Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Group B streptococcus (GBS) is the leading cause of sepsis in neonates. Nitric oxide (NO) release plays a role in the hypotension that characterizes septic shock. It has been shown that GBS beta-hemolysin/cytolysin (beta-h/c) stimulates the transcription of inducible NO synthase (iNOS) in murine macrophages via intracellular pathways similar to those that mediate lipopolysaccharide-induced iNOS activation. Here, it is demonstrated that the GBS cell wall and beta-h/c act synergistically to induce iNOS in interferon (IFN)-gamma-primed [corrected] RAW 264.7 murine macrophages. In nonprimed macrophages, combined activation by the GBS cell wall plus beta-h/c is necessary to induce an NO response, which indicates that both virulence factors cooperate to substitute for the priming signal typically provided by IFN-gamma [corrected].
 ...
PMID:Synergistic action of nitric oxide release from murine macrophages caused by group B streptococcal cell wall and beta-hemolysin/cytolysin. 1240 73

Sepsis is thought to result from an exaggerated innate immune response to microbial components such as lipopolysaccharide (LPS), but the involvement of a specific mechanism(s) has not been identified. We studied the role of caspase 1 (Cas-1) in the murine innate immune response to infection with gram-negative bacteria and to nonlethal and lethal doses of LPS. cas-1(-/-) and Cas-1 inhibitor (Ac-YVAD-CHO)-treated cas-1(+/+) mice were two- to threefold more susceptible to lethal Escherichia coli infection than cas-1(+/+) mice. Administration of Cas-1 products, interleukin-18 (IL-18) or IL-1beta, protected three of three and six of seven mice, respectively, from lethal infection with E. coli compared to none of six of untreated mice (P = 0.0082). Therefore, cas-1 is essential for antibacterial host defense. Nonlethal (75 micro g) and lethal (500 micro g) doses of LPS induce different patterns of gamma interferon, IL-1beta, and IL-18 expression. Consequently, the role of Cas-1, which cleaves pro-IL-18 and pro-IL-1beta to their active forms, was investigated in these disparate conditions by using enzymatic assay and reverse transcription-PCR. At 75 micro g, LPS induced a transient increase in IL-1beta and IL-18 levels in serum, whereas at 500 micro g it induced a 1.5-fold-higher IL-18 level in serum, which increased till death. At 75 micro g of LPS, splenic cas-1 mRNA expression remained unchanged at all time points, but activity increased transiently at 3 h. In lethally treated mice, Cas-1 activity remained elevated until death; however, cas-1 mRNA levels increased at 3 h and decreased to basal levels by 8 h. Treatment with Cas-1 inhibitor protected mice from lethal endotoxemia. Thus, Cas-1 is essential for innate antibacterial host defenses and may represent a mechanism of innate immunity that upon excessive stimulation by microbial components may lead to endotoxic shock.
 ...
PMID:Role of caspase 1 in murine antibacterial host defenses and lethal endotoxemia. 1243 67

It has been demonstrated that lipopolysaccharide (LPS)-induced cytokine response in patients with sepsis differ from the normal host, yet this has not been controlled for the presence of underlying disease. We studied the ability of LPS and killed gram-negative bacteria (GNB) to induce tumor necrosis factor (TNF)-alpha and interleukin (IL) 10, and of phytohemagglutinin (PHA) to induce interferon (IFN)-gamma, in whole blood from patients with sepsis (SP, n = 20), patients with matched underlying disease and without sepsis (control patients, n = 20), and healthy volunteers (HV, n = 20). LPS-induced TNF-alpha production was lower in SP (median = 638 pg/mL) compared with control patients (4060 pg/mL; P= 0.003), and control patients production was lower compared with HV (5329 pg/mL; P < 0.001). Pseudomonas aeruginosa-induced TNF-alpha production was lower in SP (1443 pg/mL) than in control patients (7319 pg/mL; P < 0.05), and was not different between control patients and HV (6612 pg/mL; P = 0.6). IFNy production was lower in SP (948 pg/mL) compared with control patients (5516 pg/mL; P < 0.001), and the control patients production was lower compared with HV (11,282 pg/mL; P < 0.001). IL-10 production was not different among the three groups. Down-regulation of TNF-alpha production in patients with sepsis, although not restricted to them, was more pronounced with LPS than with GNB. Although the presence of underlying disease may be involved in the regulatory mechanisms of host response, the use of controls with matched underlying diseases provides strong evidence for the septic condition in the down-regulation of inflammatory response in patients with sepsis.
 ...
PMID:Impaired production of interferon-gamma and tumor necrosis factor-alpha but not of interleukin 10 in whole blood of patients with sepsis. 1257 17

Sepsis induces an early inflammatory cascade initiated by the innate immune response. This often results in the development of multisystem organ failure. We examined the role of CD40, a costimulatory molecule that is integral in adaptive immunity, by using a murine model of polymicrobial sepsis. CD40 knockout (KO) mice had delayed death and improved survival after cecal ligation and puncture (CLP). In addition, they had less remote organ injury as manifested by reduced pulmonary capillary leakage. The improvements in survival and remote organ dysfunction in CD40 KO mice were associated with reduced interleukin-6 (IL-6) and IL-10 levels in serum and bronchoalveolar lavage fluid compared to the levels in wild-type (WT) controls. Furthermore, in contrast to WT mice, CD40 KO mice had no induction of the Th1 cytokines IL-12 and gamma interferon in serum or lungs after CLP. The alterations in cytokine production in CD40 KO mice were associated with similar changes in transcription factor activity. After CLP, CD40 KO mice had attenuated activation of nuclear factor kappaB and signal transducer and activator of transcription 3 in both the lung and the liver. Finally, WT mice had increased expression of CD40 on their alveolar macrophages. These data highlight the importance of CD40 activation in the innate immune response during polymicrobial sepsis and the subsequent development of remote organ dysfunction.
 ...
PMID:CD40 contributes to lethality in acute sepsis: in vivo role for CD40 in innate immunity. 1276 Nov 37

Hepatic hemangioendothelioma (HE) is a tumor that presents in infancy and toddler. It manifests hepatomegaly, abdominal mass, jaundice, abdominal distention, or high output cardiac failure. We reviewed patients with HE in our hospital in the past 15 years (from July 1986 to June 2001). The diagnosis was made by the histology specimen or various imaging studies. There were thirteen patients (9 males, 4 females) enrolled in our study. Their ages ranged from neonate to 2 years old. The common clinical manifestations included abdominal distention (53%), congestive heart failure (38.5%), abdominal mass (30.8%), jaundice (30.8%), and skin hemangioma (23.1%). Nine patients had serum alanine aminotransferase examination and were abnormal in 2. Anemia was noted in 7 of 13 (53.8%) patients, thrombocytopenia and hyperconsumptive coagulopathy were found in 4 and 5 patients, respectively. Serum alpha-fetoprotein was elevated in 4 of 7 patients. Abdominal ultrasonography (n = 13) showed heterogeneous and hypoechoic lesions in the liver. Computed tomography (n = 11) revealed central hypointensity with peripheral enhancement after contrast of the liver masses. Magnetic resonance imaging studies of the hepatic masses (n = 3) showed decreased signal intensity on T1 images and high signal intensity on T2. Most patients were treated with steroid. Other management included interferon, chemotherapy, embolization and/or surgery. Four patients were managed conservatively. Among the other nine patients, four patients died of sepsis, hepatic failure, disseminated intravascular coagulopathy or tumor rupture with hemorrhagic shock. HE appears to be a histologically benign tumor but may have a poor outcome because of complications. For its management, steroid is a first-line medication. Other methods of treatment were interferon, hepatic artery embolization, chemotherapy and surgery. Long term follow up is needed for the evaluation of treatment response.
 ...
PMID:Hepatic hemangioendothelioma in children: analysis of thirteen cases. 1280 Mar 77

Infections are a leading cause of death in stroke patients. In a mouse model of focal cerebral ischemia, we tested the hypothesis that a stroke-induced immunodeficiency increases the susceptibility to bacterial infections. 3 d after ischemia, all animals developed spontaneous septicemia and pneumonia. Stroke induced an extensive apoptotic loss of lymphocytes and a shift from T helper cell (Th)1 to Th2 cytokine production. Adoptive transfer of T and natural killer cells from wild-type mice, but not from interferon (IFN)-gamma-deficient mice, or administration of IFN-gamma at day 1 after stroke greatly decreased the bacterial burden. Importantly, the defective IFN-gamma response and the occurrence of bacterial infections were prevented by blocking the sympathetic nervous system but not the hypothalamo-pituitary-adrenal axis. Furthermore, administration of the beta-adrenoreceptor blocker propranolol drastically reduced mortality after stroke. These data suggest that a catecholamine-mediated defect in early lymphocyte activation is the key factor in the impaired antibacterial immune response after stroke.
 ...
PMID:Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1-like immunostimulation. 3162 20

Streptococcus pneumoniae infection may result in asymptomatic carriage, mucosal or invasive disease. We hypothesize that self-limiting or fatal disease outcome follows infection with S. pneumoniae differential activation of the host immune response. BALB/c and C57BL/6 mice were inoculated intranasally with S. pneumoniae serotype 3 strain WU2 and serotype 14 strain DW14 and mortality, bacterial load, pathological changes in the lungs and cytokines mRNA levels in the spleen were analysed. No differences between the C57BL/6 and the BALB/c inbred mice were observed except for the severity of their lung pathology and IL-4 expression. Infection of the two mouse strains with S. pneumoniae WU2 resulted in sepsis and death that occurred within 4 days post-inoculation. This death was preceded, in both mouse strains, in an increase over time of the lung bacterial load and bacteraemia. The lung pathology was characterized by diffuse pneumonia with marked congestion of the lungs. Analysis of mRNA expression of cytokines in the spleen revealed no alterations in tumour necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta, interleukin (IL)-12 and interferon (IFN)-gamma and induction of IL-10 and IL-4. The two strains of mice survived infection with S. pneumoniae DW14. This was accompanied by a reduction over time of lung bacterial load and bacteraemia. The lung pathology was characterized by focal lymphocyte infiltration and preserved architecture of the organ. Analysis of mRNA expression of cytokines in the spleen revealed a significant decrease in the levels of TNF-alpha, TGF-beta, IL-12 and IFN-gamma mRNA expression, which usually precedes cytokine protein expression. Interestingly, a significant increase in the levels of IL-4 mRNA expression was found in BALB/c mice only. This study suggests that differential activation or evasion of cytokine expression by S. pneumoniae virulent strains determines disease outcome regardless of the host's immunogenetic background.
 ...
PMID:Differential activation of the immune system by virulent Streptococcus pneumoniae strains determines recovery or death of the host. 1297 50

Neisseria meningitidis serogroup B is a major cause of life-threatening meningitis and septicemia worldwide, and no effective vaccine is available. Initiation of innate and acquired immune responses to N. meningitidis is likely to be dependent on cellular responses of dendritic cells (DC) to antigens present in the outer membrane (OM) of the meningococcus. In this study, the responses of human monocyte-derived DC (mo-DC) to OM isolated from parent (lipopolysaccharide [LPS]-replete) meningococci and from a mutant deficient in LPS were investigated. Parent OM selectively up-regulated Toll-like receptor 4 (TLR4) mRNA expression and induced mo-DC maturation, as reflected by increased production of chemokines, proinflammatory cytokines, and CD83, CD80, CD86, CD40, and major histocompatibility complex (MHC) class II molecules. In contrast, LPS-deficient OM selectively up-regulated TLR2 mRNA expression and induced moderate increases in both cytokine production and expression of CD86 and MHC class II molecules. Preexposure to OM, with or without LPS, augmented the allostimulatory properties of mo-DC, which induced proliferation of naive CD4+ CD45RA+ T cells. In addition, LPS-replete OM induced a greater gamma interferon/interleukin-13 ratio in naive T cells, whereas LPS-deficient OM induced the reverse profile. These data demonstrate that components of the OM, other than LPS, are also likely to be involved in determining the levels of DC activation and the nature of the T-helper immune response.
 ...
PMID:Activation of human dendritic cells is modulated by components of the outer membranes of Neisseria meningitidis. 1450 Apr 78

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.
 ...
PMID:Modulation of death receptor pathways in oncology. 1498 48

Donor lymphocyte infusion (DLI) results in complete cytogenetic remission (CCR) of relapsed chronic-phase chronic myeloid leukemia (CML-CP) after allogeneic stem cell transplantation (SCT) in up to 80% of patients. The main complication of DLI is graft-versus-host disease (GVHD). Decreasing the dose of DLI is associated with less GVHD but also with a longer interval between treatment and CCR. We postulated that combining alpha-interferon (alpha-IFN) with DLI would enable us to decrease the dose of DLI, thereby limiting GVHD, and at the same time to decrease the interval between DLI and CCR for patients with either a hematologic or cytogenetic relapse. For molecular relapses, we hypothesized that because of a lower tumor load, very low doses of DLI without alpha-IFN could be an effective treatment. Two groups of CML-CP patients treated with DLI at a very low dose of 0.5 to 1.0 x 10(7) mononuclear cells per kilogram, containing 2 to 6 x 10(6) CD3+ T cells per kilogram, were analyzed: 13 patients with a cytogenetic or a hematologic relapse after allogeneic SCT (group A) were treated with additional alpha-IFN therapy at a dose of 3 x 10(6) U 5 d/wk, and 8 patients with a molecular relapse were treated without alpha-IFN (group B). Twelve patients from group A reached a CCR. The median interval between DLI and CCR was 7 weeks (range, 5-18 weeks) for group A. All patients with a CCR reached complete donor chimerism at a median of 10 weeks after DLI (range, 6-121 weeks). Eleven patients reached molecular remission at a median of 15 weeks after DLI (range, 8-34 weeks). In group B, all patients reached a molecular remission at a median of 14 weeks (range, 12-29 weeks). Five patients from group A developed acute GVHD grade II to IV and extensive chronic GVHD. In group B, 1 patient developed acute GVHD grade II to IV and subsequently developed extensive chronic GVHD. With a median follow-up of 62 months, 10 patients in group A are alive and in continuous CCR. One patient had a molecular relapse, for which she successfully received additional DLI; another patient reached molecular remission only after 5 doses of DLI. Two patients from group A died of a gram-negative sepsis, and 1 died of an acute myocardial infection. In group B, all patients are alive and in molecular remission with a median follow-up of 20 months. One patient's disease progressed but was successfully treated with DLI plus alpha-IFN. In conclusion, very-low-dose DLI in combination with alpha-IFN as treatment for cytogenetic or hematologic relapses of CML-CP after allogeneic SCT reduced the interval to obtain a CCR with acceptable GVHD when compared with the literature. Patients with a CCR also reached complete donor chimerism and complete molecular remissions. For patients with a molecular relapse, very-low-dose DLI alone is sufficient to induce molecular remissions in most patients and is associated with limited GVHD.
 ...
PMID:Alpha-interferon with very-low-dose donor lymphocyte infusion for hematologic or cytogenetic relapse of chronic myeloid leukemia induces rapid and durable complete remissions and is associated with acceptable graft-versus-host disease. 1499 86


<< Previous 1 2 3 4 5 6 7 8 9 10