摘要:

&NA;It has been suggested that excessive activation of the anti‐inflammatory pathways in sepsis may lead to poor outcome of patients with sepsis. The aim of this study was to test the value of histocompatibility leukocyte antigen (HLA)‐DR‐expression on blood monocytes and plasma levels of interleukin (IL)‐4 and ‐10 in prediction of hospital mortality in patients with sepsis. Sixty‐one critically ill patients with sepsis were prospectively enrolled to this study in two university hospital intensive care units. Survivors (n = 41) and nonsurvivors (n = 20) differed significantly in HLA‐DR expression at admission: survivors' median 84% (interquartile range 64%‐98%) versus nonsurvivors' median 62% (interquartile range 47%‐83%,P= 0.025 by Mann‐Whitney test). Similarly, the analysis revealed statistically significant differences between survivors and nonsurvivors in admission plasma IL‐10 levels and in admission Sequential Organ Failure Assessment (SOFA) and Acute Physiology and Chronic Health Evaluation (APACHE) II scores, but not in IL‐4 levels. The areas under receiver operating curves (AUC) showed that both monocyte HLA‐DR expression and plasma IL‐4 level showed poor discriminative power in prediction of hospital mortality (AUC < 0.70). Only IL‐10 levels on days 1 and 2 showed reasonable predictive power (AUCs 0.706 and 0.725, respectively). The highest AUC values were those of APACHE‐II (0.786) and admission SOFA score (0.763). In conclusion, APACHE II and SOFA scores on admission showed better discriminatory power than HLA‐DR expression and IL‐10 and IL‐4 levels in prediction of hospital mortality in critically ill patients with sepsis.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

&NA;Although coagulation abnormalities may partly underlie the physiologic derangements of the sepsis syndrome, anticoagulant therapies have produced mixed results on survival in clinical studies. We hypothesized that a meta‐analysis of clinical trials of anticoagulants in sepsis may provide insight as to the therapeutic utility of targeting the clotting cascade in this syndrome. We searched electronic databases and reviewed bibliographies of pertinent articles to identify controlled clinical studies in which anticoagulants had been administered as adjunctive therapy to patients with sepsis. After establishing statistical homogeneity, odds ratios (OR; with 95% confidence intervals [CI]) for effect of these agents on mortality and bleeding complications were determined using Mantel‐Haenszel methodology. Potential for publication bias was assessed by the use of a statistical test of funnel plot asymmetry. Weighted linear regression was performed to examine the effect of control group mortality rate on treatment efficacy. We identified 11 studies that satisfied our inclusion criteria. Collectively, these studies enrolled 4690 patients (range of 29‐2314) and examined three agents: antithrombin III (2659 patients), tissue factor pathway inhibitor (210 patients), and activated protein C (1821 patients). After establishing statistical homogeneity (P > 0.10,chi‐square), we found that the OR (with 95% CI) for effect on mortality for these agents, relative to control treatment, was 0.8692 (0.7519‐1.006). Weighted linear regression analysis was consistent with a control group mortality dependent effect for these agents (P = 0.02). Only five of the studies reported bleeding complications. Pooling the results of these five studies (4376 patients) resulted in an OR (with 95% CI) of 1.70 (1.40‐2.07) relative to control treatment for bleeding risk. Anticoagulants as adjuvant therapy do not appear to improve outcome in sepsis and are associated with a significant risk of bleeding complications. To the extent that their treatment effect is dependent upon disease severity, the safety and efficacy of these agents may be enhanced by refinement in techniques of clinical stratification.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

&NA;Mononuclear cells represent the major source of cytokines in blood; however, it has been postulated that neutrophils may produce and/or release modest amounts of cytokines. In this study, we compared the production of cytokines and cytokine inhibitors in lipopolysaccharide (LPS)‐stimulated whole blood, peripheral blood mononuclear cells (PBMCs), and neutrophils (PMNs) separated by density gradient centrifugation. Contamination of PBMCs in the isolated PMNs was less than 0.1% as determined by morphological analysis and flow cytometry. LPS (50 ng/mL) induced a strong increase of the proinflammatory cytokines tumor necrosis factor, interleukin (IL)‐1&bgr;, IL‐8, and IL‐6 in whole blood. In the isolated cell preparations, proinflammatory cytokine production was significantly greater in the PBMCs compared with the PMNs. On a per cell basis, PMNs produced less than 1.5% of these cytokines compared with PBMCs. For cytokine inhibitors, TNF‐soluble receptor type II and IL‐1 receptor antagonist were increased by LPS stimulation in whole blood, PBMCs, and PMNs. On a per cell basis, LPS‐induced TNF‐soluble receptor type II and IL‐1 receptor antagonist production by PMNs was 9.8% and 15.4% of those of PBMCs, respectively. These data show that a highly purified population of PMNs makes a relatively minor to nonexistent contribution to the production of proinflammatory cytokines.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

&NA;Platelet‐activating factor (PAF) is an important proinflammatory mediator of septic shock. PAF is produced by activated macrophages and acts to perpetuate the response to endotoxin. PAF is metabolized by an endogenous PAF‐acetylhydrolase (PAF‐AH). Low circulating levels of PAF‐AH have been associated with the development of postinjury multiple organ failure. We have previously shown that PAF‐AH significantly inhibits macrophage activation by lipopolysaccharide (LPS)in vitro. The purpose of these studies was to determine whether this effect would translate to anin vivomodel of remote lung injury. Wistar rats were administered a single intravenous dose of PAF‐AH (5 mg/kg) or its carrier solution simultaneous with the induction of zymosan peritonitis. After 24 h, alveolar macrophages were obtained by bronchoalveolar lavage and stimulatedin vitrowith LPS (1 μg/mL). Supernatants were collected at 18 h for cytokine production and cellular and nuclear protein extractions were performed at 30 and 60 min to assess the activation of p38 and extracellular signal‐regulated kinase (ERK) 1/2 kinases and the nuclear translocation of nuclear factor (NF)‐&kgr;B. Administration of PAF‐AH significantly inhibited LPS‐induced tumor necrosis factor &agr; and interleukin‐1&bgr; production by alveolar macrophages from zymosan‐treated animals. This functional inhibition was associated with inhibition of ERK 1/2 kinase and NF‐&kgr;B activation but not p38 kinase activation. Interleukin 6 production was depressed in the macrophages from zymosan‐treated animals but no additional inhibition resulted from PAF‐AH treatment. In conclusion, zymosan peritonitis leads to priming of alveolar macrophages such that their subsequent tumor necrosis factor &agr; response to LPS is enhanced.In vivoadministration of PAF‐AH abrogates this response, suggesting that this priming may be PAF dependent. This effect of PAF‐AH may be mediated by the inhibition of intracellular signaling via inhibition of ERK kinase and NF‐&kgr;B activation.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

&NA;The effect of hypertonic saline resuscitation on intestinal damage and the incidence of apoptosis after hemorrhagic shock were investigated. After anesthesia, male BALB/c mice weighing 24‐34 g were hemorrhaged to the mean arterial pressure of 40 ± 5 mmHg for 90 min. Animals were randomly assigned to four groups: 1) resuscitation with 4 mL/kg of 7.5% NaCl (hypertonic saline; HS) + shed blood (SB); 2) resuscitation with two times the volume of shed blood of lactated Ringer's solution (2LR) + SB; 3) sham (catheter only); or 4) control (no treatment). Intestinal damage was graded based on the extent of the vacuolation at the basal area of the intestinal villi. Apoptosis of the small intestines was examined with the terminal deoxynucleotidyl transferase‐mediated deoxyuridine 5‐triphosphate nick‐end labeling method and with DNA laddering. Caspase‐3 activation, heat shock protein (HSP) 70, and HSP40 were assessed by western blotting. Apoptosis of the small intestine and intestinal damage were significantly lower (P< 0.01) in the HS+SB group compared with the 2LR+SB group 2 h and 6 h after hemorrhagic shock and resuscitation, respectively. This corresponded with more DNA fragmentation in the small intestine of the 2LR+SB group compared with the HS+SB group 2 h after hemorrhage and resuscitation. In addition, we observed less caspase‐3 activation in the small intestine of the HS+SB group compared with the 2LR+SB group at 2 h after resuscitation. The content of HSP40 and HSP70 in the HS+SB group was similar to that in controls, but slightly decreased in the 2LR+SB group. HS resuscitation reduced intestinal damage and apoptosis after hemorrhagic shock, suggesting that HS resuscitation may improve the outcome after hemorrhagic shock by reducing apoptosis and damage to the small intestine.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

&NA;Recent studies have shown that hypertonic saline (HS) resuscitation can reduce hemorrhage‐induced lung damage by preventing neutrophil activation. In this study, we examined whether this protective effect can be improved by increasing the HS dose used for resuscitation. The protective effect of two HS doses was tested in a mouse model of hemorrhagic shock. BALB/c mice were bled to a mean arterial blood pressure of 35 ± 5 mmHg for 1 h. Then the animals were resuscitated with lactated Ringer's (LR) or with HS (7.5% NaCl) at doses of 4 mL/kg or 6 mL/kg body weight, sacrificed after 24 h, and lung tissue samples were collected. Evidence of lung injury was evaluated morphologically by scoring histology specimens in a blinded fashion. In a separate set of mice, plasma Na+and osmolarity were determined 15 min after resuscitation. Resuscitation of hemorrhaged mice with 4 and 6 mL/kg HS increased plasma Na+concentrations by 5 and 11 mM, respectively. LR treatment reduced plasma Na+concentrations by 6 mM and resulted in a lung injury score of 6.1 ± 0.8, accompanied by focal thickening of alveolar membranes, congestion, pulmonary edema, and interstitial and intra‐alveolar neutrophil infiltration. HS at 4 mL/kg decreased focal thickening, congestion, pulmonary edema, and neutrophil infiltration, and the injury score to 3.8 ± 0.9, which was not significantly different from controls (3.6 ± 0.8), and lung damage was lowest in animals that received 6 mL/kg HS (2.5 ± 0.2,P< 0.005 vs. LR). Lung damage scores inversely correlated with plasma Na+concentrations (r> 0.9999). Our data suggest that the protective effect of HS may be a function of the plasma Na+concentration and that HS at 6 mL/kg is at least equally effective in reducing hemorrhage‐induced lung damage compared to the more commonly used HS dose of 4 mL/kg.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

&NA;The anti‐inflammatory cytokine interleukin (IL)‐10 has been detected in serum after visceral ischemiareperfusion injury and exogenous IL‐10 administration has been shown to attenuate the associated distant organ injury. This study was designed to examine the role that endogenous IL‐10 production plays on both local and distant organ injury after visceral ischemia‐reperfusion injury. Wild‐type and IL‐10−/−‐null C57BL/6 mice were subjected to 20 min of supraceliac aortic occlusion or sham laparotomy. Serum and lung tissue cytokine levels (tumor necrosis factor alpha, IL‐1&bgr;, IL‐6, KC/GRO, and IL‐10) were measured after reperfusion (1, 2, and/or 4 h) using either enzyme‐linked immunoassay or bioassay. Lung neutrophil infiltration and injury were quantified after reperfusion injury using myeloperoxidase concentration (2 h) and mean capillary permeability (4 h), respectively, whereas the direct liver injury was quantified with serum aspartate aminotransferase levels (1, 2, and 4 h). A subset of IL‐10−/−‐null animals was administered human recombinant IL‐10 before the visceral ischemia and lung MPO was measured after reperfusion (2 h). Visceral ischemia‐reperfusion in the wild‐type and IL‐10−/−‐null mice was associated with in an increase in both serum (IL‐1&bgr;, KC/GRO, IL‐6) and lung tissue (IL‐1&bgr;, KC/GRO) cytokine levels and resulted in lung neutrophil infiltration (myeloperoxidase), lung injury (mean capillary permeability) and liver injury (aspartate aminotransferase). The magnitude of the lung tissue cytokine response (IL‐1&bgr;, KC/GRO), neutrophil infiltration, and injury were greater in the IL‐10−/−‐null mice. Exogenous IL‐10 resulted in a decrease in the lung neutrophil infiltration in the IL‐10−/−‐null mice. The endogenous IL‐10 response to visceral ischemiareperfusion attenuates the associated lung neutrophil infiltration and injury but has no effect upon either the hepatic injury or the magnitude of the systemic inflammatory response. The beneficial effects of IL‐10 may be mediated by the inhibition of IL‐1&bgr; and KC/GRO through an endocrine rather than paracrine signal.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

&NA;We recently reported that hypothermia protects against intrapulmonary nitric oxide overproduction and nitric oxide‐mediated lung injury in endotoxemic rats. Few studies have been performed to investigate whether hypothermia reduces inflammation by affecting favorable changes in chemokine and pro‐and anti‐inflammatory cytokine profiles. In this study, we tested the hypothesis that hypothermia decreases concentrations of growth‐related oncogene/cytokine‐induced neutrophil chemoattractant‐1 (GRO/CINC‐1), interleukin (IL)‐1&bgr;, IL‐6, and myeloperoxidase and increases concentration of IL‐10 in the lungs endotoxemic rats. Twelve rats were anesthetized and randomized to treatment with either hypothermia (T = 18‐24°C; n = 6) or normothermia (T = 36‐38°C, n = 6). Endotoxin (15 mg/kg ofEscherichia colilipopolysaccharide) was administered intravascularly and lung tissue was harvested 150 min later. Three additional rats were sham instrumented and maintained as normothermic but not given endotoxin. Hematoxylin & eosin staining was performed for qualitative inspection of tissues. Quantitative analyses of lung homogenates were performed using enzyme‐linked immunosorbent assays for IL‐1&bgr;, IL‐6, IL‐10, and GRO/CINC‐1. Myeloperoxidase concentrations were determined using a colorimetric assay. Hypothermia attenuated the induction of intrapulmonary IL‐1&bgr;(P< 0.05), IL‐6 (P< 0.05), GRO/CINC‐1 (P< 0.05), and myeloperoxidase (P< 0.05) caused by endotoxin. Inspection of the lungs revealed that hypothermia similarly attenuated histological signs of injury, such as interstitial edema and neutrophil accumulation. Hypothermia increased the intrapulmonary concentration of IL‐10 more than 3‐fold over that measured in the normothermia (endotoxinexposed) group (P< 0.05). Hypothermia inhibits neutrophil recruitment in the lungs of endotoxemic rats in part by decreasing proinflammatory cytokine expression. Additionally, hypothermia induces intrapulmonary IL‐10 expression. Further studies are needed to investigate whether IL‐10 mediates the anti‐inflammatory effects of hypothermia.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

&NA;Sepsis is a life‐threatening event when it occurs in patients suffering from smoke inhalation injury. Pneumonia is one of the most frequent sources of infection in sepsis. Activated leukocytes likely play a role in the pathogenesis of sepsis. Cepharanthin is a biscoclaurine alkaloid that reportedly inhibits the activation of neutrophils. In this study, we investigated the effects of cephranthin on a post‐smoke inhalation model of sepsis in sheep. Female sheep (n = 15) were surgically prepared for the study. After 5 days recovery from the operative procedures, tracheostomy was performed in all animals and 48 breaths of cotton smoke (<40°C) were given via a modified bee smoker under halothane anesthesia. After smoke insufflation,Pseudomonas aeruginosa(5 × 109cfu/kg) was instilled into the airway using a bronchoscope. All of the animals were mechanically ventilated with 100% O2. Cepharanthin (1.3 mg/kg/h) was infused in five sheep continuously beginning 1 h after the insult and thereafter for the remainder of the 24‐h study period. Control animals (n = 6) were treated with 5% dextrose as a vehicle control. Cepharanthin significantly attenuated changes in lung histology as well as in lung wet/dry weight ratio. Anin vitrostudy revealed that cepharanthin inhibited the release of neutrophil elastase from isolated neutrophils stimulated with either formyl‐methyl‐leucyl‐phenylalanine (fMLP) or phorbol myristate acetate with an IC50of 60 μM. Cepharanthin also inhibited the fMLP‐induced increase in intracellular calcium levels of neutrophils. This result indicates cepharanthin inhibits protein kinase C or a more downstream signaling pathway in neutrophil activation. In conclusion, cepharanthin attenuates acute lung injury and septic shock after smoke inhalation in sheep.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

&NA;—Iron metabolism is dysregulated in critically ill patients. A mouse model of dysregulated iron metabolism was used to examine the consequence of iron loading upon sepsis. Mice deleted in thehfegene (hfe−/−) abnormally accumulate iron in tissue; defects in the humanhfegene are clinically expressed as hemochromatosis.Hfe−/−mice and wild‐type counterparts were randomized to receive either high‐ or low‐iron diets for 2 weeks. After iron loading, mice were subjected to cecal ligation and puncture (CLP), a clinically relevant animal model of intra‐abdominal sepsis. A preliminary (but underpowered) study suggested that iron‐loadedhfe−/−mice had increased mortality as compared withhfe−/−mice fed a low‐iron diet. There was no difference between wild‐type andhfe−/−mice fed a low‐iron diet or between wild‐type mice fed hihg‐ and low‐iron diets. A subsequent, appropriately powered study showed that iron‐loadedhfe−/−mice had significantly higher mortality from intra‐abdominal sepsis thanhfe−/−mice fed a low‐iron diet. Iron loading was confirmed through chemical assay of iron concentration in hepatic tissue. Animals with dysregulated iron handling, loaded with iron and subjected to CLP, had double the mortality of animals with normal iron levels. Critical care patients often have altered iron metabolism. In clinical practice, critically ill patients may receive iron through direct administration and the transfusion of blood products. Iron therapy may adversely affect the clinical outcome from sepsis.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID