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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinical similarities between the sepsis syndrome seen in severe acute pancreatitis (AP) and that seen after burns, postoperative infection and trauma led to a series of investigations to elucidate the nature of immunological compromise in cases of severe AP. Significant alterations in lymphocyte surface marker antigen expression were demonstrated with reduced total T-lymphocyte (CD3), T-helper (CD4) and T-suppressor (CD8) cell numbers (P < 0.001, Mann-Whitney U test) during the acute phase of severe attacks compared with mild attacks. These abnormalities were reversible with increased CD3 (P < 0.005, Student's t test), CD4 (P < 0.01) and CD8 (P < 0.05) numbers in the convalescent phase of severe attacks. Experiments with a murine model of acute pancreatitis demonstrated further cellular immune abnormalities in AP as have previously been documented in models of burn, trauma and sepsis. Decreased interleukin-2 production by mononuclear cells (P < 0.005) was associated with susceptibility to endotoxin challenge. Immunomodulatory therapy in the form of exogenous IL-2 therapy or with induction of endotoxin tolerance not only led to increased IL-2 production (P < 0.01) but also to significantly reduced mortality after endotoxin exposure compared with control animals (P < 0.05, Wilcoxon-Gehan statistic). Cellular immune dysfunction in acute pancreatitis is seen in humans and in a murine model; it is associated with endotoxin exposure and with susceptibility to the deleterious effects of endotoxin and can be partially reversed by exogenous IL-2 therapy and by induction of endotoxin tolerance.
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PMID:Endotoxin, cellular immune dysfunction and acute pancreatitis. 894 39

Cytokines serve to initiate the acute inflammatory response and to integrate nonspecific and specific immunological responses to infections occurring in perioperative patients. Microbial substances induce macrophages to produce pivotal cytokines (TNF-alpha and IL-1 beta). This results in an activation of other cytokine productions including IL-2, IL-3, IL-4, IL-6, chemokines, and IL-10. Also, other host-originated humoral mediators are released from macrophages, neutrophils, platelets, and endothelial cells Various cytokines are also produced by helper-T (Th) cells, and the Th1/Th2 balance is regulated by cytokines and stress hormones. This nonspecific inflammatory response and specific immunological response which are mediated by cytokines are crucial for the host defense against invading pathogens. On the other hand, the blood levels of TNF-alpha, IL-6, IL-8, and MIP-1 alpha were correlated with the severity and mortality in patients with sepsis. Also we found that in patients with inhalation injury the high IL-8 levels in bronchoalveolar lavage fluid on admission predicted the development of respiratory insufficiency. In severe infection, a systemic release of various cytokines is not properly regulated, and the high blood levels of the proinflammatory cytokines cause an autodestructive systemic inflammatory response syndrome (SIRS). This condition is termed "Cytokine Storm" by the author. In cytokine storm, not only proinflamamtory cytokines, but also anti-inflammatory cytokines appear in circulating blood, leading to septic shock, multiple organ dysfunction, and immunosuppression. With further understanding of the roles of cytokines in sepsis, modulation of cytokine responses could be a new modality of the treatment.
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PMID:[Cytokine-mediated biological response to severe infections in surgical patients]. 903 81

Sepsis is associated with depressed T-cell functions and increased circulating levels of immunosuppressive agents. TGF-beta is a potential anti-inflammatory cytokine that can modify T-cell growth and differentiation. The up-regulation of TGF-beta and the mechanism of its action on the T-cells during septic injury have not been resolved. We hypothesized that in sepsis TGF-beta produced by macrophages acts on T-cells in a paracrine manner to suppress interleukin (IL)-2 production and proliferation. In this study, we examined the circulating TGF-beta levels in a rat model of Gram-negative bacterial sepsis, and compared the abilities of adherent and non-adherent splenocytes to produce TGF-beta. Additionally, we investigated the causal relationships of hrTGF-beta to concanavalin A (ConA)-induced T-cell responses and the intracellular mechanism of the generation of these responses in normal splenic rat T-cells. Sepsis was induced in rats by intraabdominally implanting fecal pellets containing Escherichia coli (150 CFU) and Bacteroides fragilis (10000 CFU). Adherent and non-adherent splenocytes were isolated by differential adherence using Ficoll gradient centrifugation. T-cells were purified by use of Nylon wool columns. We observed a 3-6-fold increase in the circulating levels of TGF-beta in sepsis. Western blots and ELISA determinations revealed a 2.5-3-fold increase in cell-associated TGF-beta protein levels in adherent splenic cells. Northern analyses also showed a marked increase in TGF-beta mRNA expression in adherent cells during sepsis. On the other hand, a significant change was not observed in the TGF-beta protein and mRNA expression in non-adherent splenocytes. Pretreatment of control rat T-cells with hrTGF-beta decreased both ConA-induced proliferation (by 35-40%) and IL-2 mRNA expression (by > 50%). Further, whereas incubation of control rat T-cells with either ConA or TGF-beta for 24 h resulted in a 10-15-fold increase in cAMP generation, the addition of hrTGF-beta along with ConA resulted in a 50-60-fold increase in cAMP. These results suggest that in sepsis, TGF-beta produced by splenic macrophages can act in a paracrine manner on T-cells to depress their IL-2 mRNA expression, IL-2 production and proliferation after up-regulation of cAMP which can interfere with T-cell signaling for proliferation.
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PMID:Transforming growth factor-beta negatively modulates T-cell responses in sepsis. 903 98

Distinct cytokine profiles are clearly associated with and relate to the severity of several types of infections. Cytokine networks are apparent with selected human infectious diseases, such as mycobacterial infections (leprosy, tuberculosis), the parasitic infection leishmaniasis, human immunodeficiency virus (HIV) infection, and gram-negative sepsis. Cytokine profiles are determined to some extent by two functional subsets of T lymphocytes, Th1 and Th2. The Th1 cytokines (interferon gamma, interleukin-2 [IL-2], IL-12) enhance cell-mediated immunity, inhibit humoral immunity, and result in protective effect for pathogens that are removed primarily through cell-mediated immunity (Mycobacterium tuberculosis, Mycobacterium leprae, Leishmania). The Th2 cytokines (IL-4, IL-5, IL-10, IL-13) enhance humoral immunity and inhibit cell-mediated immunity, and result in protective effect for pathogens removed primarily through humoral mechanisms. Progression of HIV infection is associated with a switch from a Th1 to a Th2 profile. For sepsis, uncontrolled activation of proinflammatory cytokines (IL-1, tumor necrosis factor-alpha, interferon-gamma) may be a fundamental defect that promotes the detrimental aspects of inflammation, whereas Th2 cytokines may be beneficial in controlling inflammation. Knowledge of basic cytokine immunopharmacology, networks, and relationships with infectious processes will aid clinicians in determining treatment approaches that are likely to be effective.
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PMID:Cytokine networks with infection: mycobacterial infections, leishmaniasis, human immunodeficiency virus infection, and sepsis. 908 11

Studies indicate that the liver, in particular the Kupffer cells, appear to be key contributors in the systemic inflammatory mediator response associated with shock and sepsis. Although several of these agents have been implicated as mediators of depressed immunoresponsiveness observed during sepsis, it remains unknown whether or not mediators released specifically by Kupffer cells play any significant role in producing the cellular dysfunction in distant organs. The aim of this study, therefore, was to determine whether or not acute Kupffer cell reduction before the onset of sepsis would protect splenic lymphocyte function. Kupffer cell number was reduced by prior (48 hours) treatment of mice with gadolinium chloride (GdCl2, 10 mg/kg of body weight, intravenously) or saline vehicle. Animals were then subjected to either sham-CLP (sham) or polymicrobial sepsis in the form of cecal ligation and puncture (CLP). Plasma and splenocytes were harvested at 2 or 24 hours after CLP. Splenocyte cultures were exposed to 2.5 micrograms concanavalin A/mL to assess their ability to release lymphokines. Cytokine (interleukin (IL)-2, IL-6, interferon-gamma, tumor necrosis factor-alpha) concentration in plasma or cell supernatants was assessed by bioassay. The results indicated that GdCl2 treated mice exhibited a marked reduction in circulating IL-6 levels at both 2 and 24 hours after CLP. Furthermore, the reduction of Kupffer cell number before the onset of sepsis completely prevented the depression of splenocyte IL-2 and interferon-gamma release, capacity. Thus mediators released by Kupffer cells during the systemic inflammatory response to polymicrobial sepsis play a significant role in producing immune dysfunction in resident splenic lymphocytes. In view of this, it appears that modulation of Kupffer cell hyperactivity during sepsis may be a novel approach for maintaining distant organ host defense mechanisms.
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PMID:Mechanism of splenic immunosuppression during sepsis: key role of Kupffer cell mediators. 919 70

A burned rabbit's model (20% TBSA) was used in this study. The sera taken from the burned rabbits without bacteremia and sepsis showed immune suppressive effects, especially the sera obtained 4 days after injury. After being separated by ultrafiltration, the burned sera were divided into three groups. The ultrafiltrating substances with molecular weight below 10 Kd or between 10 to 30 Kd were found to reduce the production of IL-2 and the lymphocyte blastogensis stimulated by Con A. The substances with molecular weight greater than 30 Kd also showed profound immune suppressive action on lymphocyte. No obviously abnormal protein was found in the burned serum analysed with SDS electrophoresis. It is concluded that the immune suppressive substances in the burned serum were characterised by complexity in components and a wide range of molecular weight.
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PMID:[A study of immune suppression activity of serum from burned rabbits]. 920 60

Following trauma, there is an increase of Th2 cytokines (IL-4, IL-6, and IL-10) and a decrease in Th1 cytokines (IFN-gamma and IL-2) that may account for impaired cellular immunity. However, the functional significance of a dominant Th2 pattern to the host remains unclear. The aim of this study was to evaluate whether Candida albicans (CA) sepsis in the setting of a Th2 response to trauma leads to increased mortality and to examine the mediators involved. Female BALB/c mice were randomized (12 per group) to receive no injury (C); trauma, consisting of a combined femur fracture and 40% total blood loss (T); no injury plus CA infection (C+CA); and CA infection 1 week following trauma (T+CA). Survival was then followed for 3 weeks. In a separate study, mice were treated as above (5 per group) and sacrificed. Harvested splenocytes were evaluated for concanavalin A-stimulated cytokine production and liver and kidney homogenates were plated to evaluate CA growth per organ and examined histologically. Candida infection at 1 week following trauma resulted in significantly increased mortality compared to infected controls. Furthermore, the Th2 dominant cytokine pattern was significantly augmented in the presence of CA infection in both C+CA and T+CA groups. Additional analysis showed significant growth of CA in liver and kidney homogenates from T+CA compared to C+CA mice. These results suggest that injured and infected mice demonstrate augmentation of Th2 dominant responses above that of injury or infection alone, as well as a decreased ability to clear Candida which may partially explain the increase in mortality observed. Therapies designed to neutralize Th2 cytokines or augment Th1 cytokines may prove beneficial in the setting of sepsis following trauma.
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PMID:Candida infection following severe trauma exacerbates Th2 cytokines and increases mortality. 922 14

We measured the plasma levels of anti-inflammatory cytokines, including interleukin 1 receptor antagonist (IL-1ra), IL-4 and IL-10; inflammatory cytokines, including IL-2, IL-6, IL-8 and tumor necrosis factor receptor I and II (TNFR I and TNFR II); and endotoxin in 11 patients with septic shock associated with gram-negative bacteria and 12 patients with sepsis not associated with shock. The plasma levels of IL-1ra and IL-10 were elevated in the septic shock group compared with the sepsis group. TNFR I and TNFR II levels tend to be higher in the septic shock group. The plasma level of TRNF-alpha was significantly correlated with levels of IL-1ra, IL-4, IL-10, TNFR I, and TNFR II. The elevated levels of the anti-inflammatory cytokines, TNFR I, and TNFR II, appeared to reflect an attempt to suppress the shock syndrome.
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PMID:Anti-inflammatory cytokine levels in patients with septic shock. 943 13

Bone fracture, soft-tissue trauma and hemorrhagic shock are frequent complications in trauma patients, and these patients are known to be immunocompromised. Nonetheless, it is difficult to differentiate the effect of soft-tissue trauma plus hemorrhage from that of bone fracture and hemorrhage on host immune function in the clinical setting. To determine this experimentally, closed bone fracture (right lower leg) and/or soft-tissue trauma (2.5 cm midline laparotomy) were induced prior to hemorrhagic shock (mean arterial BP of 35 +/- 5 mm Hg for 90 min) in male C3H/HeN mice. All animals were killed at 72 h after initiation of the experiment and the spleens were collected aseptically. More significant depression of splenocyte IL-2 and IL-3 release occurred with the combined insult than after bony injury or tissue trauma alone with hemorrhage. The present study suggests that different traumatic insults, i.e. bone fracture as well as soft-tissue trauma in conjunction with hemorrhagic shock, produce comparable depression of host immune function. Moreover, combination of closed bone fracture and soft-tissue trauma prior to hemorrhagic shock leads to even more compromised immunity. This indicates that different mechanisms of immune depression may be involved following soft-tissue trauma or bony injury coupled with hemorrhage. The markedly depressed immune function following bony injury, soft-tissue trauma and hemorrhagic shock may contribute to the increased susceptibility of severely injured patients to sepsis and the ensuing multiple organ failure in the clinical situation.
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PMID:[Contribution of soft tissue trauma and/or bone fracture to immune suppression after hemorrhagic shock in the animal experiment]. 952 70

Nitric oxide is an uncharged free radical that mediates a range of physiologic processes in the vasculature. As a principal determinant of vascular tone, the overproduction of nitric oxide has been implicated in the pathogenesis of sepsis- and cytokine-induced hypotension. The enzyme that produces nitric oxide, nitric oxide synthase, exists in three isoforms. One of the three isoforms, inducible nitric oxide synthase, is expressed in many cell types only after stimulation by cytokines and/or endotoxin. Compared to the constitutive nitric oxide synthase enzymes, the inducible enzyme generates larger quantities of nitric oxide for longer periods. Expression of the inducible isoform in vitro requires stimulation by a mixture of cytokines including interferon-gamma, tumor necrosis factor-alpha, and interleukin-1 beta. These proinflammatory cytokines are known mediators of sepsis and are also produced in the serum of cancer patients during interleukin-2 therapy, thereby leading to excessive production of nitric oxide. Interleukin-2 therapy is associated with a spectrum of cardiovascular toxicities and hemodynamic alterations that are indistinguishable from those seen in septic shock. Many of these hemodynamic effects have been linked to the overproduction of nitric oxide via a cytokine-inducible nitric oxide pathway. In this regard, inhibition of nitric oxide synthesis represents a novel approach to limit the cardiovascular toxicity associated with interleukin-2 therapy and to improve its therapeutic index. Clinical trials to evaluate the efficacy of nitric oxide synthase inhibitors in reversing the hypotension associated with IL-2 therapy are now underway.
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PMID:The role of nitric oxide in interleukin-2 therapy induced hypotension. 954 27


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