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

Endotoxin tolerance, the transient, secondary down-regulation of a subset of endotoxin-driven responses after exposure to bacterial products, is thought to be an adaptive response providing protection from pathological hyperactivation of the innate immune system during bacterial infection. However, although protecting from the development of sepsis, endotoxin tolerance also can lead to fatal blunting of immunological responses to subsequent infections in survivors of septic shock. Despite considerable experimental effort aimed at characterizing the molecular mechanisms responsible for a variety of endotoxin tolerance-related phenomena, no consensus has been achieved yet. IL-12 is a macrophage- and dendritic cell (DC)-derived cytokine that plays a key role in pathological responses to endotoxin as well as in the induction of protective responses to pathogens. It recently has been shown that IL-12 production is suppressed in endotoxin tolerance, providing a likely partial mechanism for the increased risk of secondary infections in sepsis survivors. We examined the development of IL-12 suppression during endotoxin tolerance in mice. Decreased IL-12 production in vivo is clearly multifactorial, involving both loss of CD11c(high) DCs as well as alterations in the responsiveness of macrophages and remaining splenic DCs. We find no demonstrable mechanistic role for B or T lymphocytes, the soluble mediators IL-10, TNF-alpha, IFN-alphabeta, or nitric oxide, or the NF-kappaB family members p50, p52, or RelB.
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PMID:IL-12 suppression during experimental endotoxin tolerance: dendritic cell loss and macrophage hyporesponsiveness. 1139 May 4

Interleukin-1 (IL-1) plays an important role in host defenses against microbial pathogens. Excessive production of this cytokine, however, may be responsible in part for the lethality observed during sepsis. Our studies show that interferon-gamma (IFN-gamma) downregulates lipopolysaccharide (LPS)-induced interleukin-1beta (IL-1beta) transcription in primary macrophages. This phenomenon does not occur in splenocytes or bone marrow-derived macrophages from signal transducer and activator of transcription (Stat1)-deficient mice, suggesting that Stat1, a transcription factor involved in IFN signaling, plays a critical role in this process. Moreover, nitric oxide (NO) was also involved in the downregulation of LPS-induced IL-1 by IFN, as addition of the inducible nitric oxide synthase (iNOS) inhibitor L-N(6)-(1-iminoethyl)lysine (NIL) negated the effect. Kinetic analysis of IL-1 and IFN levels in LPS-treated mice in vivo suggests that IFN-mediated inhibition of IL-1 might be an important negative feedback mechanism for limiting IL-1 generation in vivo.
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PMID:IFN-gamma inhibits lipopolysaccharide-induced interleukin-1 beta in primary murine macrophages via a Stat1-dependent pathway. 1150 42

Sepsis caused by gram-negative bacteria is a common finding having high incidence and mortality. Fc alpha RI (CD89), a receptor for immunoglobulin A (IgA), has been shown to mediate bacterial phagocytosis, which might play a role in the pathogenesis of sepsis. In this study the expression and function of Fc alpha RI were analyzed on blood monocytes and neutrophils of patients with bacteremia. We found a marked increased in expression of the alpha- and gamma-subunits of the Fc alpha RI on both types of cells in patients with gram-negative bacteremia, but not in patients with gram-positive bacteremia. This increase was independent of serum IgA levels. Fc alpha RI M(r) was lower on cells from gram-negative patients than on cells from controls (50-65 kDa versus 55-75 kDa), despite a similar 32-kDa backbone, indicating altered glycosylation. Increased levels of Fc alpha RI on blood phagocytes correlated with enhanced serum IL-6 levels, but not with IFN gamma or TNF-alpha. FcR-gamma chain associated with Fc alpha RI was phosphorylated in patients neutrophils, indicating functional engagement of this receptor during gram-negative sepsis. Increased expression and activation of Fc alpha RI-gamma 2 complexes following gram-negative infections suggests its involvement in host defense against bacteria.
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PMID:Enhanced expression of Fc alpha receptor I on blood phagocytes of patients with gram-negative bacteremia is associated with tyrosine phosphorylation of the FcR-gamma subunit. 1169 71

Sepsis and septic shock are a major cause of morbidity and mortality in patients admitted to the intensive care unit. Since the introduction of antibiotic therapy, the mortality associated with sepsis has remained within the 30- 50% range. Sepsis constitutes the systemic response to infection. This response encompasses both pro-inflammatory and anti-inflammatory phases that are marked by the sequential generation of pro- and anti-inflammatory cytokines. Among the most important pro-inflammatory cytokines are TNF-alpha and IL-1beta. The pro-inflammatory effects of such cytokines are inhibited by soluble receptors/receptor antagonists and anti-inflammatory cytokines including IL-10 and transforming growth factor-beta. Modulation of the activity of both pro- and anti-inflammatory cytokines to improve outcome in patients with sepsis has been subject of multiple clinical studies. This review will examine clinical trials evaluating several strategies for blocking or attenuating TNF-alpha and IL-1beta activity. This review will also survey the current state of experimental therapies involving IL-10, transforming growth factor-beta, granulocyte colony-stimulating factor and IFN-phi. Finally, newer developments related to less known cytokines such as macrophage migration inhibitory factor and high mobility group 1 protein will be evaluated.
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PMID:Cytokine modulation in sepsis and septic shock. 1215 Jul 2

The aim of the work was to develop accessible methods of laboratory diagnosis of the systemic inflammatory reaction, based on an assessment of biological (inflammatory and immunosuppressive) activity of serum of surgical sepsis patients (n = 104). The investigation has shown that surgical sepsis patients are characterized by marked immune dysfunctions, immunosuppressive bioactivity of blood serum being detected in most patients (in 65.6%) beginning from the earliest stages of the development of the sepsis process. It was found that in patients with dominating suppressive activity of serum the immune disturbances were more pronounced and in every second case they were of combined type. The authors propose to use the degree of the immunosuppressive potential of serum factors as the key classification sign determining the presence of CARS-positive or CARS-negative phenotype in such patients. The results obtained suggest that it is expedient for complex therapy of surgical sepsis to include immunocorrection aimed at the weakening of immunosuppresive action of antiinflammatory mediators and shift of the balance towards the reinforcement of activity of proinflammatory ones (IL-12, IL-1) and Th-1 cytokines (IL-2, IFN-g).
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PMID:[Surgical sepsis. Part I. Immunologic markers of systemic inflammatory reaction]. 1252 36

The analysis has been made for the basic immunocorrection drugs, used in clinical practice. By their features, the drugs are divided into 6 groups: immunoactive structures of pathogens, polyelectrolites, inductors of IFN-alpha, thymic hormones and their analogs, bone marrow regulators (myelopeptides) and cytokines. The first 3 groups of drugs are characterized by the inductive mechanism of action, whereas thymic hormones, myelopeptides and cytokines by the substitutive mechanism. The substitutive immunomodulators are preferential drugs at the advanced stages of infection. Immunocorrection should be used by the adequate courses and under the control of clinical dynamics, immunogram or differential blood counts. Transplantation of heterologous tissues and organs, transfusion of blood cell fractions and the first trimester of gestation may be called as contraindications for administration of immunocorrection. The high clinical efficiency of immunocorrection is shown on the usage of leukinferon in an extremely severe human pathology, such as sepsis, complicated by syndrome of polyorgan insufficiency.
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PMID:Immunocorrection Therapy: Drugs and Prospects. 1268 72

To date, there is no available treatment of hepatitis C virus (HCV) infection after renal transplantation (RT). Among 55 anti-HCV-positive/HCV RNA-positive hemodialysis patients who were treated with IFN-alpha (9 MU/wk during 6 or 12 mo), 21 of them (38%) had a sustained virologic response. Of these, 16 (76%) underwent RT 38 mo (range, 2 to 57 mo) after alpha-IFN therapy. There were 13 men and 3 women aged 46 yr (range, 27 to 68 yr). At RT, HCV serology was still positive in 15 patients, and HCV viremia was negative in all patients. Immunosuppression relied on anticalcineurin agents with or without steroids and/or antimetabolites; in addition, 12 of them received induction therapy with antithymocyte globulins. At the last follow-up after RT, at 22.5 mo (range, 2 to 88 mo), HCV viremia remained negative in all patients. Moreover, HCV RNA was not present in peripheral blood mononuclear cells when assessed in eight patients. HCV serology was found to be still positive in 13 patients. Three patients presented with acute rejection, one presented with a suppurative lymphocele, one died from a sepsis, and four presented with a cytomegalovirus infection. None of them developed posttransplant diabetes mellitus. In conclusion, hemodialysis patients waiting for a RT need to be treated with alpha-IFN because when HCV RNA clearance occurred, they experienced no relapse after transplantation despite chronic immunosuppressive treatment.
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PMID:Evidence that clearance of hepatitis C virus RNA after alpha-interferon therapy in dialysis patients is sustained after renal transplantation. 1287 63

How lipopolysaccharide (LPS) signals through toll-like receptors (TLRs) to induce nuclear factor (NF)-kappa B inflammatory cytokines in sepsis remains unclear. Major candidates for that process are myeloid differentiation protein 88 (MyD88) and MyD88 adaptor-like/TIR domain-containing adaptor protein (Mal/TIRAP) but their role needs to be further defined. Here, we have examined the role of MyD88 and Mal/TIRAP in primary human cells of nonmyeloid and myeloid origin as physiologically relevant systems. We found that MyD88 and Mal/TIRAP are essential for LPS-induced I kappa B alpha phosphorylation, NF-kappa B activation, and interleukin 6 (IL-6) or IL-8 production in fibroblasts and endothelial cells in a pathway that also requires IKK2. In contrast, in macrophages neither MyD88, Mal/TIRAP, nor I kappa B kinase 2 (IKK2) are required for NF-kappa B activation or tumor necrosis factor alpha (TNF alpha), IL-6, or IL-8 production, although Mal/TIRAP is still involved in the production of interferon beta (IFN beta). Differential usage of TLRs may account for that, as in macrophages but not fibroblasts or endothelial cells, TLR4 is expressed in high levels at the cell surface, and neutralization of TLR4 but not TLR2 blocks LPS signaling. These observations demonstrate for the first time the existence of 2 distinct pathways of LPS-induced NF-kappa B activation and cytokine production in human myeloid and nonmyeloid cells defined by selective utilization of TLR4, MyD88, Mal/TIRAP, and IKK2, and reveal a layer of complexity not previously expected.
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PMID:Distinct pathways of LPS-induced NF-kappa B activation and cytokine production in human myeloid and nonmyeloid cells defined by selective utilization of MyD88 and Mal/TIRAP. 1463 Aug 16

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.
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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

Idiopathic hypereosinophilic syndrome (HES) is a rare, chronic hematological disease mainly characterized by unexplained prolonged eosinophilia, with frequent evidence of secondary organ damage. Treatment with steroids, chemotherapy, interferon-alpha (IFN-alpha), or imatinib-mesylate may improve the prognosis. Here we describe the case of a young male patient with a six-year history of HES and severe heart involvement who, after unsuccessful treatment attempts with steroids, hydroxyurea and IFN-alpha, had a prompt, clinical and hematological complete remission following administration of imatinib. As his cardiac function also markedly improved, he was considered for heart transplant. However, seven years after the onset of the disease and four months after the termination of imatinib treatment the patient died of a cerebral hemorrhage that occurred during an episode of acute respiratory sepsis. Imatinib has been previously reported to be effective in some hematological conditions with no evidence of the BCR/ABL transcript. The mechanisms that are probably involved in the response to imatinib in HES are also discussed.
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PMID:Efficacy of imatinib mesylate in a patient with idiopathic hypereosinophilic syndrome and severe heart involvement. 1585 7


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