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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The immune response to trauma, shock, and/or sepsis appears to exhibit a bimodal response, in which there is an early exaggerated inflammatory response, giving way over time to a state of hyporesponsiveness or immune dysfunction. This state of immune dysfunction is frequently associated with increased infectious complications and/or mortality, seen following shock or trauma. In this article, we present an overview of some of those changes that have been seen with respect to the process of major histocompatibility class II (MHC class II) antigen presentation by macrophage, a key component of the overall host immune response to foreign bacterial and/or fungal pathogens encountered following shock/trauma (with a particular emphasis on hemorrhagic shock as a component of traumatic shock). With respect to the overall process of antigen presentation, defects (dysfunction) are evident not only in models of shock and sepsis, but also in traumatized patients. Studies of the capacity of a monocyte's/macrophage's ability to present antigen indicate that defects can be detected, not only in those steps involved in antigenic processing, but also in MHC class II molecule expression and accessory molecule function (or its inhibition) following shock. Those changes in the macrophage's capacity to process antigen seen during the first 24 h after hemorrhagic shock appear to be associated with the cell's metabolic response to regional hypoxia and/or the shift to proinflammatory mediator release (tumor necrosis factor, interleukin [IL]-1, IL-6, etc.). This initial acute response to shock appears to act as the nidus for chronic anti-inflammatory mediator release (prostaglandin E2, transforming growth factor-beta, IL-10, IL-4, nitric oxide, etc.), which may mediate the sustained depression of the antigen-presenting cell's function.
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PMID:Trauma-induced suppression of antigen presentation and expression of major histocompatibility class II antigen complex in leukocytes. 870 94

Despite recent advances in antibiotic therapy, aggressive operative intervention and intravenous hyperalimentation, sepsis, and multiple organ failure are still reported to contribute to significant morbidity and mortality in the surgical intensive care unit. In light of this, it is essential to determine the mechanism underlying the pathophysiology of sepsis so that better therapeutic interventions can be designed. Experimental studies indicate that murine polymicrobial sepsis induces a marked suppression in both lymphocytic and macrophage function associated with decreased cellular adenosine triphosphate levels and increased Ca2+. However, such changes are not detectable until approximately 12 h after the onset of sepsis. Alternatively, early (0-4 h) in sepsis, macrophages from the liver and peritoneum exhibit augmented innate secretion of proinflammatory cytokines, tumor necrosis factor, interleukin (IL)-6, and IL-1, associated with the systemic release of these agents. Sustained release of immunosuppressive agents transforming growth factor-beta, IL-4, IL-10, and PGE2, as well as glucocorticoids, are also observed during sepsis. In this regard, many investigators, including us, have suggested that an agent(s) released as a part of this systemic inflammatory response to sepsis may be responsible for the protracted suppression of immune cell function. Studies examining the effects of these mediators in vitro on various immune cells have shown that many of these agents also have the capacity to induce a process referred to as programmed cell death (PCD) or apoptosis (Ao). We have presented evidence of marked changes in the rate of Ao in immune cells after the onset of sepsis. These data suggest the possibility that mediators released in response to septic insult contribute to the observed changes in immune cell function through the induction of Ao. Inasmuch, understanding the contribution of PCD to the pathophysiology of sepsis, should provide a better basis from which to develop more effective therapy for the septic patient.
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PMID:Immune dysfunction in murine polymicrobial sepsis: mediators, macrophages, lymphocytes and apoptosis. 882 95

Monocyte/T-cell interactions play a critical role in the systemic response to infection. Distinct patterns of cytokines are produced by two different types of T-helper cells (Th). Th1 cells secrete interleukin-2 (IL-2) and interferon-gamma (IFN-gamma), whereas Th2 cells produce IL-4, IL-5, IL-6, IL-10, and IL-13. In volunteers systemic endotoxin administration initiates many features of gram-negative sepsis including cytokine release, but the patterns (i.e., Th1/Th2 patterns) have not yet been studied. In this institutional review board-approved study we investigated the effect of an intravenous bolus of endotoxin from Escherichia coli (4 ng/kg body weight) on the Th1/Th2 response in four female and four male volunteers (mean age 27.1 +/- 0.8 years). Plasma cytokine levels for IL-2, IL-4, IL-10, IL-12, and IFN-gamma and heart rate, mean arterial pressure, temperature, white blood cell, and differential blood count were determined before and hourly for 5 hours after endotoxin administration. All volunteers had tachycardia, decreased mean arterial pressure, fever, and leukocytosis. IL-10 was significantly (p < 0.05) elevated (9.4 +/- 3.9 pg/ml vs 60.9 +/- 19.3 pg/ml) 3 hours after endotoxin was administered, whereas IL-2 levels were decreased (69 +/- 26 U/ml vs 30.6 +/- 14.9 U/ml). IL-4 and IFN-gamma were not detectable in plasma. No changes were seen in the plasma levels of IL-12. Systemic responses did not correlate with changes in cytokine levels. Cytokine patterns found in this study suggest that after low-dose endotoxin administration the T-cell immune response is shifted towards the Th2 cell type response. This early shift towards a Th2 cell response may contribute to the depressed cell-mediated immune response associated with sepsis.
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PMID:The 1996 Moyer Award. Effects of endotoxin on the Th1/Th2 response in humans. 895 35

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

Cytokine aberrations may contribute to sepsis-associated mortality after trauma. We have previously documented that IL-10 (a Th-2 cytokine) is downregulated after tissue trauma, and the administration of exogenous IL-10 improved survival and anti-IL-10 antibody increased lethality in a murine injury-lethal endotox-emia model. IL-4 activates the Th-2 subset of T cells, and functions in a paracrine manner to inhibit proinflammatory cytokine synthesis. The purpose of this study was to investigate the kinetics of IL-4 production in this murine trauma-sepsis model. Mice (n = 50) were randomized to five groups: Control, Femur Fracture (FFx), FFx-lipopolysaccharide (LPS), FFx-LPS-IL10, and FFx-LPS-Anti-IL10. LPS (400 micrograms ip) was administered 4 days after FFx to induce lethal sepsis. IL-10 (0.5 microgram ip) or anti-IL-10 (100 micrograms IP) was administered at resuscitation, 30 min after LPS. IL-4 production was measured in ex vivo splenocyte culture supernatants at 24-hr intervals. Splenocyte IL-4 production was significantly upregulated in the FFx-LPS group that received anti-IL-10; maximal IL-4 production was on Day 5, with a greater than sevenfold increase compared to all other groups. A transient early rise in IL-4 production was noted in the FFx-LPS group that received exogenous IL-10; however, a subsequent rapid decline was documented. Treatment with anti-IL-10 antibody after FFx injury and septic challenge with LPS is associated with an upregulation of splenocyte IL-4 synthesis, as well as an increase in mortality in this murine model. IL-4 and IL-10 interaction postinjury may profoundly influence monocyte activation, cell-mediated immunity, and the subsequent host immune response to infection.
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PMID:Kinetics of splenocyte interleukin-4 production after injury and lethal endotoxin challenge. 907 Jan 78

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

Altered host defense mechanisms after major surgery or trauma are considered important for the development of infectious complications and sepsis. In the present study, we demonstrate that major surgery results in a severe defect of T-lymphocyte proliferation and cytokine secretion in response to coligation of the antigen receptor complex and CD28. During the early postoperative course, reduced cytokine secretion was observed for interleukin-2 (IL-2), gamma interferon, and tumor necrosis factor alpha, which are associated with the Th1 phenotype of helper T lymphocytes, and for IL-4, the index cytokine of Th2 cells. During the late postoperative course, T-cell cytokine secretion increased to normal levels. Production of the anti-inflammatory cytokine IL-10 was altered, with different kinetics being selectively elevated during the late postoperative course. In contrast, the capacity of peripheral blood monocytes to present bacterial superantigens and to stimulate T-cell proliferation was normal or enhanced after surgery despite a significant loss of cell surface HLA-DR molecules. Thus, the level of major histocompatibility complex class II protein expression does not appear to predict the antigen-presenting capacity of monocytes obtained from surgical patients with uneventful postoperative recovery. Secretion of IL-1beta and IL-10 by endotoxin-stimulated peripheral blood monocytes was increased at different time points after surgery. Major surgery therefore results in a distinct pattern of immune defects with a predominant defect in the T-cell response to T-cell receptor- and CD28 coreceptor-mediated signals rather than an impaired monocyte antigen-presenting capacity. Suppression of T-cell effector functions during the early phase of the postoperative course may define a state of impaired defense against pathogens and increased susceptibility to infection and septic complications.
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PMID:Distinct mechanisms of immunosuppression as a consequence of major surgery. 916 65

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

Nitric oxide (NO), produced in large amounts by inducible NO synthase (iNOS), has emerged recently as an important microbicidal and immunomodulatory mediator. We have investigated its role in bacterial septic arthritis caused by Staphylococcus aureus infection using iNOS-deficient mice. The incidence, rate of development, and severity of arthritis were greater in iNOS-deficient than in heterozygous or wild-type control mice. Similarly, the incidence and severity of septicemia and mortality were significantly higher in iNOS-deficient mice compared with controls. Increased TNF-alpha synthesis in vivo and in vitro and enhanced IFN-gamma compared with IL-4 production in vitro in iNOS-mutant mice demonstrated exaggerated Th1 polarization of the host response. These data indicate that high output NO production is not a prerequisite for severe articular destruction and imply that NO is of importance in synovial defense against staphylococcal infection.
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PMID:Septic arthritis following Staphylococcus aureus infection in mice lacking inducible nitric oxide synthase. 955 85


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