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)

Soluble receptors have been identified for most members of the TNF-receptor/NGF receptor superfamily. CD95 (Fas/Apo-1) is of particular importance, since its triggering may induce apoptosis in sensitive cells. Recently, a soluble form of the CD95 molecule was described which interacts with the CD95-CD95 ligand death pathway. Increased concentrations of soluble CD95 (sCD95) were previously detected in some patients with T and B cell leukemias and lymphomas. In the present study we investigated sCD95 in the serum of patients with myeloid leukemias, myeloproliferative and myelodysplastic syndromes. A total of 72 patients was studied (29 AML, 17 MDS, 20 CML and six other myeloproliferative disorders). In AML with active disease, the levels of sCD95 tended to be elevated, but did not correlate with defined clinical or laboratory parameters. In the other disorders, the levels of sCD95 were not generally increased, although some patients had elevated levels. These data strongly suggest that sCD95 in AML patients is not derived from leukemic cells, but is possibly secreted or shed from reactive or stromal cells. This hypothesis is also supported by a group of eight patients with septicemia but not leukemia who had elevated sCD95 (P < 0.05). Furthermore, all three patients with elevated sCD95 who had undergone chemotherapy for AML had major infections. Taken together, this study shows that measuring soluble Fas-receptor in myeloid leukemia is not diagnostically useful, but increased sCD95 may be associated with clinical complications like septicemias.
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PMID:Soluble FAS (CD95) is not elevated in the serum of patients with myeloid leukemias, myeloproliferative and myelodysplastic syndromes. 875 76

Sepsis is reported to induce an increase in the rate of apoptosis (Ao), in immature lymphoid cells residing in hematopoietic tissues such as the thymus and bone marrow. Alternatively, secondary lymphoid tissue, such as the spleen exhibit little innate (unstimulated) Ao. However, it is unknown whether or not polymicrobial sepsis has any effects on the frequency of Ao in mucosal lymphoid tissue and what, if any, are the functional consequences of such a change. To assess this, Peyer's patch cells were harvested from C3H/HeN (endotoxin-sensitive) mice killed 12 or 24 hours after the onset of polymicrobial sepsis (cecal ligation and puncture [CLP]). The results indicate that the percentage of cells that were Ao+ as determined by flow cytometry were markedly increased at 24 hours, but not at 12 hours post-CLP. This correlates well with evidence of increased DNA fragmentation as well as histological changes observed both at a light and transmission electron microscopic level of the Peyer's patch Ao. Phenotypically, these changes were restricted to the B220+ (B-cell) population that also exhibited a marked increase of Fas/Apo-1 antigen expression. The functional consequence of this increased apoptosis appears to be associated with the endogenous stimulation (activation) of IgA production by mucosal B lymphocytes and increased nuclear c-Rel expression. Furthermore, we found that Peyer's patch lymphocytes isolated from C3H/HeJ-Faslgld (endotoxin-tolerant/Fas ligand- [FasL] deficient) as opposed to C3H/HeJ (endotoxin-tolerant) inbred mice did not exhibit increased Ao after CLP. These findings indicate that increased B-cell Ao appears to be a FasL-Fas antigen-mediated process, but is not due to endotoxin sensitivity. In conclusion, we speculate that the increased Fas-associated apoptosis detected in mucosal B cells (as opposed to splenic or bone marrow B cells) may be due to increased luminal antigens other than endotoxin, released due to gut barrier integrity breakdown during sepsis.
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PMID:Increased mucosal B-lymphocyte apoptosis during polymicrobial sepsis is a Fas ligand but not an endotoxin-mediated process. 945 67

The heart is a tumor necrosis factor (TNF)-producing organ. Both myocardial macrophages and cardiac myocytes themselves synthesize TNF. Accumulating evidence indicates that myocardial TNF is an autocrine contributor to myocardial dysfunction and cardiomyocyte death in ischemia-reperfusion injury, sepsis, chronic heart failure, viral myocarditis, and cardiac allograft rejection. Indeed, locally (vs. systemically) produced TNF contributes to postischemic myocardial dysfunction via direct depression of contractility and induction of myocyte apoptosis. Lipopolysaccharide or ischemia-reperfusion activates myocardial P38 mitogen-activated protein (MAP) kinase and nuclear factor kappa B, which lead to TNF production. TNF depresses myocardial function by nitric oxide (NO)-dependent and NO-independent (sphingosine dependent) mechanisms. TNF activation of TNF receptor 1 or Fas may induce cardiac myocyte apoptosis. MAP kinases and TNF transcription factors are feasible targets for anti-TNF (i.e., cardioprotective) strategies. Endogenous anti-inflammatory ligands, which trigger the gp130 signaling cascade, heat shock proteins, and TNF-binding proteins, also control TNF production and activity. Thus modulation of TNF in cardiovascular disease represents a realistic goal for clinical medicine.
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PMID:Tumor necrosis factor in the heart. 953 Feb 22

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by chronic, histologically benign splenomegaly and generalized lymphadenopathy, hypergammaglobulinemia, and autoantibody formation. ALPS has been attributed to defective programmed cell death of lymphocytes, most often arising as a result of mutations in the gene encoding the lymphocyte apoptosis receptor Fas/APO-l/CD95. We identified a novel mutation in the intracellular apoptosis signaling domain of Fas in 11 members of a family, individual members of which have been monitored for up to 25 years, with 1 or more features of ALPS. This study of a large number of family members carrying the same Fas defect demonstrates that ALPS is inherited in an autosomal dominant fashion but with a high degree of variability in clinical expression. Although 1 affected individual died of postsplenectomy sepsis and 1 has been treated for lymphoma, the Fas mutation in this family has been compatible with a healthy adulthood, as clinical features of ALPS have receded with increasing age.
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PMID:The clinical spectrum in a large kindred with autoimmune lymphoproliferative syndrome caused by a Fas mutation that impairs lymphocyte apoptosis. 982 19

Recent studies have shown that with the onset of sepsis there is an increase in apoptosis (Ao) in the thymus, mediated in part by steroids, which may contribute to a loss of T-cell progenitors, thereby, reducing immune functions. However, reports also suggest that these steroid effects could be mediated by Fas ligand (FasL) and/or by endotoxin (ETX). Thus, our study was to determine: 1) if polymicrobial sepsis (cecal ligation and puncture; CLP) alters thymocyte Fas antigen/receptor (Fas+) expression and 2) if the increase in Ao in septic ETX-sensitive C3H/HeN mice is seen in thymocytes from ETX-tolerant, C3H/HeJ, or the FasL-deficient/ETX-tolerant, C3H/HeJ-FasL(gld), male mouse strains subjected to CLP or sham-CLP (Sham) 12 or 24 h before they were killed. The results of flow cytometric analysis indicated that increased %Ao+ seen in thymocytes of CLP C3H/HeN mice was associated with either no change (12 h) or a decrease in %Fas+ expression at 24 h, although the %Bcl-2+ (an antiapoptotic protein) cells was depressed at both times. Additional studies examining C3H/HeJ or C3H/HeJ-FasL(gld) mice subjected to CLP show that as with the ETX-sensitive mouse, thymocyte Fas and Bcl-2 antigen expression as well as Bcl-2/Bcl-X(L/S) mRNA levels decreased although the %Ao+ increased after CLP in both ETX-tolerant and ETX-tolerant/FasL-deficient mice. Furthermore, if ETX-tolerant/FasL-deficient CLP animals were administered the steroid receptor antagonist RU-38486 (s.c., immediately after CLP) the increase in Ao was markedly attenuated, along with restoration of the percentage of cells expressing Bcl-2 and Fas antigen as well as Bcl-2/Bcl-X(L/S) mRNA levels. Thus, we concluded that increased septic thymocyte Ao is not regulated through either Fas mediated pathway or ETX, but is a result of the release of endogenous steroids possibly acting directly or indirectly on Bcl-2 expression.
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PMID:Does Fas ligand or endotoxin contribute to thymic apoptosis during polymicrobial sepsis? 1018 75

Recent studies suggest that increased lymphocyte apoptosis (Ao) detected in peripheral blood T cells from burn patients appears to contribute to decreased lymphocyte immunoresponsiveness. However, while it is known that sepsis induces a marked depression in the splenocyte immune response (i.e. decreased interleukin-2, interferon-gamma production and proliferation) in response to the T-cell mitogen concanavalin A (Con A), it is unknown whether this depression is associated with an increase in inducible Ao and if so, which mediators control this process. To assess this, splenocytes were harvested from mice at 24 hr (a period associated with decreased Con A response) after the onset of polymicrobial sepsis [caecal ligation and puncture (CLP)] or sham-CLP (Sham) and then stimulated with 2.5 microg Con A/ml (24 hr). Septic mouse splenocytes stimulated with Con A, while not showing a change in their phenotypic make-up, did exhibit a marked increase in the percentage of splenocyte that were Ao+ which was associated with altered cytokine release. This appears to be due to an increase in the percentage of Ao+ cells in the CD4+ CD8- population and was associated with enhanced Fas antigen expression as well as an increase in mRNA for the Fas-FasL gene family. To determine if the changes in Ao are due to either endotoxin (a product of Gram-negative bacteria seen in CLP mice) or the expression of Fas ligand (FasL; a mediator of activation-induced lymphocyte Ao), a second set of studies examining Con A-inducible Ao was performed with splenocytes harvested from septic endotoxin-tolerant C3H/HeJ and the FasL-deficient C3H/HeJ-Fasl gld mice. The results show that increased splenocyte Ao detected following CLP is due to a FasL-mediated process and not to endotoxin. Thus the inadvertent up-regulation of FasL-mediated splenocyte Ao may contribute to the depression of splenocyte immune responses seen during polymicrobial sepsis.
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PMID:Increased inducible apoptosis in CD4+ T lymphocytes during polymicrobial sepsis is mediated by Fas ligand and not endotoxin. 1044 13

Accumulation and activation of inflammatory cells in the lung characterize the acute respiratory distress syndrome (ARDS). However, the precise mechanism for lung epithelial and endothelial cell damage remains unknown. Based on evidence that rapid apoptosis caused by CD8(+) cytolytic T cells can induce pathological cell death, we hypothesized that this mechanism may also participate in the acute lung injury, and attempted to evaluate apoptosis-related factors in bronchoalveolar lavage fluid (BALF) from ARDS patients. Quantitative polymerase chain reaction (PCR) analysis revealed that the messenger ribonucleic acids (mRNAs) for several apoptosis molecules, such as perforin, granzyme A, granzyme B, FasL, and Fas were highly upregulated in the acute phase of ARDS following sepsis. In contrast, low or negligible mRNA expression of these molecules was detected in patients with normal lung function, in septic patients without lung injury (septic non-ARDS), and in patients in the late phase of septic ARDS (late ARDS). While the genes of the classic proinflammatory cytokines interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), IL-6, and IL-8, and inducible nitric oxide synthase (iNOS) were upregulated in septic non-ARDS or late ARDS patients, expressions of these genes in the acute phase of septic ARDS were most distinct. The immunofluorescence flow cytometry showed that only the lymphocyte population in BALF from acute phase of septic ARDS patients expressed perforin and granzyme. The level of soluble FasL in the BALF increased only in the acute ARDS patients. These results thus suggested that the dual apoptosis pathway, perforin/granzyme and FasL/Fas system, is likely to be another participant for the pathogenesis of acute lung injury.
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PMID:Upregulation of two death pathways of perforin/granzyme and FasL/Fas in septic acute respiratory distress syndrome. 1137 24

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

Listeria monocytogenes causes sepsis and meningitis in immunocompromised hosts and a devastating maternal/fetal infection in pregnant women. In recent years a more benign gastroenteritis in normal hosts has been described. Listeria has been increasingly identified as a food-borne pathogen, and large-scale contamination of processed foods with resulting outbreaks has occurred in recent years, possibly as a result of consolidation of the food industry. Experimental listeriosis in mice has proven to be an extraordinarily useful model for analyzing cell-mediated immune host defenses. Contrary to original concepts, we found that neutrophils, not macrophages, are the prime effectors during early infection. CD8+ T cells are then responsible for lysing infected hepatocytes through perforin-related (early primary and secondary infection) or Fas-L/Fas mechanism (late primary). Of interest, non-classical MHC class Ib restricted recognition mechanisms exist early, whereas MHC class Ia mechanisms can be detected throughout infection.
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PMID:An updated model of cell-mediated immunity--listeriosis: clinical and research aspects. 1095 86

Recent studies from our laboratory demonstrated that mucosal lymphoid tissue such as Peyer's patch cells and lamina propria (LP) B lymphocytes from mice shows evidence of increased apoptosis after sepsis that is associated with localized inflammation/activation. The mechanism for this is poorly understood. Endotoxin as well as Fas/Fas ligand (FasL) have been shown to augment lymphocyte apoptosis; however, their contribution to the increase of apoptosis in LP B-cells during sepsis is not known. To study this, sepsis was induced by cecal ligation and puncture (CLP) in endotoxin-tolerant C3H/HeJ or FasL-deficient C3H/HeJ-FasL(gld) (FasL(-)) mice and LP lymphocytes were isolated 24 h later. Phenotypic, apoptotic, and functional indexes were assessed. The number of LP B cells decreased markedly in C3H/HeJ mice but not in FasL-deficient animals at 24 h after CLP. This was associated with comparable alteration in apoptosis and Fas antigen expression in the B cells of these mice. Septic LP lymphocytes also showed increased IgA production, which was absent in the FasL-deficient CLP mice. Furthermore, Fas ligand deficiency appeared to improve survival of septic challenge. These data suggest that the increase in B cell apoptosis in septic animals is partially due to a Fas/FasL-mediated process but not endotoxin.
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PMID:Increased apoptosis in lamina propria B cells during polymicrobial sepsis is FasL but not endotoxin mediated. 1129 88


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