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Biomedical subjects

S Bahrami

Publications and source records attributed to S Bahrami.

At least 55 records · Page 3Linked to original sources
PubMed1995

Effect of anti-tumor necrosis factor alpha on leukocyte adhesion in the liver after hemorrhagic shock: an intravital microscopic study in the rat.

Tumor necrosis factor (TNF) plays a well known role during the development of multiple organ failure, in part due to its role for the expression of adhesion molecules on endothelial cells, thereby contributing to inflammatory reactions. The purpose of this study was to investigate the effects of TNF on leukocyte-endothelial interactions in the liver as a key organ during the systemic inflammatory response syndrome. In Sprague-Dawley rats (n = 6/group) hemorrhagic shock was induced by reduction of the mean arterial blood pressure (MAP) to 40 mmHg for 45 min; resuscitation was initiated by retransfusion of shed blood (60%) and Ringer's lactate. At 1 and 5 h after resuscitation, intravital microscopy of the liver was performed after injection of acridine orange as marker of leukocytes in sham-control animals and in shock animals pretreated with anti-TNF monoclonal antibody (2 mg/kg b.w. TN3; Celltech, Slough, UK) or NaCl .9% 2 h prior to shock induction, respectively. At constant systemic hemodynamic conditions in all groups (e.g., normal MAP), sinusoidal diameters and sinusoidal blood flow were comparably decreased to approximately 75% of control values in all shock groups. Significant differences were observed particularly in respect to permanent adherent leukocytes with 31.8 +/- 4.7% in the shock/NaCl group and 20.7 +/- 2.6% (mean +/- S.E., p < .05) in the shock/TN3 group 5 h after resuscitation following hemorrhagic shock. Consistently higher adhesion rates were observed in the portal regions compared to pericentral regions of the liver lobules.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Similar cytokine but different coagulation responses to lipopolysaccharide injection in D-galactosamine-sensitized versus nonsensitized rats.

To compare cytokine release and coagulation disturbances induced by administration of high versus low doses of endotoxin (lipopolysaccharide [LPS]), we used two endotoxin test systems similar in mortality but different in the degree of endotoxemia. One group of rats (n = 11) randomly received endotoxin (15.0 mg/kg of body weight intraperitoneally [i.p.]) and 1 ml of Ringer's solution (nonsensitized animals). The second group (n = 11) received 1 ml of D-galactosamine (500 mg/kg i.p.) and endotoxin (100 micrograms/kg i.p.) simultaneously (sensitized animals). Endotoxin levels in the plasma of nonsensitized rats were 1,000-fold higher than those in the plasma of sensitized rats (69.33 x 10(3) +/- 22.42 x 10(3) versus 75.8 +/- 27.08 ng of LPS per ml), leading to a mortality of 91% in nonsensitized rats versus 82% in the sensitized-rat model within 48 h postendotoxemia. Serum transaminase activity increased up to 100-fold in sensitized rats as a sign of hepatocyte damage. Despite the large difference in LPS levels in plasma, the time courses of the plasma tumor necrosis factor (TNF) increase were similar in the two groups, with a peak at 2 h (54 +/- 12 ng/ml in nonsensitized rats versus 43 +/- 12 ng/ml in sensitized rats), and also similar to that of a group of nonsensitized rats (n = 5) that received a low dose of LPS (100 micrograms/kg) only (52 +/- 21 ng/ml), while D-galactosamine alone did not induce TNF release. Despite similar TNF levels, a more pronounced coagulation disorder was observed at 4 h in nonsensitized rats (with the high LPS dose) as measured by platelet counts, plasma fibrinogen levels, and activated partial thromboplastin time prolongation (191 x 10(3) +/- 107 x 10(3) cells per microliter, 40 +/- 24 mg/dl, and 53 +/- 15 s, respectively) than in rats with the low LPS dose either sensitized (495 x 10(3) +/- 153 x 10(3), 95 +/- 49, and 38 +/- 16, respectively) or nonsensitized (439 x 10(3) +/- 62 x 10(3), 170 +/- 18, and 35 +/- 11, respectively).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Big-endothelin release in baboon bacteremia is partially TNF dependent.

Big-endothelin (big-ET) is one of the endothelium-derived vasoactive substances that plays an important role in regulating the vascular tone. Because the role of this agent in bacteremia remains unknown, we investigated whether bacteremia induces the release of big-ET in a subhuman primate model and whether tumor necrosis factor (TNF) is an important mediator of big-ET release. To study this, we infused 8 male baboons (17 to 19 kg body weight) intravenously for 2 hours with Escherichia coli (5 x 10(8) CFU/kg) and observed them for 72 hours. Plasma was obtained at various intervals and assayed for big-ET by using immunoassay. Four bacteremic animals given vehicle only showed a peak big-ET plasma concentration of 15.1 +/- 4.6 fmol/ml at 10 hours, as compared with a baseline concentration of 0.9 +/- 0.5 fmol/ml. Administration of anti-TNF monoclonal antibodies (CB6, 15 mg/kg) 2 hours before E. coli infusion in additional animals prevented the rise in plasma TNF levels (5.7 +/- 2.5 ng/ml versus nondetectable) and significantly (p < 0.01) attenuated the release of big-ET. Hemodynamic measurements revealed the typical pattern of sepsis, with generally more stable circulatory conditions in the anti-TNF-treated animals. Moreover, the mortality rate decreased from 100% to 0% with anti-TNF treatment. These studies, therefore, lead us to conclude that TNF, directly or indirectly through another mediator, plays an important role in the endothelin production/release during bacteremia and that neutralization of circulating TNF appears to be beneficial for improving the survival after bacteremia.

Animals↗
PubMed1993

Clinical detection of LPS and animal models of endotoxemia.

The interest in the study of endotoxemia in the clinical area has increased recently as a result of a) improved and simplified endotoxin determination e.g. chromogenic-kinetic microplate methods (also an improved blood sampling tool is available), b) incidence of sepsis has increased due to improvement in early (e.g. posttraumatic) survival, c) interest in and good evidence for gut translocation as a source of endotoxemia, d) agents have developed, which can antagonize endotoxins. There is evidence that patients with positive endotoxin test in the ICU have a higher incidence of organ failure. To study the pathophysiological consequences of endotoxemia and possible ways of intervention animal models are necessary. The choice of the experimental setting depends on the aim of the study e.g. whether prolonged observation is necessary in survival studies or whether hemodynamic variables have to be measured or whether therapeutic agents only crossreact with primates. Since LPS levels are quite low in clinical studies, an important factor for selection of a relevant animal might be LPS sensitivity, or the use of additional sensitization techniques e.g. galactosamine. Another important aspect in this context is whether LPS is given as bolus or infused up to several days. In this review the dose, time, and route of LPS administration is also discussed. For screening purposes rodents are usually used, or sometimes rabbits due to their higher LPS sensitivity. Another very sensitive animal model is the sheep, which can be chronically instrumented and as a specialty allows lung lymph drainage and thus studies of LPS effects on pulmonary permeability. Pigs are used for hemodynamic studies and often in therapeutical studies if species-specificity of the drug tested is not important, in cases where a large animal is necessary. Finally the non-human primates offer a number of advantages due to human-like physiology, due to the cross-reactivity of human assay systems and accordingly also cross-reactivity of human therapeutic agents. While the chimpanzee also shares the LPS sensitivity of humans, baboons are insensitive like rodents. Thus each model serves to provide some useful purpose and the selection must be made to meet the requirements of the specific questions to be asked, with special emphasis of the chosen endotoxin model on relevance for the human sepsis state.

Animals↗
PubMed1992

Influence of the xanthine derivate HWA 138 on endotoxin-related coagulation disturbances: effects in non-sensitized vs D-galactosamine sensitized rats.

We have evaluated the effects of the xanthine derivate HWA 138 in rat endotoxemia in order to 1) prevent coagulation disturbances and other endotoxin-induced physiological abnormalities and 2) to reduce mortality. We performed two studies using two different models (sensitized vs non-sensitized rats) with a similar mortality but different severity of coagulation disturbances: a) LPS (15 mg/kg) alone or with HWA 138 (80 mg/kg) as a treatment modality 30 min pre LPS, b) galactosamine (500 mg/kg) simultaneously with LPS (100 micrograms/kg) with or without HWA 138 (80 mg/kg) pretreatment. Experiments c) and d) employed D-galactosamine and/or LPS similar to experiments a) and b), while HWA 138 was applied simultaneously. We found significant 1) amelioration of life-threatening coagulation disturbances in non-sensitized rats, 2) prevention of liver dysfunction in sensitized rats, 3) reduction of TNF formation in both models, and 4) improvement of survival in all groups receiving HWA 138. Our data indicate protective effects of HWA 138 against clotting disturbances either directly via reduced LPS-induced formation of procoagulant activity or indirectly via reduced TNF formation.

Animals↗
PubMed1992

Special collection and storage tubes for blood endotoxin and cytokine measurements.

Commercially available blood-collection tubes may be contaminated with endotoxin (315 +/- 95 pg/tube) and could therefore be unsuitable for blood collection for endotoxin measurement. Plasma separation and storage are a potential source of contamination. To avoid contamination and error, we have developed new blood collection tubes that contain heparin free of endotoxin (LPS) and a gel to separate plasma and blood cells. The LPS content is less than 4 pg/tube. Samples can be stored and frozen without plasma withdrawal to preclude contamination. LPS recovery experiments have shown that the new blood-collection tubes do not bind LPS to the separation gel or vial wall. With these tubes, in vitro formation of tumor necrosis factor (404 +/- 163 ng/L in standard tubes vs less than 40 ng/L in special collection tubes) is minimized.

Blood Specimen Collection↗
PubMed1991

Plasma neutrophil-activating peptide-1/interleukin-8 and neutrophil elastase in a primate bacteremia model.

A hyperdynamic sepsis model was set up in seven adult baboons to evaluate neutrophil-activating peptide-1/interleukin (IL)-8 (NAP-1/IL-8), IL-1 beta, IL-6, tumor necrosis factor-alpha (TNF alpha), and IFN-gamma in plasma. By continuous intravenous administration of 10(10) cfu/kg live Escherichia coli over 8 h with additional infusion therapy (less than or equal to 50 ml/kg/h), endotoxin plasma levels of 2.7-22.3 ng/ml were observed. In plasma the kinetics of NAP-1/IL-8 and IL-6 were similar to those of IL-1 at the end of the experiment (8 h) (peak median values, 34, 4197, and 230 ng/ml, respectively). Differences were greatest for IL-6. Monocyte activation during sepsis was confirmed by elevated plasma neopterin levels (91-139 mumol/mmol of creatine). Granulocyte activation was evident from both incipient neutropenia and the massive release of neutrophil elastase into the plasma as measured by a new immunoassay (peak level, 374 ng/ml). Thus, in primate bacteremia, early TNF release is followed by a concomitant increase of NAP-1/IL-8 with plasma kinetics similar to those of IL-6 and IL-1 and accompanied by massive activation of neutrophils.

Animals↗
PubMed1990

Effect of the PAF antagonist BN 52021 in ovine endotoxin shock.

It has been reported that a platelet-activating factor (PAF) antagonist ONO-6240 had little effect on pulmonary hypertension and lung lymph in sheep injected with endotoxin lipopolysaccharide (LPS); consequently we evaluated a new PAF antagonist, BN 52021. Twelve adult sheep were surgically prepared for chronic study including lung lymph drainage. LPS (S. abortus equii, 36 ng/kg/h over 7 h) was then administered with (BN group) or without (control group) infusion (1 h before LPS) of the PAF antagonist BN 52021 (4 mg/kg/30 min). Comparison of the hemodynamic data between the control group and the BN group reveals an almost identical pattern. In contrast, we find differences in the pulmonary response of the two experimental groups. The early elevation of pulmonary artery pressure after LPS administration is less in the treatment group, as is the duration of pulmonary hypertension. Similarly, thromboxane levels are lower in the treated animals. The increases in lymph flow (LQ) and transvascular protein clearance (L/P X LQ) as well as the protein flux were less prominent in the treatment group. The mean lymph flow per hour was significantly higher in the control group. The mean lymph flow per hour was significantly higher in the control group, as were the corresponding parameters for clearance and protein flux. Thus the pulmonary vasculature and lung fluid balance disruption produced by LPS was markedly reduced by treatment with the PAF blocker.

Animals↗
PubMed1989

Neutrophil function and lipid peroxidation in a rat model of multiple organ failure.

Multiple organ failure (MOF) was induced by sterile intraperitoneal inoculation of zymosan in the rat. This results in a typical triphasic illness with maximal clinical signs at Days 2 and 14. In this study, granulocyte superoxide production (unstimulated and phorbol myristic acid stimulated) was studied as well as lipid peroxidation (TBAR) in plasma, liver, and lung tissue. Mainly TBAR levels in liver and lung tissue closely correlated with the triphasic clinical illness, while bacteriological data did not. It is concluded that the severe inflammatory response in this experimental model probably is the result of excessive toxic oxygen radical production. The first phase of illness may mainly be due to oxygen radical formation by activated PMN, the third phase of illness to the production of lysosomal enzymes (proteinases) from PMN, and activated macrophages as indicated by elevated N-acetylglucosaminidase levels.

Alanine Transaminase↗