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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptosis (AO) is a process by which cells typically undergo a form of nonnecrotic cellular suicide. AO normally allows the host to selectively delete cells from a given tissue site without producing bystander injury associated with necrosis. However, inappropriate induction of AO has been associated with a variety of acute as well as chronic pathological states and may contribute to the therapeutic nonresponsiveness frequently encountered in the septic animal/patient's organ function. In this respect, while AO has been demonstrated in a variety of immune cell tissues of septic animals it is unclear if it is present in the septic liver. Therefore, it was the aim of our study to determine if AO is evident in hepatocytes of polymicrobial septic animals. To assess this, C3H/HeN male mice were subjected to polymicrobial sepsis (cecal ligation and puncture) or sham- CLP (Sham). Hepatocytes were then harvested at 4 h (early hyperdynamic phase) or 24 h (late hypodynamic state) later, and indices of AO were assessed [cell cycle analysis of Annexin V/propidium iodide (PI) staining for flow cytometric analysis, DNA extracted, and cell death ELISA]. Plasma glutamic pyruvic transaminase (GPT) was also colorimetrically assessed as well as total viable cell yield as an index of hepatocellular necrosis. The results indicate that indices of hepatocellular AO, as determined by cell cycle analysis and cell death ELISA, were markedly increased in polymicrobial septic mice at 24 h. However, while an increase in DNA fragmentation/degradation could be consistently detected, the pattern was typically faint. Similarly, although there was an increase in Annexin V staining it was not dissociated from that of PI (necrotic index). Alternatively, necrosis (as evidenced by increased GPT levels at both 4 and 24 h) preceded the induction of all the indices of AO. Taken together, these data suggest a role for both necrosis and apoptosis in the evolution of hepatocellular injury encountered in the polymicrobial septic animal/patient which may represent a unique pattern of cell death under such conditions.
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PMID:Does hepatocellular injury in sepsis involve apoptosis? 969 18

Lymphocyte apoptosis occurs in response to stressors such as thermal injury, trauma, sepsis, and surgery. This study evaluated the effect of a single bout of physical exercise stress on the induction of apoptosis in murine thymocytes and splenic lymphocytes. Female C57BL/6 mice, treadmill exercised at a submaximal intensity (35 m/min, 6% grade) for 90 min or serving as controls (walking on treadmill at 12 m/min, 6% grade, 5 min), were sacrificed 5 min or 120 min after completion of exercise. The percent of apoptotic, necrotic, and viable thymocytes and splenocytes were determined by flow cytometry using annexin V FITC and propidium iodide. There was a significantly higher percent of viable splenocytes in the mice sampled 120 min after cessation of exercise than treadmill control animals (p<0.05). In the thymus, there was a significantly lower percent of apoptotic (p<0.5) and a significantly higher percent of viable (p<0.05) cells in exercised mice sampled at 120 min after exercise relative to controls. Absolute numbers of thymocytes and splenocytes did not differ by exercise treatment condition. Plasma corticosterone levels were elevated immediately after exercise and were negatively correlated with the percent of viable lymphocytes in the spleen. During the time frame sampled, submaximal exercise is associated with a lower % of thymocytes expressing early markers of apoptosis, despite elevated plasma corticosterone levels. Retention of self-reactive, viable thymocytes which would normally be deleted or selective trafficking of apoptotic thymocytes out of the thymus may be involved in the exercise effect. Additional studies are necessary to identify the mechanisms for this shift in proportions of apoptotic and viable cells in lymphoid compartments with exercise.
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PMID:Impact of treadmill exercise on early apoptotic cells in mouse thymus and spleen. 1002 50

Acute tubular injury in sepsis is associated with proximal tubular epithelial cell (PTEC) detachment into the lumen leading to back-leakage of glomerular ultrafiltrate and tubule obstruction. Inflammatory cytokines, such as IL-1alpha, IFNgamma and TNFalpha, are important mediators in sepsis-induced acute renal failure, although their precise role is unclear. We used primary cultures of human PTEC to investigate the hypothesis that inflammatory cytokines exert cytotoxic effects and cause detachment of cells from adherent monolayers, possibly through the intermediate nitric oxide (NO). At 5 days post-confluence, PTEC monolayers were stimulated for 24 hours with IL-1alpha (10 ng/ml), IFNgamma (200 u/ml) and TNFalpha (10 ng/ml). Monolayer viability was assessed by a live/dead dual fluorescence labeling technique. Apoptosis within monolayers was determined by morphological examination and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). PTEC in supernatants were counted and then analyzed by flow cytometry, using propidium iodide to assess cell viability and annexin V labeling to determine apoptosis. Results (mean +/- SEM; monolayers, n = 4; cell counts, n = 3; flow cytometry, n = 2) are shown below (at test, p < 0.05). Monolayers Supernatants Viable necrotic% of cells apoptotic countsx104/ml viable necrotic% of cells apoptotic Unstimulated 99.0+/-0.5 1.0+/-0.5 0 8.0+/-0.6a 64.6+/-2.5a 26.7+/-1.9a 6.2+/-0.6a Stimulated 92.4+/-3.2 7.6+/-3.2 0 14.7+/-0.6a 37.9+/-0.05a 48.0+/-0.3a 14.1+/-0.35a Following cytokine stimulation, there were significantly increased numbers of shed cells in supernatants. This cell population demonstrated significant loss of viability with increased numbers of both necrotic and apoptotic cells, as compared to unstimulated PTEC supernatants. Cytokine-stimulated monolayers maintained viability with no significant cell necrosis and no evidence of apoptosis. Preliminary experiments with the NO synthase inhibitor L-NMMA show that it reduces the number of cytokine-induced shed cells to the levels found in unstimulated cells (8.0 +/- 1.0 x 104/ml), although the percentages of necrotic and apoptotic cells are unchanged from cytokine-stimulated PTEC (44% and 15%, respectively). In conclusion, inflammatory cytokines induce necrotic and apoptotic cell shedding from PTEC monolayers with maintenance of monolayer viability. Preliminary data suggest that NO plays a cytotoxic role in this process.
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PMID:Inflammatory cytokines induce apoptotic and necrotic cell shedding from human proximal tubular epithelial cell monolayers 1035 8

Sepsis induces extensive apoptosis of lymphocytes, which may be responsible for the profound immune suppression of the disorder. Two potential pathways of sepsis-induced lymphocyte apoptosis, Fas and p53, were investigated. Lymphocyte apoptosis was evaluated 20-22 h after sepsis by annexin V or DNA nick-end labeling. Fas receptor-deficient mice had no protection against sepsis-induced apoptosis in thymocytes or splenocytes. p53 knockout mice (p53-/-) had complete protection against thymocyte apoptosis but, surprisingly, had no protection in splenocytes. p53-/- mice had no improvement in sepsis survival compared with appropriately matched control mice with sepsis. We conclude that both p53-dependent and p53-independent pathways of cell death exist in sepsis. This differential apoptotic response of thymocytes vs splenocytes in p53-/- mice suggests that either the cellular response or the death-inducing signal is cell-type specific in sepsis. The fact that p53-/- lymphocytes of an identical subtype (CD8-CD4+) were protected in thymi but not in spleens indicates that cell susceptibility to apoptosis differs depending upon other unidentified factors.
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PMID:p53-dependent and -independent pathways of apoptotic cell death in sepsis. 1072 25

Multiorgan apoptosis occurs during sepsis. Following cecal ligation and puncture (CLP) in rats, thymocytes underwent apoptosis in a time-dependent manner. C5a blockade dramatically reduced thymocyte apoptosis as measured by thymic weight, binding of annexin V to thymocytes, and laddering of thymocyte DNA. When C5a was generated in vivo by infusion of purified cobra venom factor (CVF), thymocyte apoptosis was significantly increased. Similar results were found when CVF was injected in vivo during the early stages of CLP. In animals 12 hours after induction of CLP, there was an increase in the activities of caspase-3, -6, and -9, but not caspase-1 and -8. Cytosolic cytochrome c levels increased by twofold, whereas mitochondrial levels showed a 50% decrease. Western blot analysis revealed that the content of Bcl-X(L) (but not of Bcl-2, BAX, Bad, and Bim) significantly decreased in thymocytes after CLP. C5a blockade in the sepsis model almost completely inhibited caspase-3, -6, and -9 activation, significantly preserved cytochrome c in the mitochondrial fraction, and restored Bcl-X(L) expression. These data suggest that systemic activation of complement induces C5a-dependent apoptosis of thymocytes and that the blockade of C5a during sepsis rescues thymocytes from apoptosis.
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PMID:Protective effects of anti-C5a in sepsis-induced thymocyte apoptosis. 1108 28

The role of lymphocyte apoptosis in septic shock remains a controversial issue. Using Annexin V and flow cytometry analysis on freshly isolated cells, we evaluated circulating lymphocyte apoptosis in 23 septic shock, 25 sepsis without shock, 7 nonseptic critically ill, and 25 control patients. In patients with sepsis, we compared day 1 lymphocyte apoptosis (i.e., within 3 days of the onset of infection) with that observed 5-7 days after (day 6) according to shock state, mortality, and seventy factors. At day 1, patients in septic shock exhibited higher lymphocyte apoptosis than that present in controls (16.5% +/- 3.5% vs. 3% +/- 0.5%, respectively, P = 0.0001). At day 6, patients with sepsis without shock restored undamaged CD4+ T and CD8+ T lymphocyte counts, whereas patients in septic shock increased only CD4+ T cells. Similarly, survivors restored undamaged lymphocyte count at day 6 (+70%, P < 0.001), whereas nonsurvivors did not. Day 6 undamaged lymphocyte count negatively correlated with day 1 SAPS II, day 6 LOD score, mechanical ventilation, and ICU stay duration. We observed no apoptotic effect of septic shock plasma or septic shock circulating mononuclear cells on target lymphoid cell lines. We found no alteration in any death receptors Fas, TRAIL-R1, TRAIL-R2, or in their ligands on circulating blood cells. Catecholamines and interleukin 10 levels significantly increased in patients with septic shock, but did not correlate with apoptosis levels. We conclude that lymphocyte apoptosis is rapidly increased in blood of patients in septic shock and that lymphocyte apoptosis leads to a profound and persistent lymphopenia associated with poor outcome. These results suggest that lymphocyte apoptosis is one of the main components of human septic shock immune dysfunction and could be related more to microcirculatory disturbance than to circulating factors.
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PMID:Early circulating lymphocyte apoptosis in human septic shock is associated with poor outcome. 1246 54

We evaluated neutrophil activation by measuring its phagocytic ability and oxidative burst activity in 16 patients with sepsis and 16 healthy volunteers. We also focused on neutrophil apoptosis as a regulatory mechanism of the inflammatory response. Neutrophil phagocytosis was evaluated by the detection of propidium iodide (PI)-labeled Staphylococcus aureus added to whole blood. Reactive oxygen species (ROS) formation was quantified by measuring the oxidation of 2',7' dichlorofluorescein diacetate (DCFH-DA) at baseline and after cell stimulation with phorbol myristate acetate (PMA), and bacterial cells (killed S. aureus) or products (lipopolysaccharide [LPS] and N-formyl-methionyl-leucyl-phenylalanine [FMLP]). Apoptosis was assessed in neutrophils stained with annexin V and PI. Neutrophil phagocytic ability was increased in patients with sepsis compared with healthy controls (median geometric mean fluorescence intensity [GMFI] was 101.9 and 54.7, respectively; P = 0.05). ROS formation was enhanced in patients with sepsis compared with healthy volunteers at baseline (median GMFI 275.6 and 52.1, respectively; P < 0.001), and after stimulation with S. aureus (median GMFI 2395.8 and 454.9, respectively; P < 0.001), PMA (median GMFI 1120.6 and 307.5, respectively; P = 0.003), FMLP (median GMFI 792.4 and 123.2, respectively; P < 0.001), and LPS (median GMFI 624.8 and 144.8, respectively; P < 0.001). Early neutrophil apoptosis was increased in patients with sepsis compared with healthy volunteers (median 11.3% and 9.1%, respectively; P = 0.03). These data demonstrate that neutrophil function is enhanced in patients with sepsis. Additionally, circulating neutrophils from patients with sepsis presented with increased early apoptosis, which may be consequence of a regulatory mechanism of the inflammatory response.
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PMID:Upregulation of reactive oxygen species generation and phagocytosis, and increased apoptosis in human neutrophils during severe sepsis and septic shock. 1292 90

Neutrophil apoptosis is delayed under trauma and/or sepsis conditions. The mechanism for the delay has remained unclear. We hypothesize that modulation of the mitochondrial pathway of apoptosis contributes to the delay in neutrophil apoptosis with burn injury. Rats were subjected to burn injury (30% of total body surface area, 98 degrees C for 10 s) and euthanatized 24 h postinjury. Blood neutrophils from sham and burn-injured rats were isolated by Ficoll gradient centrifugation and cultured for 2 or 8 h. Neutrophil apoptosis was determined by annexin V and propidium iodide (PI) labeling and flow cytometry. Neutrophil mitochondrial morphology was assessed via histochemical staining (MitoTracker GreenFM) and confocal microscopy. Neutrophils from rats with burn injury showed a decreased level of apoptosis compared with sham rat neutrophils at both 2 and 8 h of incubation. In incubated sham rat neutrophils, mitochondria showed a change from normal "tubular" to an "aggregated" morphology. In contrast, cultured neutrophils from burn rats did not exhibit this mitochondrial morphological transition until 8 h of incubation. Compared with sham rat neutrophils, neutrophils from burn rats showed decreased levels of active caspase-9 and -3. Whereas an upregulation of Bcl-xL and a downregulation of Bax seemed to contribute to decreased apoptosis in burn rat neutrophils at 2 h of incubation, the decreased apoptosis at 8 h appeared to be associated with a decrease in Bax and increased phosphorylated Bad. These data suggest that suppression of the mitochondrial pathway plays an essential role in the delay of polymorphonuclear neutrophil apoptosis with burn injury.
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PMID:Suppression of mitochondria-dependent neutrophil apoptosis with thermal injury. 1367 4

Pro-apoptotic molecules are generated during sepsis which may be responsible for alteration of organ function in sepsis. Removal of systemic apoptotic activity may affect recovery from sepsis. Current high flux membranes might not be sufficiently permeable to eliminate pro-apoptotic factors. We evaluated the elimination of pro-apoptotic factors induced by LPS in human whole blood by a super-permeable cellulose triacetate membrane (SUREFLUX FH 150, Nipro, Osaka, Japan) in comparison to a standard high flux cellulose triacetate membrane (UT 700, Nipro, Osaka, Japan) and a polyethersulfone plasmafilter (Bellco, Mirandola Italy) in an in vitro blood circulation. We spiked human whole blood with lipopolysaccharide from Escherichia coli (Serotype 026-86, 10 mg/ml), incubated it for 3 hours to allow cytokine generation and recirculated it at 300 ml/min for 3 hours. The UF line was first returned to the blood module at 10 min. After this, the UF was drained from 10 to 60 min at a rate of 1000 ml/h. Zero balance was obtained by re-infusion of bicarbonate buffered hemofiltration fluid. Apoptosis was assessed on U937 monocytes (incubated with plasma or ultrafiltrate) by fluorescence microscopy dyes (Hoechst 33342, propidium iodide) and annexin V flow cytometry. Caspase-3 and Caspase-8 activity was assessed on the recirculated blood monocytes by spectrophotometric methods. IL-2, IL-10 and TNFalpha were determined by commercially available ELISAs. Sieving coefficients and clearances were determined for the different cytokines. Caspase-3 and Caspase-8 were activated by LPS and remained either stable or increased during in vitro circulation. Apoptosis activity of U937 cells, when incubated with the ultrafiltrate, increased in parallel with arterial plasma values (for Uf: UT700 = 23.1%; Sureflux FH150 = 42.5%). However, by 60 min the apoptotic activity recorded with the ultrafiltrate was reduced to the levels of arterial plasma (for Uf: UT700 = 19.8%; Sureflux FH150 = 11.2%). Sieving coefficients in the super-permeable membrane were significantly higher for all measured cytokines in comparison to the standard high flux membrane (e.g. TNFalpha 0.72 vs 0.03 p < 0.001) and close to the values observed for the plasmafiltration membrane. Nevertheless protein losses measured by albumin leakage were much lower with the Sureflux filter in comparison to the plasmafilter. In conclusion, pro-apoptotic factors can be eliminated by dialytic membranes with the removal rate maximized by using super high flux dialysers which may represent a compromise between hemofiltration and plasmafiltration membranes.
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PMID:Caspase-3 and -8 activation and cytokine removal with a novel cellulose triacetate super-permeable membrane in an in vitro sepsis model. 1463 5

The most likely source of autoantigens in systemic lupus erythematosus (SLE) is apoptotic material. Because increased levels of circulating apoptotic cells are found in SLE we wanted to investigate the capacity of serum from patients with SLE or other autoimmune or infectious diseases and normal healthy donors (NHD) to induce apoptosis in normal monocytes, lymphocytes and corresponding cell lines, in relation to clinical and immunological data. Monocytes and lymphocytes from healthy donors were incubated with sera from 37 SLE patients, 37 sex- and age-matched NHD and sera from patients with rheumatoid arthritis, vasculitis, sepsis and mononucleosis. Sera from SLE patients were sampled at both active and inactive disease. The apoptosis-inducing effect (AIE) of these sera was monitored with flow cytometry using annexin V and propidium iodide (PI) binding. The AIE in monocytes and lymphocytes was significantly higher in sera from SLE patients than in other patient groups and NHD (P < 0.001) and was also higher when cell lines were used. Level of C5a in cell culture supernatant correlated with AIE in monocytes (r = 0.451, P = 0.005), suggesting involvement of complement. Heat-inactivation of sera did not affect the AIE, nor did depletion of IgG by protein G absorption of serum. Kinetic analyses showed a peak in apoptosis induction at 12-16 h, with a delayed PI positivity. AIE was equally high using sera from active and inactive SLE cases, and did not correlate with the SLE Disease Activity Index (SLEDAI). Thus, SLE serum has a strong and apparently disease-specific apoptosis-inducing capacity, which could contribute to a high load of potential autoantigen.
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PMID:Induction of apoptosis in monocytes and lymphocytes by serum from patients with systemic lupus erythematosus - an additional mechanism to increased autoantigen load? 1500 90


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