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

Listeria monocytogenes, a small gram-positive bacillus, causes sepsis and meningitis in immunocompromised patients and a devastating maternal/fetal infection in pregnant women. Recent outbreaks demonstrated that L. monocytogenes can cause gastroenteritis in otherwise healthy individuals and more severe invasive disease in immunocompromised patients. Centralized processing in the food industry may be the cause of these large-scale listeriosis outbreaks. The mouse model of listeriosis, which was developed in the 1960s, has been extraordinarily useful for studying T cell-mediated immunity. Contrary to the original concept that macrophages are the principal effector cells in listeriosis, we found that immigrating neutrophils play the predominant role in early liver defenses. At later time points, CD8(+) T cells lyse infected hepatocytes by both perforin- and Fas-L/Fas--dependent mechanisms. Of interest, nonclassical major histocompatibility complex (MHC) class Ib--restricted cytolytic activity is expressed early during primary infection, whereas MHC class Ia--restricted activity is predominant through late primary and secondary infections.
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PMID:Listeria monocytogenes: clinical and experimental update. 1186 36

The Fas-Fas ligand system is important for apoptosis of activated immune cells. Perturbation of this system occurs in diseases with dysregulated inflammation. Increased soluble Fas (sFas) occurs in systemic inflammatory response syndrome (SIRS) and can block apoptosis. Increased shedding of FasL (sFasL) occurs in viral infection and hepatitis. Although dysregulated inflammation is associated with sepsis-induced multiple organ failure (MOF) in children, a role for Fas has not been established. We hypothesize that 1) sFas will be increased in children with severe and persistent sepsis-induced MOF and will correlate with inflammatory markers suggesting a role for sFas in inflammatory dysregulation in severe sepsis, and 2) sFasL will be increased when viral sepsis or sepsis-induced liver failure-associated MOF is present in children. Plasma sFas, sFasL, IL-6, IL-10, nitrite + nitrates, and organ failure scores were measured on d 1 and d 3 in 92 children with severe sepsis and 12 critically ill control children. sFas levels were increased in severe sepsis, continued to increase in persistent MOF and nonsurvivors, and were correlated with serum inflammatory markers (IL-6, IL-10, nitrite + nitrate levels). In contrast, sFasL was not increased in severe sepsis and did not correlate with inflammation. sFasL was, however, increased in liver failure-associated MOF and in nonsurvivors, and was associated with viral infection. At autopsy, hepatocyte destruction and lymphocyte infiltration were associated with increased sFas and sFasL levels. sFas may interfere with activated immune cell death and contribute to dysregulation of inflammation, worsening outcome from severe sepsis. sFasL may contribute to hepatic injury and the development of liver failure-associated MOF.
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PMID:sFas and sFas ligand and pediatric sepsis-induced multiple organ failure syndrome. 1243 71

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 measured the levels of tumor necrosis factor alpha (TNF-alpha), interleukins (IL)-6 and -18, and soluble Fas (sFas) in 11 patients with postoperative hepatic failure and assessed whether IL-18-mediated apoptosis is involved in the onset of liver dysfunction. The serum TNF-alpha, IL-18, and sFas levels were significantly higher in patients with sepsis as a complication than in those without sepsis. The TNF-alpha and IL-18 levels were significantly higher in nonsurvivors than in survivors. Significant correlations were observed between TNF-alpha and IL-6, between TNF-alpha and IL-18, and between TNF-alpha and sFas levels. These results showed that Fas-mediated hepatocyte apoptosis functions as an important mechanism responsible for the onset of postoperative hepatic failure in humans. They especially suggested that IL-18 and TNF-alpha function both as apoptosis-promoting factors and as apoptosis-inhibiting factors, depending on the conditions to which hepatocytes are subjected.
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PMID:Involvement of IL-18 and soluble fas in patients with postoperative hepatic failure. 1267 13

Resolution of inflammation/infection involves removal of neutrophils and other inflammatory cells by the induction of apoptosis. Fas/Apo-1 is a widely occurring apoptotic signal receptor molecule expressed by almost any type of cell, which is also released in a soluble circulating form. In this study we investigated the role of circulating Fas/Apo-1 in patients with systemic inflammatory response syndrome (SIRS). We evaluated 57 critically ill patients, 34 with infectious SIRS (sepsis and septic shock), and 23 patients with noninfectious SIRS. Circulating Fas/Apo-1 was determined by a commercially available immunoassay. Our results clearly show that levels of Fas/Apo-1 were significantly elevated in patients with infectious and noninfectious SIRS (10.4 +/- 8.1 pg/mL, controls: 5.0 +/- 0.7 pg/mL; p < 0.0001). In addition, Fas/Apo-1 levels were not able in predicting in predicting poor outcome of patients with SIRS. In conclusion, these results show that increased levels of Fas/Apo-1 from patients with SIRS is a mechanism which contribute to inflammatory response through accumulation of neutrophils at sites of inflammation/infection.
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PMID:Circulating levels of FAS/APO-1 in patients with the systemic inflammatory response syndrome. 1272 91

Induction of apoptosis in immune cells is a crucial mechanism used by the body to produce immune resolution. The homeostatic mechanisms employed are currently being identified and, to date, studies have highlighted some of the signals that regulate the immune response. The exposure of phosphatidylserine on the surface of an apoptotic neutrophil is sufficient to limit the immune response in acute inflammation, whereas apoptosis of key effector cells can limit the response in chronic inflammation. Other therapeutic approaches that are being investigated include the inhibition of apoptosis by blocking the caspase cascade. This approach will be of particular relevance for the treatment of inflammatory central nervous system diseases and sepsis. An alternative approach being examined is forced resolution, whereby apoptosis is induced in effector cells, principally T cells, through activation-induced cell death mediated by Fas receptors. Inhibitors of this mechanism have been identified and targeted in several studies.
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PMID:Targeting inflammatory diseases via apoptotic mechanisms. 1290 51

Signaling through the Fas/Fas ligand (FasL) pathway plays a central role in immune-cell response and function; however, under certain pathological conditions such as sepsis, it may contribute to the animal's or patient's morbidity and mortality. To determine the contribution of FasL to mortality, we conducted survival studies by blocking Fas/FasL with Fas receptor fusion protein (FasFP) in vivo. C3H/HeN mice received FasFP or the saline vehicle (veh) immediately (0 h) or delayed (12 h), after sepsis induced by cecal ligation and puncture (CLP). Subsequently, we examined the effect of FasFP treatment (12 h post-CLP) on macrophage apoptosis and functional capacities. Peritoneal and splenic macrophages and Kupffer cells from sham-veh-, CLP-veh-, sham-FasFP-, or CLP-FasFP-treated mice were harvested 24 h after CLP and stimulated with lipopolysaccharide (LPS) for 24 h. The results indicate that only delayed (12 h) but not 0 h administration of FasFP demonstrated a significant increase in survival. The ability of all macrophage populations to release interleukin (IL)-6 was significantly depressed, and IL-10 release was augmented after CLP. FasFP treatment attenuated the increased IL-10 release in Kupffer cells. However, althogh enhanced susceptibility to LPS-induced apoptosis could be suppressed in CLP mouse Kupffer cells by FasFP, FasFP did not change the peritoneal or splenic macrophage response. Furthermore, FasFP attenuated the elevated plasma levels of liver enzymes after sepsis. These data indicate that in vivo inhibition of Fas/FasL signaling has tissue-specific effects on the induction of macrophage apoptosis, functional changes, and liver damage, which may contribute to the host's ability to ward off a septic challenge.
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PMID:Inhibition of Fas/Fas ligand signaling improves septic survival: differential effects on macrophage apoptotic and functional capacity. 1294 37

Toxic epidermal necrolysis (TEN) is a rare severe reaction of the skin resulting in full thickness damage to the epidermis. The condition has significant morbidity as a result of dehydration, protein loss, thermoregulatory difficulties, and renal, lung, liver and heart failure. The mortality rate approaches 30%, most commonly from bacterial sepsis. Management of this condition is cessation of the suspected causative agent and supportive care on a burns or intensive care unit. There have been recent reports of treatment using intravenous immunoglobulin (IVIG) therapy, though its efficacy is yet to be established. It has been proposed that IVIG inhibits the Fas-FasL mediated apoptosis of keratinocytes affected by TEN. We describe a case of extensive drug-induced TEN in a 33-year-old woman who showed rapid improvement with IVIG therapy at a dose of 0.75 g/kg/day given for four consecutive days.
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PMID:Treatment of toxic epidermal necrolysis with intravenous immunoglobulin. 1452 73

A potential role of Fas/FasL in sepsis is suggested by recent clinical studies showing that Fas and FasL could serve as markers for severity of sepsis. We sought to determine the effect of endotoxin infusion on expression of Fas and FasL. Healthy volunteers (n = 30) received 2 ng/kg endotoxin i.v. Endotoxin infusion decreased Fas expression on neutrophils and monocytes by 15-20% at 2-4 h in vivo and also in vitro. A rebound increase in Fas (30%) was seen on neutrophils at 24 h, and soluble FasL levels increased by 100% at 24 h. Fas mRNA levels increased 6-fold 4-6 h after endotoxin infusion as measured by real-time polymerase chain reaction. In contrast, FasL-mRNA levels in circulating leukocytes decreased by >80% 2h after lipopolysaccharide infusion. In summary, low-grade endotoxemia induces early down-modulation of Fas on leukocytes, followed by a several-fold increase in Fas-mRNA expression leading to later Fas surface upregulation on neutrophils. The upregulation of Fas expression, Fas mRNA, and later in FasL and sFas levels in endotoxemia replicates the increased fas levels found in septic patients.
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PMID:Regulation of Fas (APO-1, CD95) and Fas ligand expression in leukocytes during systemic inflammation in humans. 1462 71

Chemotherapeutic efficacy is hampered by occurrence of drug resistance. Several mechanisms cause this phenomenon. A final common factor is the reduced capacity of resistant cells to go into apoptosis following treatment with DNA-damaging agents. It is therefore interesting to search for ways to facilitate this apoptotic process following use of chemotherapeutic drugs. The death receptor ligands tumor necrosis factor (TNF), FasL and TNF-related apoptosis-inducing ligand (TRAIL) might be interesting candidates as they are able to induce apoptosis by binding to their cell membrane receptors. Recombinant forms of these ligands potentiate chemotherapeutic drug effects in preclinical models. For the clinical application of TNF, FasL and TRAIL, it is of primary importance that their safety be guaranteed. RhTNF is the only ligand currently used in humans. However, systemic rhTNF has shown low antitumor activity and higher doses induce severe sepsis-like toxicity. Perfusion setting aimed at limb preservation with rhTNF plus melphalan is currently used in sarcoma patients. A number of options have been tested in the preclinical setting that might allow circumvention of TNF toxicity in the clinic. Systemic rhFasL administration in humans is not yet feasible because of observed severe liver toxicity in mice due to Fas-mediated apoptosis of hepatocytes. Measures to circumvent liver toxicity have not yet been exploited. Another option for using FasL in the clinic may be to identify an alternative route of administration. In the animal model, FasL appeared to be less toxic for the liver compared with anti-Fas antibodies when administered intraperitoneally. There are relatively nontoxic modulators of the Fas death pathway, such as interferon and nonsteroidal antiinflammatory drugs (NSAIDs), which might prove interesting in combination with chemotherapy. Finally, it may be possible to produce a modified FasL with a reduced toxicity profile. TRAIL, produced as soluble, zinc-stabilized rhTRAIL seems to be without preclinical toxicity. Agonistic DR4 and DR5 antibodies against their TRAIL death receptor are being studied as another potential clinical option to induce apoptosis. Due to the synergistic effect observed in the preclinical setting between death receptor ligands and other modulators of the death receptor pathways and chemotherapy, it may well be that this approach is especially of value in the clinic when combined with chemotherapy. Ideally, choices for specific (modified) death receptor ligands for the treatment of patients can be rationally made based on tumor characteristics.
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PMID:Modulation of death receptor pathways in oncology. 1498 48


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