摘要:

In an uncontrolled clinical trial the effects of repeated administration of the F(ab')2fragment of a murine monoclonal anti-tumor necrosis factor α (TNFα)-antibody (MAK 195F) on cytokine levels and the cardiovascular system were studied in 20 patients with severe sepsis. Patients were treated with a total of 11 single dosages of the anti-TNFα-antibody intravenously over 5 days using either 1 mg/kg (n = 10) or 3 mg/kg (n = 10). The anti-TNFα-antibody was well tolerated in all patients without signs of toxicity and without development of anti-murine antibodies. As assessed by cytokine levels (TNFα, Interleukin-6) and hemodynamics there was no evidence that the higher dosage of the anti-TNFα-antibody (3 mg/kg per dose) was more effective than the lower dosage (1 mg/kg per dose). Comparison of our data with recent data from phase I or II trials using a complete murine monoclonal anti-TNFα-antibody suggest that the F(ab')2fragments of the murine monoclonal anti-TNFα-antibody may be of similar efficacy. Definitive conclusions, however, with respect to improvement of mortality and improvement of the cardiovascular system, await the results of larger ongoing placebo-controlled trials.

ISSN:1073-2322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

In 20 patients with severe sepsis, skeletal muscle pO2was continuously measured in order to assess whether a decrease of skeletal muscle pO2was accompanied by an improvement of sepsis after repeated administration of F(ab‘)2fragments of a murine anti-TNFα-antibody. Abnormally high skeletal muscle pO2decreased from 43.5 ± 10.9 mmHg (day 0) to 36.4 ± 10.1 mmHg within 24 h after the first administration of anti-TNFα-antibody (day 1,p= .006, n = 20) and remained at 34.6 ± 7.7 mmHg thereafter (mean day 2–7,p= .004). The decrease of skeletal muscle pO2within 24 h exceeded 5 mmHg (-7 to −19 mmHg) in 11 patients in contrast to nine patients (-4 to +4 mmHg). Only in the patients showing a decrease of skeletal muscle pO2did sepsis improve as determined by Elebute score, APACHE II score, and interleukin-6 serum levels. The change of skeletal muscle pO2within 24 h was associated with a change of interleukin-6 serum levels within 24 h (r = .5, n = 20), with a change of Elebute score (r = .7, n = 20) and of APACHE II score (r = 62). These data suggest that a decrease of skeletal muscle pO2might be an early indicator of improvement of sepsis after administration of anti-TNFα-antibodies.

ISSN:1073-2322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The effect of (R)-1-(5-hydroxyhexyl)-3,7-dimethylxanthine (CT-1501R; the nonproprietary name for CT-1501R approved by the United States Name Council is lisofylline), an inhibitor of second messenger signaling through phosphatidic acid, on release of endogenous mediators important in the systemic inflammatory response syndrome (SIRS) was studied using the human whole bloodex vivoassay system. Human blood was stimulated with various endotoxin preparations, zymosan, or protein A, and the levels of secreted monokines were measured by enzyme-linked immunosorbent assay. CT-1501R inhibited tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and IL-6 release in a dose-dependent manner and was active with all stimuli tested includingSalmonellaandEscherichia coli-derived endotoxin, endotoxin from both rough and smoothE. colistrains, as well as zymosan and protein A. CT-1501R inhibited monokine release by approximately 50% at 200 μM and 30% at 50 μM and was independent of the relative potency of stimulus. CT-1501R also inhibited IL-1α or IL-1β induction of either TNF-α or IL-1β and inhibited the synergistic effects of stimulation with both human IL-1β and murine TNF-α on release of human TNF-α. Inhibition of monokine release following stimulation with monokine) was, in general, greater than that achieved with lipopolysaccharide (LPS) stimulation. Northern blot analysis showed decreased mRNA accumulation of TNF-α and IL-1β in CT-1501R-treated samples following LPS stimulation suggesting that CT-1501R acts at least in part, at the pretranslational level. In contrast, CT-1501R does not inhibit LPS-stimulated IL-8 or IL-1 receptor antagonist (IL-1ra) release in human whole blood or IL-1α-induced release of PGE2in human foreskin fibroblast cells. These data suggest that CT-1501R may be of use for clinical intervention in SIRS.

ISSN:1073-2322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Alterations in T-lymphocyte kinetics and/or activation have been implicated in burn and traumatic injury. This study evaluated concanavalin A (Con A) regulation of both intracellular Ca2+(Cai2+) and proliferation in T-lymphocytes harvested from spleens of septic rats. Rats were implanted with fecal pellets containingEscherichia coli(150 colony forming units (CFU)) andBacteroides fragilis(104CFU). T-cell [Ca2+]iwas measured before and after treatment of cells with Con A, using Fura-2 and microfluorophotometry. Splenic lymphocytes were cultured for 72 h with Con A to assess their proliferative response. As compared to sterile-implanted rats, the septic rat T-lymphocytes Cai2+response to Con A significantly decreased on days 1 and 2 after implantation. A significant decrease in T-cell proliferative response to Con A, compared to sterile controls, was found in septic rats on day 2 but not on day 1. These results suggest that Con A-mediated proliferation in T-cells occurs secondarily to a decrease in cellular Ca2+signalling. The depression in the T-cell proliferative response during sepsis could contribute to a decrease in host's resistance against sepsis.

ISSN:1073-2322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Polymorphonuclear neutrophils (PMNs) have been implicated in microvascular injury following ischemia and reperfusion (I/R) but the relative contribution of obstruction versus toxic mediators is not well defined. Therefore, the present study was performed to determine the contribution of exogenous or endogenous activation on PMN-induced microvascular and hepatocyte injury. Rat livers were isolated and perfused at constant pressure with Krebs buffer with red cells (Hct-10%) and monitored for perfused sinusoids (PS) and dead hepatocytes (propidium iodide-stained, DH) by intravital microscopy. PMNs isolated from the peritoneum after oyster glycogen injection were added to the perfusate either without or with activation by phorbol myristate acetate (PMA, 160 nM). Unactivated PMNs stuck in the liver but had no significant effect on either perfused sinusoids (11.1 ± .4/field, unactivated PMNs versus 11.9 ± .5/field, the time-matched control) or dead hepatocytes (1.2 ± .4/field, unactivated PMNs versus 1 ± .3/field, the time-matched control). Infusion of PMA-activated PMNs resulted in significant decrease in perfused sinusoids and increase in DH (9.5 ± .3/field for PS and 3.2 ± .6/field for DH, respectively). In contrast, when PMNs were “activated” by infusion into a liver previously made ischemic for 30 min, DH were significantly increased after 60 min (26.2 ± 4.5/field, I/R plus PMNs versus 12.4 ± 2/field, I/R only) but perfused sinusoids were not different from ischemia alone. These results demonstrate that oxidatively quiescent PMNs do not cause cellular or microvascular injury in spite of microvascular accumulation. Activated PMNs damage microcirculation or hepatocytes depending on the nature of the activation.

ISSN:1073-2322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

In order to examine the effects ofEscherichia coliendotoxemia on coronary and pulmonary microvascular responses to serotonin (5-HT) and ADP, arterioles (80–190 μm diameter) were isolated from pigs 3 h after administration ofE. coliendotoxin (150 μg/kg, intravenously over 1 h, n = 8) or Ringer's lactate (control, n = 8). Arterioles were studiedin vitroin a pressurized, partially contracted, no-flow state with video-microscopy. Precontracted (30–50% of baseline diameter) control coronary arterioles dilated in responses to either 5-HT (24 ± 2%) or ADP (89 ± 2%). These relaxations were partially inhibited by indomethacin, but were markedly reduced with nitric oxide synthase inhibition. After 3 h of endotoxemia, 5-HT caused contraction of coronary arterioles which was inhibited with indomethacin. In the presence of indomethacin, coronary vessels from endotoxic pigs relaxed slightly, but significantly, more to 5-HT than did control vessels exposed to indomethacin. In contrast, the relaxation response to ADP was unchanged following endotoxemia. Precontracted (15–30% of baseline diameter) pulmonary arterioles dilated in response to 5-HT (13 ± 1%) or ADP (67 ± 3%). Following 3 h of endotoxemia, the pulmonary arteriolar relaxation induced by 5-HT was reduced, whereas the response to ADP was not altered. In both coronary and pulmonary arterioles, relaxation induced by the endothelium-independent vasodilator, sodium nitroprusside, was unaffected by endotoxemia. Thus, coronary and pulmonary microvascular relaxation responses to ADP are minimally affected by 3 h of endotoxemia, but relaxation responses to 5-HT are significantly reduced or converted to contractile responses.

ISSN:1073-2322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Bacterial translocation (BT) has been shown to occur in stress and trauma. In this study, we examined the contribution of altered intestinal permeability (measured with51Cr-EDTA) and intestinal blood flow (radioactive microspheres) to the loss of intestinal barrier function after burn injury. A 42.6 ± 0.6% total body surface area scald burn was produced in Sprague-Dawley rats; sham burn animals served as controls. Rats (29 burn and 20 sham burn) were sacrificed 24 h postburn, and mesenteric nodes (MLN), cecum, spleen, and liver were cultured. The incidence of BT was significantly higher in burn compared to shams (MLN, 55 vs. 15%; spleen, 31 vs. 10%; liver, 31 vs. 10%;p< .05). Cecal concentration of Gram-negative bacteria were similar in all rats (5.2 ± 0.2 X 108colony forming units/g). 5 h postburn, intestinal blood flow decreased significantly in burn (1.60 ± .20) compared to shams (2.49 ± .24 ml/min/g,p= .01); at this time, plasma to luminal clearance of51Cr-EDTA was greater in the burn (.146 ± .033, N = 9) than in shams (.050 ± .010 ml/min/100 g, N = 9,p= .001); 24 h postburn, there was no significant difference in intestinal blood flow in sham (2.86 ± .46, N = 10) and burn rats (2.29 ± .44 ml/min/g, N = 11); plasma to intestinal lumen clearance of51Cr-EDTA was similar in sham (.054 ± .010, N = 11) and burn rats (.051 ± .006 ml/min/100 g, N = 12) 24 h postburn. These data confirm that after a major cutaneous burn, bacteria indigenous to the gut can translocate out of the intestine to systemic organs; loss of gut barrier function is related to transient intestinal hypoperfusion and increased intestinal permeability after burn injury.

ISSN:1073-2322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Sixteen sheep were surgically prepared for chronic study. Seven days later,Escherichia coliendotoxin (10 ng/kg/min, lipopolysaccharide (LPS) group, n = 10) or an equivalent amount of 0.9% NaCl (Control group n = 6) was administered. Between 1 and 8 h post-LPS, there was a hypodynamic state with low cardiac index (Cl, LPS 5.0 ± 0.2; sham 6.3 ± 0.4 liters/min/m2at 4 h). During this period, the left ventricular end-systolic pressure-diameter relationship (ESPDR), a sensitive index of myocardial contractility, was also lower (LPS 10.4 ± 1.2; sham 17.2 ± 0.8 mmHg/mm). Mean pulmonary arterial pressure (PAP) and pulmonary vascular resistance index (PVRI) were remarkably increased 1 h after the administration of LPS (PAP: LPS 37.5 ± 1.9; sham 21.8 ± 0.9 mmHg, PVRI: LPS 600 ± 58; sham 158 ± 23 dynes · s · cm-5· m2). The early changes in cardiopulmonary function occurred concomitantly with an elevation in tumor necrosis factor (LPS 1221 ± 520; sham 0 ± 0 pg/ml) and thromboxane B2(LPS 1382 ± 266; baseline 82 ± 20 pg/ml) in arterial blood. Following this first phase, the sheep presented a persistent hyperdynamic state characterized by a significant increase in Cl. The ESPDR continued to fall. By 24 h post-LPS the Cl was 10.1 ± 0.5 liters/min/m2(sham, 6.3 ± 0.3) but the ESPDR had fallen to 8.2 ± 2.3 mmHg/mm (sham 16.0 ± 3.0). The pulmonary hypertension was maintained for the duration of the LPS infusion. On the other hand, the pulmonary vascular resistance had returned to near the baseline value by 16 h after the endotoxin infusion. PaO2fell and pulmonary shunt fraction rose in the LPS group at 24 h (PaO2: LPS 85 ± 9; sham 115 ± 4 mmHg, shunt: LPS 0.28 ± 0.04; sham 0.09 ± 0.01). Lung lymph flow (LPS 39.1 ± 6.5; sham 8.1 ± 0.8 ml/h) and wet: dry ratio (LPS 5.54 ± 0.13; sham 4.89 ± 0.09) were increased in LPS group at 24 h post-LPS. In our model of hyperdynamic state of sepsis simulating the human condition there is an increased Cl despite a significant depression in myocardial contractility and acute lung injury.

ISSN:1073-2322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Increased histamine release and formation (induced histamine) are two hypotheses considered in the pathogenesis of endotoxic shock development. To prove both hypotheses a sequence of four randomized controlled studies in rats was performed. Histamine release was measured indirectly as a decrease in tissue-histamine contents (lung, liver, spleen, stomach); histamine formation was estimated directly as an increase in histidine decarboxylase (HDC) activity in the same organs. Changes in contents and enzymatic activities were determined 4 and 8 h after shock induction; in addition, at the time of death, the activity of HDC was measured in heart, kidney, and small intestine. 4 h after shock induction, there was a significant decrease in the tissue-histamine content as measured only in the liver, with the same trend in lung and spleen. 8 h after endotoxin application, however, histamine concentration increased in the liver (significantlyp< .05) and lung compared to the NaCl control group. The manifestation of changes in HDC activity in various organs was selective (i.e., not all organs showed alterations), not uniform (decreased as well as increased activities were measured), and time-dependent (no increase in HDC activity in animals dying at < 20 h). At 4 and 8 h, only the liver showed a strong increase in HDC activity which can explain the increase in histamine content. In lung, spleen, and stomach, a significant decrease occurred. The results on histamine release and formation let us conclude that histamine is involved in the pathogenesis of endotoxic shock development.

ISSN:1073-2322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

We determined whether plasma levels of reduced glutathione (GSH) and oxidized glutathione (GSSG) accurately reflect the tissue GSH and GSSG levels in lung and liver during a progressive acute inflammation-induced increased oxidant activity. We also determined whether plasma GSH also reflected other antioxidant defenses. Male Wistar rats (n = 38) were given intraperitoneal zymosan (.75 mg/g body weight) producing an acute progressive peritonitis and generalized inflammation. Animals were resuscitated then killed at 4 or 24 h. Plasma and tissue levels of GSH, GSSG, vitamin C, α-tocopherol, and catalase were measured. Conjugated dienes and malondialdehyde were used as tissue markers of lipid peroxidation.We found lung and liver tissue GSH to be decreased significantly at 4 h while GSSG was increased. Lipid peroxidation was also present in the lung. At 24 h, GSH remained decreased in liver and GSSG remained increased in lung along with the lipid peroxides conjugated dienes and malondialdehyde. In addition, overall antioxidant defenses were decreased in both lung and liver. Plasma GSH remained decreased at 24 h corresponding with the decrease in liver GSH as well as the decrease in other plasma and tissue antioxidants. However, plasma GSSG levels were not significantly increased, at any time point, indicating plasma GSSG does not accurately reflect tissue oxidant activity.

ISSN:1073-2322    

出版商:OVID    

年代:1994

数据来源: OVID