. Because there is extensive apoptosis of vascular endothelial cells in sepsis, we examined whether the death receptor pathway of apoptotic signaling is altered in thoracic aortas from mice with polymicrobial sepsis, as produced by cecal ligation and puncture (CLP). In septic aorta, total and surface expression levels of the two death receptors tumor necrosis factor receptor 1 and Fas were highly upregulated. Furthermore, marked increases in the mRNA and protein levels of Fas-associated death domain (FADD), an adaptor molecule to recruit procaspase-8 into the death-inducing signal complex, were observed in septic aorta, which were strongly suppressed by systemic delivery of small interfering RNA (siRNA) against FADD. No increase in expression of death receptors and FADD was observed in endothelium-denuded aortic tissues from septic animals. Systemic administration of FADD siRNA also resulted in great attenuation of sepsis-induced increases in expression and activation of caspase-3, an effector protease in the apoptosis cascade. Terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling (TUNEL) revealed that the significant appearance of cell apoptosis in aortic endothelium after CLP-induced sepsis was eliminated when FADD siRNA was systemically applied. Light and electron microscopic examinations of septic aorta showed cell swelling, nuclear fragmentation, and partial detachment of endothelial cells from the basal membrane, which were prevented by systemic treatment with FADD siRNA. Finally, FADD siRNA administration dramatically improved survival of CLP mice, supporting the feasibility of this gene-based approach for treating septic shock.
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PMID:Increased death receptor pathway of apoptotic signaling in septic mouse aorta: effect of systemic delivery of FADD siRNA. 1985 68

Interleukin (IL)-15 serves as a survival factor for a broad array of cells. Renal cells express both IL-15 and its receptor (IL-15R); however, the role of IL-15 in the kidney is yet to be determined. We examined IL-15 and IL-15R levels in sepsis-related renal injury, ischemia-reperfusion injury (IRI), and cisplatin-induced nephrotoxicity. To test the anti-apoptotic effect of IL-15, Bcl-2/Bax mRNA levels were assessed in kidneys of IL-15Ralpha(-/-) mice and in IL-15-stimulated renal epithelial cells (RECs). In addition, RECs were exposed to cisplatin and apoptosis was evaluated by TUNEL staining, caspase-3 activity, and cell cycle analysis. Intrarenal IL-15 levels decreased 24 h after initiation of all three examined pathologies by 5.8-fold (sepsis), 11-fold (IRI), and 23-fold (cisplatin-induced nephrotoxicity). Further experiments revealed that while addition of rIL-15 (1 ng/mL) to wild-type (WT) RECs increased Bcl-2/Bax ratio by 2-fold, kidneys of IL-15Ralpha(-/-) mice exhibited 4-fold lower Bcl-2/Bax ratio compared to WT mice. Accordingly, IL-15 lowered the apoptotic rate in cisplatin-treated cultured REC, and IL-15Ralpha(-/-) renal cells exhibited a higher rate of cisplatin-induced apoptosis. Furthermore, IL-15 levels negatively correlated with BUN of cisplatin-treated mice (R = -0.69, P = 0.003), suggesting that a decline in renal-derived IL-15 is detrimental to renal cell survival and kidney function during pathological stress.
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PMID:Association between renal injury and reduced interleukin-15 and interleukin-15 receptor levels in acute kidney injury. 1995 57

The histamine H(4) receptor is the most recently identified receptor and is considered to play a role in a variety of inflammatory diseases. Histamine levels in the plasma are known to be elevated in animal models of sepsis and in septic patients. The aim of this study was to test the hypothesis that the H(4) receptor may play a significant role in the pathophysiology of sepsis. Polymicrobial sepsis was induced by cecal ligation and puncture in BALB/c mice. Although the H(4) receptor gene was undetectable in normal peripheral key organs, with the exception of the spleen, the expression levels of this gene were highly up-regulated in all those organs of septic mice. In vivo transfection of nuclear factor-kappaB (NF-kappaB) decoy oligodeoxynucleotide, but not of its scrambled form, resulted in a great inhibition of sepsis-induced overexpression of the H(4) receptor gene. In septic mice, marked increases in caspase-3 activation and follicular lymphocyte apoptosis in spleens were strongly suppressed by systemic treatment with synthetic small interfering RNA (siRNA) targeted to the H(4) receptor. This was associated with the up-regulation of a number of antiapoptotic proteins. These antiapoptotic effects of H(4) receptor siRNA treatment were all inhibited by further application of NF-kappaB decoy oligonucleotide. Our results suggest that superinduction of the histamine H(4) receptor gene in peripheral key organs, including the spleen, that is promoted by sepsis is transcriptionally controlled by NF-kappaB, whereas stimulation of this receptor is involved in the development of sepsis-induced splenic apoptosis through counteraction of the antiapoptotic action of NF-kappaB.
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PMID:Up-regulation of histamine H4 receptors contributes to splenic apoptosis in septic mice: counteraction of the antiapoptotic action of nuclear factor-kappaB. 2000 88


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