摘要:

Today the basic principles of septic conditions are understood. Nevertheless, sepsis research has reached a critical point. To integrate our knowledge towards a consistent theory of the disease process and to derive effective therapies, new perspectives for future research that fit the complexity of the problem have to be found. We conducted a review of the literature concerning systemic inflammatory response syndrome (SIRS) and sepsis with particular reference to liver pathophysiology. And compared our findings with characteristic features of complex systems. The complexity of sepsis is broadly recognized. A review of the different aspects of liver inflammation during SIRS and sepsis, i.e. endotoxin challenge, cytokine induced dysfunction, the mechanisms of leukocyte transmigration, and hormonal and neuroendocrine regulatory mechanisms is given. Key aspects of complex systems, including parallelism, locality, emergence, and cross-scale interactions are introduced. We conclude that sepsis research needs new perspectives that allow us to handle the complex interactions occurring during the disease process. We propose to focus research on the interactions between the constituents of the system rather than only describing isolated aspects of the disease process. We also conclude that the ideas and techniques of non-linear systems theory are suitable tools for the analysis of complex and dynamic diseases like SIRS and sepsis.

ISSN:1073-2322    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Our objective was to evaluate the influence of pre-operative oral application of an immunoglobulin-enriched milk preparation on endotoxin translocation and mediator release during and after abdominal surgery. Forty patients who had been treated by partial (n = 4) or total gastrectomy (n = 8) or pancreatic resection (n = 28) were enrolled in a placebo-controlled pilot study. Pre-operatively, patients were randomly treated for 3 days by oral application of a bovine milk preparation (lactobin® 56g/day, n = 20) or placebo (n = 20). In both groups, endotoxin translocation and mediator release was studied pre- and intraoperatively by measuring endotoxin, endotoxin-neutralizing capacity (ENC), interleukin 6, C-reactive protein, transferrin, &agr;-2-macroglobulin, albumin, apoliprotein-A1/-B, IgG, IgA, and IgM. The clinical course was followed up by daily evaluation of the Apache-II-score. Clinical data were comparable in both groups. The lactobin group showed significantly lower levels of endotoxin and ENC compared to the placebo group. Acute phase response, endotoxin-binding proteins, and clinical outcome did not differ between both groups. We conclude that prophylactic oral application of lactobin reduces perioperative endotoxemia and prevents reduction of ENC, suggesting a stabilization of gut barrier during abdominal surgery.

ISSN:1073-2322    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The role of nitric oxide (NO) in maintaining homeostasis and regulating organ function during hemorrhagic shock is complex. The inducible NO synthase (iNOS) has been hypothesized to play a critical role in the pathophysiologic consequences of severe hemorrhage. Heat shock protein (HSP) expression is increased by hemorrhage and is a marker of the magnitude of ischemic injury in the liver. HSP induction is protective against injury in animal models of inflammation and is regulated by NO in hepatocytes. To clarify the role of iNOS in hepatic injury and its relationship to HSP expression in hemorrhagic shock, NOS was inhibited with L-N-6-(1-iminoethyl) lysine (L-NIL), which is reported to be a selective inhibitor of the inducible NOS isoform. Doses of 50 &mgr;g/kg or 150 &mgr;g/kg were infused over 1 h at the end of compensated shock. Plasma ornithine carbamoyltransferase (OCT), a specific marker of liver injury, was significantly reduced after hemorrhage with low-dose L-NIL (7.1 ± 1.5 IU/L) compared to saline-treated control rats (13.0 ± 1.5 IU/L,P< 0.005), while high-dose L-NIL significantly increased OCT release (35.9 ± 7.2 IU/L,P< 0.05 versus shock alone) despite a greater MAP after resuscitation. HSP expression (HSP-72 and HSP-32) after hemorrhage was increased by L-NIL treatment at the highest dose. We conclude that excessive NO production from iNOS contributes to shock-induced hepatic injury. Our data suggest HSP expression may reflect the degree of ischemic injury after hemorrhage.

ISSN:1073-2322    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Bacterial walls contain lipopolysaccharide (LPS), lipoteichoic acid (LTA), or peptidoglycan. Pretreatment of rats with low doses of LPS (fromE. coli) or LTA (fromS. aureus,a pathogenic gram-positive bacterium) for 16–24 h reduces myocardial infarct size caused by a subsequent period of myocardial ischemia-reperfusion. This phenomenon of enhanced tolerance to an ischemic insult has been termed delayed preconditioning (DP). The aim of this study was to investigate whether LTA fromB. subtilis(a nonpathogenic gram-positive bacterium) induces DP when administered 16 h before left anterior descending coronary artery (LAD) occlusion-reperfusion in the rat. Furthermore, we investigated whether the specific mitochondrial KATP(mitoKATP) channel inhibitor 5-hydroxydecanoate (5-HD, 5 mg/kg) blocks DP afforded by LTA of both strains of bacteria. Male Wistar rats were subjected to LAD occlusion-reperfusion (25–120 min) and infarct size was determined. In rats pretreated with saline (1 mL/kg i.p.), LAD occlusion-reperfusion resulted in an infarct size of 58%. Pretreatment of animals with LTA (S. aureus,1 mg/kg i.p.) or LTA (B. subtilis,1 mg/kg i.p.) reduced infarct size by 22% or 33%, respectively. Administration of 5-HD 10 min before LAD occlusion-reperfusion did not abolish DP afforded by LTA fromS. aureusorB. subtilis,respectively. These results imply that late (after 16 h) opening of the mitoKATPchannel is not part of the signaling pathway of LTA-induced DP.

ISSN:1073-2322    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

As the applications of hematopoietic growth factors increase, their complex impact on host defense and immune responses continues to unfold. The effect of the administration of granulocyte colony-stimulating factor (G-CSF) on bacterial defense, proliferation of lymphocytes, and cytokine production by lymphocytes and peripheral blood mononuclear cells (PBMC) was studied. The effect of G-CSF administration on the phenotype of the cells in the major hematopoietic organs was studied as well. ACI rats were given 10 mg/kg/day G-CSF or vehicle daily for 4 days. Isolated bone marrow neutrophils and enterocytes from treated animals showed a greater bactericidal activity than controls. Proliferation of mitogen-stimulated lymphocytes and PBMC was reduced in G-CSF-treated animals. The production of proinflammatory cytokines, tumor necrosis factor (TNF), and interleukin 6 (IL-6) by lymphocytes and PBMC was reduced by G-CSF pretreatment. G-CSF administration caused an increase in IL-4 (Th2 cytokine) release and a decrease in interferon-gamma (IFN&ggr;, Th1 cytokine) release by mitogen-stimulated lymphocytes. Cytometric analysis of cells in the progenitor cell region indicated a large increase in immature cells in the bone marrow of G-CSF-treated animals compared with sham along with an increase in B cells and a decrease in polymorphonuclear leukocytes (PMNs). In addition, cytometric analysis showed a large increase in PMNs in blood and splenocytes of the treated animals compared with sham. This study confirms and extends previous observations that G-CSF administration has a number of effects that might simultaneously enhance host defense while reducing the risk of developing uncontrolled systemic inflammation. This may also be efficacious in prolonging graft survival and reducing graft vs. host disease.

ISSN:1073-2322    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The effect ofStaphylococcus aureusalpha toxin (&agr;-toxin) on selectin-mediated neutrophil adhesion was investigated in polymorphonuclear leukocyte- (PMN) induced vasocontraction and endothelial dysfunction. Adherence of human PMNs to rat aortic endothelium increased significantly following stimulation of the endothelium with &agr;-toxin (0.1, 0.5, and 1 &mgr;g/mL). This effect could be significantly attenuated by monoclonal antibodies directed against P-selectin or fucoidin, a carbohydrate known to block selectins. Unstimulated human PMNs (106cells/mL) were added to organ chambers containing rat aortic rings stimulated with &agr;-toxin (0.5 &mgr;g/mL). PMNs elicited a significant vasocontraction in &agr;-toxin-stimulated, but not in control aortic, rings (142 ± 12 mg versus 12 ± 4 mg,P< 0.05). This PMN-induced vasocontraction was virtually blunted by pretreatment with MAb directed against P-selectin or fucoidin (P< 0.05). Endothelial function as assessed by endothelium-dependent vasorelaxation to acetylcholine was substantially inhibited after induction of PMN-induced vasocontraction in &agr;-toxin-stimulated aortic rings. This endothelial dysfunction was reduced by P-selectin MAb or fucoidin. In contrast, endothelium-independent relaxation to sodium nitrite was not altered by PMN incubation, indicating that vascular smooth muscle function was unaffected. Thus, PMN-endothelial interaction followingS. aureus&agr;-toxin activation of the vascular endothelium is at least, in part, mediated by selectins. As a consequence, PMN-induced vasocontraction and endothelial dysfunction occur. Such mechanisms may be involved in microcirculation abnormalities encountered in sepsis or septic shock due toS. aureusinfection.

ISSN:1073-2322    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The purpose of this study was to determine the changes in endothelin (ET) receptor subtype expression and their functional significance after endotoxin pretreatment. Rats were pretreated with lipopolysaccharide (LPS) or sterile saline (control). After 24 h, liver samples were homogenized and competitive receptor binding assays were performed. There was no significant difference in ET receptor binding affinity between the control and LPS groups. However, the receptor subtype density showed a significant increase in ETBreceptors in LPS-treated rats, whereas the amount of ETAreceptors was almost identical between the two groups. In control, almost all ET receptors (95%) were displaced by using combined ETAantagonist (BQ-610) and ETBagonist (IRL-1620) as competitors, whereas only 80% (P< 0.05 versus control) was displaced in LPS group, raising the possibility of novel type of ET receptor expression. An infusion of ETBagonist (Sarafotoxin 6c, S6c) through portal vein in isolated perfused livers produced the same pressure response in both LPS and control groups; however, the portal pressure increase in response to the ET-1, which binds all ET receptors, was significantly potentiated in LPS-treated rats compared to controls. We conclude that altered regulation of ET receptors, in particular, the appearance of ET binding capacity that is not displaced by ETAor ETBcompetitors, may explain the hyper-response of the portal venous system to ET-1 during endotoxemia.

ISSN:1073-2322    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The present study investigated the alteration of protein kinase C (PKC) isoforms in rat liver during the progression of sepsis. Cecal ligation and puncture (CLP) model of polymicrobial sepsis was used, with early and late sepsis referring to those animals sacrificed at 9 and 18 h, respectively, after CLP. The protein contents of various PKC isoforms were quantified by Western blot and densitometric analysis. PKC&agr; activity was performed after immunoprecipitation and assayed based on the incorporation rate of32p from [&ggr;-32p] adenosine triphosphate (ATP) into histone. The distribution of PKC&agr; was evaluated by immunohistochemical staining. The steady state expression of PKC&agr; mRNA was estimated by reverse transcriptase-polymerase chain reaction (RT-PCR). The results indicated that 1) five isoforms (&agr;, &bgr;, &dgr;, ε, ζ) could be detected in normal rat liver. PKC&agr; and &bgr; were predominantly present in the cytosolic fraction, while membrane-associated PKC&dgr; was more prominent than that of cytosolic fraction; 2) the protein content of membrane-associated PKC&agr; was significantly decreased at early (P< 0.05) and late (P< 0.01) sepsis; 3) there was no significant difference of protein contents of PKC-&dgr;, -ε and -ζ between sham-operated and septic rat liver; 4) the activity of membrane-associated PKC&agr; was significantly declined under detection level during sepsis; 5) at both early and late sepsis, the immunohistochemical staining of PKC&agr; was significantly diminished, especially in the nucleus; 6) the RT-PCR product of PKC&agr; mRNA of septic liver was significantly less than the sham-operated liver. These results suggest that inactivation and the suppression of PKC-&agr; gene transcription might be involved in modulating hepatic failure during sepsis.

ISSN:1073-2322    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Dysregulated polymorphonuclear leukocyte (PMN) apoptosis and PMN-mediated organ damage have been associated with several medical conditions such as systemic inflammatory response syndrome (SIRS), acute respiratory distress syndrome (ARDS), and ischemia/reperfusion injury. IL-1&bgr; and IL-8 are two cytokines that are elevated under similar conditions. Therefore, we hypothesized that PMN exposed to these cytokines would secrete factors that could affect PMN apoptosis in a cell contact-independent manner. We have previously shown that media conditioned by IL-1&bgr;-stimulated PMN (CM-IL1&bgr;) for 2 h suppressed spontaneous PMN apoptosis. Data presented here demonstrate that media conditioned by IL-8-stimulated PMN (CM-IL8) also have the ability to suppress spontaneous, as well as FasL- and TNF-&agr;-induced apoptosis. In contrast, CM-IL1&bgr; was able to suppress FasL-induced, but not TNF-&agr;-induced, apoptosis. To elucidate the mechanisms these media use to elicit their effects, we examined the expression and function of several apoptosis-related proteins. Experimental results demonstrate that both CM-IL1&bgr; and CM-IL8 have the ability to delay caspase activation, but have no effect on the expression of their upstream activator, Fas, or its ligand, FasL. Examination of several Bcl-2 family members revealed a selective regulation by each media: CM-IL1&bgr; up-regulated Bcl-XL, while CM-IL8 down-regulated Bak expression. Additionally, CM-IL1&bgr;, but not CM-IL8, promoted the activation of NF-&kgr;B, which has anti-apoptotic activity. Together, we can conclude that IL-1&bgr;- and IL-8-stimulated PMN have the ability to suppress PMN apoptosis in a paracrine manner, and that the extent and mechanism of suppression is specific for each.

ISSN:1073-2322    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Although the mouse has been extensively used to study immune consequences of sepsis and other genetic anomalies, the changes in various cardiovascular parameters such as cardiac output, organ perfusion, as well as oxygen utilization have not been characterized in this species during sepsis. To determine this, polymicrobial sepsis was induced in male adult C3H/NeN mice by cecal ligation and puncture (CLP, two punctures with a 22-gauge needle). The animals were then resuscitated with normal saline subcutaneously. At 5 or 24 h after CLP (time points previously shown to be within the hyperdynamic and hypodynamic stage of sepsis, respectively, in the rat), cardiac output and blood flow in major organs were determined using a well-established radioactive microsphere method, and stroke volume and total peripheral resistance were calculated. In addition, oxygen delivery and consumption were determined. The results indicate that cardiac output, stroke volume, oxygen delivery and consumption, and blood flow in the liver, small intestine, spleen, and kidneys increased significantly at 5 h after CLP. This was associated with significantly decreased total peripheral resistance. In contrast, total peripheral resistance increased and the other above-mentioned parameters, as well as mean arterial pressure, decreased significantly at 24 h after the onset of sepsis. Thus, the cardiovascular response to polymicrobial sepsis in the mouse is characterized by an early hyperdynamic phase (i.e., 5 h after CLP) followed by a late hypodynamic phase (24 h post-CLP). Since the radioactive microsphere technique provides a reliable method for determining various hemodynamic parameters in the mouse, the correlation between the cardiovascular response and immune or potentially genetic alterations can be examined in this species during the progression of sepsis.

ISSN:1073-2322    

出版商:OVID    

年代:2002

数据来源: OVID