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ABSTRACT: the mechanisms behind lipopolysaccharide (LPS) tolerance remain obscure. LPS signals through Toll-like receptor 4 (TLR4) and severe trauma/haemorrhage may influence binding and signalling through this receptor, e.g. by changing membrane expression or by releasing endogenous ligands like High Mobility Group Box 1 (HMGB1). The aim of this study was to examine these relations further in a porcine model with standardized trauma.
nine anaesthetized pigs sustained one gunshot through the femur and one pistol shot through the upper abdomen. Blood was sampled before and 90 min after shooting. The samples were stimulated for 4 h with LPS 10 ng/ml or an equivalent amount of normal saline. The leucocyte response was evaluated by measuring the tumour necrosis factor-α (TNF-α) and CXC ligand 8 (CXCL8) in the supernatant. Flow cytometry was used to measure the surface expression of TLR4 on CD14+ monocytes. HMGB1 concentrations were measured in the plasma.
trauma and treatment caused a significant decline in the LPS-stimulated concentrations of TNF-α [4.53 ± 0.24 pg/ml (ln) at 0 min, 3.54 ± 0.35 pg/ml (ln) at 90 min, P=0.026], but did not modify the release of CXCL8. Monocyte TLR4 expression was unchanged. Plasma HMGB1 increased significantly [<0.92 vs. 3.02 ± 0.19 ng/ml (ln), P<0.001]. The concentrations of TNF-α and CXCL8 did not correlate with TLR4 expression or HMGB1 concentrations.
the results suggest that trauma-induced LPS tolerance is not primarily regulated by TLR4 expression on circulating CD14+ monocytes or by the release of HMGB1 from damaged tissues.
Acta Anaesthesiologica Scandinavica 11/2010; 55(1):28-34. · 2.19 Impact Factor
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ABSTRACT: Penetrating injuries are frequently combined with polybacterial soiling. Clearance of the microorganisms depends on the ability to activate immune responses, but post-traumatic hyporeactivity of immune cells is almost universal. The aim of this study was to map the early time course of this altered leukocyte reactivity, and to compare the reactions to subsequent Gram-positive or Gram-negative challenges.
Twelve juvenile pigs sustained two standardized rounds, one through the right femur and one through the left upper abdomen. First aid treatment and acute surgery were started immediately. Blood samples were drawn before trauma and after 10, 30, 60, and 90 min, and thereafter stimulated in ex vivo whole blood for 3 h with lipopolysaccharide (LPS, 10 ng/ml), peptidoglycan (PepG, 1 microg/ml), or an equivalent amount of normal saline. The leukocyte response was evaluated by measurement of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-6, IL-8, and IL-10 in the supernatant.
In the post-traumatic in vivo serum, the concentration of TNF-alpha increased steadily (significant after 60 min). A reduced ex vivo reaction to LPS was evident after 10 min, and was statistically significant after 30 min. The lowest levels were reached after 90 min. The ex vivo synthesis of TNF-alpha after stimulation with PepG remained unaltered. A similar development was seen for IL-6. IL-1 beta levels did not change, while IL-8 increased significantly only after 60 and 90 min.
Trauma almost instantaneously reprogrammed circulating leukocytes. As measured with TNF-alpha, a profound hyporeactivity to LPS, but not to PepG, was induced. In addition, no global down-regulation of leukocyte function was found after stimulation with LPS.
Acta Anaesthesiologica Scandinavica 11/2008; 52(9):1231-7. · 2.19 Impact Factor
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ABSTRACT: Perturbation of immune homeostasis is an important determinant for organ dysfunction following multiple injuries. The aim of this study was to investigate the ability of glycine to influence the immediate post-traumatic inflammatory environment and altered reactivity of circulating leucocytes.
Twenty pigs were subjected to two standardized gunshots to the abdomen and thigh. Treatment was started immediately. The animals were randomized to receive either glycine 180 mg/kg i.v. over 30 min (n=10) or normal saline (n=10). Blood samples were drawn at baseline and 75 min after injury. In a follow-up study 12 pigs were exposed to an identical trauma. Blood was drawn at the same time-points and stimulated with lipopolysaccharide (LPS) or LPS plus glycine for 2 h in an ex vivo whole blood model.
Selected physiologic variables and organ injury did not differ between groups 75 min after trauma. Reactive oxygen species decreased to 82.7+/-5.5 % of baseline (p<0.05) in the glycine group (unaltered in the controls). Liver glutathione concentrations decreased in parallel in both groups. In vivo production of TNF-alpha and IL-1-beta increased to the same extent regardless of treatment. Trauma induced a strong LPS tolerance. In whole blood challenged with LPS, glycine inhibited cytokine synthesis, but only in samples drawn at baseline.
Post-traumatic infusion of glycine only modestly influenced the early post-traumatic inflammatory environment. Our ex vivo results confirm previous reports on the anti-inflammatory potential of glycine, but restricted to pre-trauma conditions.
Scandinavian Journal of Clinical and Laboratory Investigation 02/2007; 67(2):143-53. · 1.38 Impact Factor
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ABSTRACT: Glycine, the simplest of the amino acids, is an essential component of important biological molecules, a key substance in many metabolic reactions, the major inhibitory neurotransmitter in the spinal cord and brain stem, and an anti-inflammatory, cytoprotective, and immune modulating substance.
Based on available literature, we discuss some of the important biological properties of glycine. In addition, we describe some clinical disorders where glycine plays a central role, either as an essential structural element, or through its metabolism or receptors.
The past few years have witnessed a broadening of glycine research. The traditional prime interest in aspects related to its role as an inhibitory neurotransmitter in the central nervous system has been expanded to equally emphasize other organs and tissues. With the demonstration of glycine-gated chloride channels on neurons in the central nervous system, on most leukocytes, and subsequently on other cells as well, a unifying mechanism of action accounting for many of the widespread effects of glycine has been found.
Glycine is a simple, easily available, and inexpensive substance with few and innocuous side-effects. The diversity of biological activities is well documented in the literature. Despite this, glycine has only gained a modest place in clinical medicine.
Acta Anaesthesiologica Scandinavica 10/2005; 49(8):1108-16. · 2.19 Impact Factor
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ABSTRACT: The purpose of this study was to use an established porcine model to investigate the effects on immune function of severe gunshot injury.
Twelve pigs sustained two standardised rounds, one through right femur and one through left upper abdomen. First aid treatment and acute surgery was started immediately. Blood samples were drawn before shooting and after 75 min. Circulating neutrophils were isolated and reactive oxygen species (ROS) measured. Serum levels of tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, and IL-10 were determined at 0, 75 min, as well as 2h after incubation with 1 microg/ml endotoxin in an ex vivo whole blood model.
TNF-alpha, IL-1beta, and IL-6 significantly increased at 75 min. ROS in circulating granulocytes tended to increase (NS). Incubation with endotoxin led to a more than 100-fold increase of TNF-alpha pre-trauma, compared to a three-fold increase post-trauma (p<0.0001 between groups). A similar pattern was obtained for IL-1beta, and IL-6. IL-10 was below detection in all samples. The granulocytes maintained their ability to react to the protein kinase C activator phorbol myristate acetate (PMA) after trauma.
Severe gunshot injury and peritraumatic stress rapidly activate circulating immune cells, but reduce their capacity to react to a subsequent challenge to endotoxin.
Injury 08/2005; 36(8):949-55. · 1.98 Impact Factor
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ABSTRACT: Major insults may trigger generalized inflammatory responses that contribute to progressive multiple organ dysfunction. The present study was performed to test the potential of early hydrocortisone treatment to influence these responses as well as organ function following an episode of rapid and profound blood loss.
In isoflurane anaesthesia, 35 spontaneously breathing male Sprague-Dawley rats were bled 2.5 ml 100 g-1 body weight over 10 min. Immediately following withdrawal of blood, one group (n = 17) was given 2 mg of hydrocortisone, and the other (n = 18) had the same amount of normal saline. Seventy-five minutes after initiation of bleeding, two-thirds of the blood was retransfused, together with a new injection of hydrocortisone or saline. Thereafter the rats were observed for 2 h. Key mediators of systemic inflammation and plasma markers of organ function and integrity were measured. Internal organs were weighed and scored for visible pathology. Leukocyte infiltration of the liver was counted in a light microscope.
Hydrocortisone reduced the plasma levels of IL-6 (P < 0.05); non-significant reductions of TNF-alpha (P = 0.12) and IL-10 (P = 0.44) were noted. The synthesis of reactive oxygen species in peritoneal cells was unaffected. Relative organ weights and organ injury scores tended to be reduced, but only wet organ weight for the lungs reached statistical significance. Leukocyte infiltration of the liver was equal in both groups. Plasma levels of ALT, AST, alpha-GST and creatinine did not differ significantly between groups. Two of the hydrocortisone treated rats died compared with four controls.
Early treatment with hydrocortisone had a limited organ protective effect in this model of controlled haemorrhagic shock. Although a general tendency for better outcome in the hydrocortisone group was noted, clear-cut and significant advantages of the treatment were not obtained.
Acta Anaesthesiologica Scandinavica 11/2003; 47(9):1165-71. · 2.19 Impact Factor
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ABSTRACT: Reduced body temperature is a common companion to trauma/haemorrhage. Several clinical studies have identified hypothermia as an independent risk variable predisposing to increased morbidity and mortality. At the same time it is known that most enzymatic reactions are downregulated at temperatures below 37 degrees C. Theoretically this should restrain the inflammatory response and protect the host from remote organ injury. The study was performed to test this hypothesis.
Twenty-six male Sprague Dawley rats were used for the experiments. Volume controlled haemorrhagic shock was induced by withdrawal of 2.5 ml blood/100 g body weight over 10 min. Half of the animals (n=13) were then cooled to 32.5-33 degrees C, the other half (n=13) were kept normothermic (37.5+/-0.5 degrees C). Seventy-five minutes after initiation of bleeding, two-thirds of the blood was retransfused. Thereafter the rats were observed for 2 h. Key substances of systemic inflammation were determined (plasma values of TNF-alpha, IL-6, IL-10, and corticosterone; reactive oxygen species in peritoneal phagocytes), plasma markers of organ function and integrity (AST, ALT, alphaGST, creatinine, urea), and survival.
Hypothermia reduced the release of IL-6 (P<0.01). The reductions of plasma levels of TNFalpha (P=0.07) and IL-10 (P=0.09) were less clear-cut. The release of reactive oxygen species diminished (P<0.01). Organ injury was ameliorated, as reflected by decreased levels of AST (P<0.01), alphaGST (P<0.01), and creatinine (P<0.01). Both groups experienced an almost identical increase of plasma corticosterone. None of the hypothermic rats died, compared to two normothermic.
Moderate hypothermia had an organ protective effect in this model of controlled haemorrhagic shock. This coincided with a significant reduction of the proximal cytokine IL-6 and reactive oxygen species, which conceivably influenced the outcome.
Acta Anaesthesiologica Scandinavica 09/2001; 45(8):994-1001. · 2.19 Impact Factor
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ABSTRACT: The acute respiratory distress syndrome (ARDS) is one consequence of the body's systemic inflammatory response to a variety of powerful external stimuli. Glucocorticosteroids are highly effective anti-inflammatory drugs. During the last few years, the molecular mechanisms for their mode of action have been revealed; this has prompted a new wave of interest in corticosteroid treatment of systemic inflammatory states. Several clinical studies have been launched; the results have so far been promising.
We briefly discuss how new knowledge in this field may influence the use of corticosteroids in the treatment of ARDS. The presentation is illustrated by a case study.
The patient was a 15-year-old boy with life-threatening and therapy-resistant ARDS. He was treated in a respirator in an intensive care unit (ICU). Two weeks after admission to the ICU, his situation was desperate. High-dose corticosteroids were instituted, and during a five days' treatment his condition improved dramatically. After discontinuation of glucocorticoids he made further progress and was discharged from the ICU after another eleven days.
In this particular patient, administration of glucocorticoids had a striking effect. The influence of glucocorticoids on the activation of the transcription factor NF-kappa B and a resulting reduced synthesis of a number of key inflammatory molecules may be one explanation for the positive course.
Tidsskrift for Den norske legeforening 06/2001; 121(13):1596-8.
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ABSTRACT: Hyperbaric solutions of 0.5% bupivacaine and 0.5% amethocaine (2 and 3 ml) were compared in a double-blind study of 40 patients receiving subarachnoid anaesthesia for urological surgery. The drugs produced similar and satisfactory analgesia in the tested concentrations and volumes. Motor blockade was more profound and longer lasting with amethocaine.
BJA British Journal of Anaesthesia 03/1984; 56(2):155-9. · 4.24 Impact Factor
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ABSTRACT: The case described illustrates a most unusual course of events due to a perforation in the wall of the bladder during transurethral lithotripsy. Irrigation fluid forced its way retroperitoneally to the mediastinum. The differential diagnostic problems encountered are discussed.
Anaesthesia 08/1983; 38(7):666-8. · 2.96 Impact Factor
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Tidsskrift for Den norske legeforening 05/1983; 103(11):909-12.
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Tidsskrift for Den norske legeforening 02/1982; 102(3):169-71.
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ABSTRACT: The effects of 0.5% bupivacaine 1.5, 2 and 3 ml in 8% glucose was compared in a double-blind study involving 30 patients undergoing spinal analgesia. The time to the onset of maximum segmental spread of analgesia was approximately 15 min for all three volumes. Cephalad spread of analgesia was related to the volume used: 1.5 ml reached T10, 2 ml T8 and 3 ml T7. The duration of analgesia increased with increasing volume, 3 ml producing analgesia in T8-T12 for 1.5-2 h, and in the lumbar region for 2.5-3 h. Increasing the volume increased the extent of motor blockade and speeded up its onset. Significant decreases in arterial pressure were observed in the 2- and 3-ml groups. The changes in heart rate were moderate and not correlated with the amount of drug. Spinal headache occurred in two patients.
BJA British Journal of Anaesthesia 02/1982; 54(1):69-74. · 4.24 Impact Factor
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ABSTRACT: Purpose:The purpose of this study was to use an established porcine model to investigate the effects on immune function of severe gunshot injury.Methods:Twelve pigs sustained two standardised rounds, one through right femur and one through left upper abdomen. First aid treatment and acute surgery was started immediately. Blood samples were drawn before shooting and after 75 min. Circulating neutrophils were isolated and reactive oxygen species (ROS) measured. Serum levels of tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, and IL-10 were determined at 0, 75 min, as well as 2 h after incubation with 1 μg/ml endotoxin in an ex vivo whole blood model.Results:TNF-α, IL-1β, and IL-6 significantly increased at 75 min. ROS in circulating granulocytes tended to increase (NS). Incubation with endotoxin led to a more than 100-fold increase of TNF-α pre-trauma, compared to a three-fold increase post-trauma (p < 0.0001 between groups). A similar pattern was obtained for IL-1β, and IL-6. IL-10 was below detection in all samples. The granulocytes maintained their ability to react to the protein kinase C activator phorbol myristate acetate (PMA) after trauma.Conclusion:Severe gunshot injury and peritraumatic stress rapidly activate circulating immune cells, but reduce their capacity to react to a subsequent challenge to endotoxin.
Injury.
