Biomedical subjects

B F Becker

Publications and source records attributed to B F Becker.

At least 19 recordsLinked to original sources

PubMed2006

Insights from knock-out models concerning postischemic release of TNFalpha from isolated mouse hearts.

The inflammatory cytokine tumor necrosis factor alpha (TNFalpha) is controversially discussed in ischemia/reperfusion damage of the heart. Purpose of this study was to elucidate cellular sources of TNFalpha and parameters which possibly influence its release in the heart following ischemia. Isolated hearts of mice were subjected to 15 min of global ischemia and 90 min of reperfusion. We employed hearts of various mice knock-out strains (interleukin-6(-/-), matrix metalloprotease-7(-/-), mast-cell deficient WBB6F1-Kit(W)/Kit(W-v), TNF-R1(-/-)) and wildtype mice, the latter perfused without and with infusion of cycloheximide or TNFalpha-cleaving-enzyme inhibitor (TAPI-2). Normoxic control hearts showed basal release of TNFalpha during the whole experiment. Immunohistology identified cardiac mast cells, macrophages and endothelial cells as main sources. TNFalpha release was stimulated during postischemic reperfusion, occurring in a two-peak pattern: directly after ischemia (0-10 min) and again after 60-90 min. The first peak mainly reflects tissue washout of TNFalpha accumulated during ischemia. The second, protracted peak arose continuously from the basal level and was abolished by protein synthesis inhibitor cycloheximide. Both properties are characteristic for de novo synthesis of TNFalpha, e.g., in cardiac muscle cells. However, immunohistological staining for TNFalpha failed in cardiomyocytes after 90 min of reperfusion. In contrast to hearts of TNF-R1(-/-) and Kit(W/W-v)-mice, those of IL-6(-/-) and MMP-7(-/-) mice lacked the late TNFalpha peak. TAPI did not suppress release of TNFalpha. While autostimulation via TNF-R1 also does not seem obligatory and mast cell can be ignored as source of the second peak, IL-6 may support de novo synthesis of TNFalpha. Additionally, TNFalpha release may essentially involve cleavage of membrane bound TNFalpha by MMP-7.

Animals↗

PubMed2005

Intracoronary formation and retention of micro aggregates of leukocytes and platelets contribute to postischemic myocardial dysfunction.

OBJECTIVE: Cardiac pump function and coronary regulation can be impaired after short-term ischemia. Recent studies with platelets (P) and neutrophils (PMN) yielded contradicting results about the "cellular" contribution to reperfusion injury. METHODS: Isolated guinea pig hearts performing pressure-volume work were employed, external heart work (EHW), aortic flow (AF), coronary flow (CF) and heart rate (HR) serving as parameters of cardiac function. After global ischemia, human blood cells were given as bolus (1 min) during reperfusion (intracoronary hematocrit 7%). Expression of specific adhesion molecules (P: CD62P, CD41; PMN: integrin CD11b) was measured on cells before and after coronary passage (FACS analysis). RESULTS: Postischemic recovery of pump function was significantly reduced in hearts with blood cell application (EHW: -cells 54 +/- 14%, +cells 41 +/-12%, p <0.05). Coronary response to bradykinin and reactive hyperemia were not effected. The blood-cell dependent functional loss was partly reduced by blocking CD18 (anti-CD 18) and completely abrogated by blockage of CD41 (lamifiban). The expression of CD11b on PMN and monocytes (M) and CD62P on platelets was significantly reduced in the coronary effluent and a significant decrease of CD41 on leukocytes occurred during coronary passage after ischemia. Increases in CD41 on PMN in the presence of lamifiban demasked intracoronary formation of micro aggregates (P/PMN). These micro aggregates were visualized by light microscopy. Electron microscopy revealed no significant microvascular plugging. CONCLUSION: 1) A specifically blood-cell induced loss of myocardial pump function has been demonstrated after short-term ischemia. 2) CD41 (= GpIIbIIIa) on P is responsible for this cardiac reperfusion damage. 3) The effect is causally linked to the formation of micro aggregates between PMN and P, but seems attenuated in the presence of erythrocytes as compared to effects reported from experiments in which PMN and P were applied singly or co-perfused. 4) Intracoronary retention of PMN, M and platelet-leukocyte micro aggregates seems to be transient, as adherence was not confirmed by electron microscopy.

Animals↗

PubMed2005

Inhaled glutathione decreases PGE2 and increases lymphocytes in cystic fibrosis lungs.

Reduced glutathione (GSH), a major antioxidant and modulator of cell proliferation, is decreased in the bronchoalveolar lavage fluid (BALF) of cystic fibrosis (CF) patients. We previously have shown that GSH inhalation in CF patients significantly increased GSH levels in BALF and improved lung function (M. Griese et al., 2004, Am. J. Respir. Crit. Care Med.169, 822-828). GSH depletion in vitro enhances susceptibility to oxidative stress, increases inflammatory cytokine release, and impairs T cell responses. We therefore hypothesized that an increase in GSH in BALF reduces oxidative stress, decreases inflammation, and modulates T cell responses in lungs of CF patients. BALF from 17 CF patients (median FEV1 67% (43-105%) of predicted) was assessed before and after GSH inhalation for total protein, markers of oxidative stress (8-isoprostane, myeloperoxidase, and ascorbic and uric acid), pattern of protein oxidation, prostaglandin E2 (PGE2), and proinflammatory cytokines. BALF cells were differentiated using cytospin slides, and lymphocytes were further analyzed by flow cytometry. Inhalation of GSH decreased BALF levels of PGE2 and increased CD4+ and CD8+ lymphocytes in BALF significantly but had no effect on markers of oxidative stress. BALF lymphocytes correlated positively with lung function, whereas levels of PGE2 showed an inverse correlation. The patients with the greatest improvement in lung function after GSH treatment also had the largest decline in PGE2 levels. We conclude that GSH inhalation in CF patients increases lymphocytes and suppresses PGE2 in the bronchoalveolar space. Thus, GSH primarily affected the pulmonary immune response rather than the oxidative status in CF patients. The effect of GSH inhalation on PGE2 levels and lymphocytes in CF warrants further investigation.

Administration, Inhalation↗

PubMed2004

Urate oxidation in CSF and blood of patients with inflammatory disorders of the nervous system.

Urate is largely excluded from the brain under non-inflammatory conditions (concentration gradient serum:CSF about 10:1), but increases markedly in Guillain-Barré Syndrome and bacterial meningitis. The oxidation product allantoin is normally not passively distributed between blood and cerebrospinal fluid (gradient 3:1) and increases 5-fold in CSF of patients with meningitis. Patients with multiple sclerosis had normal levels of urate and allantoin in blood and CSF.

Allantoin↗

PubMed2003

Sevoflurane but not isoflurane can reduce prostacyclin production of endothelial cells.

BACKGROUND AND OBJECTIVE: Little is known about the interaction of newer volatile anaesthetics with endothelial eicosanoid production. Sevoflurane may possibly reduce prostacyclin formation. Thus, we compared the influences of sevoflurane and isoflurane on endothelial prostacyclin production. METHODS: Production of prostacyclin of human umbilical vein endothelial cells was measured by the ELISA technique under basal conditions and after stimulation with calcium ionophore A 23187 10 micromol or histamine 0.1 micromol in the absence and presence of 1 and 2 minimal alveolar concentrations (MAC) of sevoflurane or isoflurane. RESULTS: The basal production of prostacyclin was unaffected by the volatile anaesthetics. Stimulation of endothelial cells increased prostacyclin formation 3-5-fold. Sevoflurane at 2 MAC, but not at 1 MAC, could reduce stimulated prostacyclin production by about half (P < 0.05). Isoflurane had no inhibitory effect. Inhibition of cyclo-oxygenase function by acetylsalicylic acid abolished the induced burst of prostacyclin formation completely. CONCLUSIONS: Sevoflurane, but not isoflurane, can reduce stimulated endothelial prostacyclin production in a concentration-dependent manner. Because at least 2 MAC of sevoflurane were required, this effect should be of minor importance under clinical conditions of balanced anaesthesia.

Analysis of Variance↗

PubMed2002

Pneumococcal meningitis in the rat: evaluation of peroxynitrite scavengers for adjunctive therapy.

We evaluated the effect of different peroxynitrite scavengers for adjunctive therapy of experimental bacterial meningitis. Twenty hours after intracisternal injection of Streptococcus pneumoniae, rats were treated with ceftriaxone [100 mg/kg intraperitoneal (i.p.)] and either urate (300 mg/kg i.p.), Mn(III)tetrakis(4-benzoic acid)porphyrin (MnTBAP, 15 mg/kg i.p.), ascorbate (100 mg/kg i.p.), or urate (300 mg/kg i.p.) + ascorbate (100 mg/kg i.p.). Six hours after initiation of treatment, the cerebrospinal fluid (CSF) pleocytosis was significantly (p<0.05) reduced by urate (8697 +/- 1526 cells/microl) and MnTBAP (8542 +/- 4059 cells/microl) vs. ceftriaxone alone (15,793 +/- 3202 cells/microl). Brain concentrations of proinflammatory cytokines [interleukin-1beta (IL-beta), interleukin-6 (IL-6), and macrophage inflammatory protein-2 (MIP-2)] were also reduced by urate and MnTBAP. The intracranial hypertension was significantly reduced by MnTBAP (14.0 +/- 5.4 mm Hg), but not by urate (25.5 +/- 7.1 mm Hg) vs. ceftriaxone alone (22.5 +/- 5.9 mm Hg). Ascorbate alone had no effect on CSF pleocytosis (15,775 +/- 7058 cells/microl), intracranial pressure (25.6 +/- 8.8 mm Hg), and brain cytokine concentrations. However, the combination of urate and ascorbate was as effective as MnTBAP (CSF pleocytosis: 5392 +/- 4232 cells/microl, intracranial pressure: 13.3 +/- 6.9 mm Hg).

Animals↗

PubMed2002

Oxidative stress in bacterial meningitis in humans.

OBJECTIVE: To study reactive nitrogen species-mediated oxidative brain damage and antioxidant defenses in patients with acute bacterial meningitis. METHODS: Nitrotyrosine (a widely used marker for the formation of reactive nitrogen species, such as peroxynitrite) and the lipid peroxidation product 4-hydroxynonenal were detected by immunohistochemistry in brain specimens obtained at autopsy. CSF concentrations of nitrotyrosine were quantified by ELISA. CSF and serum concentrations of ascorbic acid, uric acid, and its oxidation product allantoin were determined by high-pressure liquid chromatography. RESULTS: Tyrosine nitration was strongly increased during meningitis. It was most evident in inflammatory cells and blood vessels in the subarachnoid space. The same cell types stained positive for the lipid peroxidation marker 4-hydroxynonenal, suggesting that reactive nitrogen species contribute to oxidative brain damage during meningitis. High CSF nitrotyrosine concentrations were associated with an unfavorable outcome according to the Glasgow Outcome Score. In the CSF, the increase of nitrotyrosine was accompanied by a depletion of the antioxidant ascorbic acid and an increased oxidation of the natural peroxynitrite scavenger uric acid to allantoin. CONCLUSION: These findings indicate that oxidative stress due to reactive nitrogen species and altered antioxidant defenses are involved in the pathophysiology of bacterial meningitis in humans.

Adolescent↗

PubMed2001

Experimental meningitis in the rat: protection by uric acid at human physiological blood concentrations.

The natural peroxynitrite scavenger uric acid was previously shown to be protective in a rat model of pneumococcal meningitis; however, rats have much lower blood uric acid levels than humans. Therefore, we evaluated its therapeutic effect at human physiological blood concentrations. Intraperitoneal pretreatment with uric acid increased its blood concentrations from 44.9+/-10.0 microM in untreated rats to 169.8+/-122.6 microM and reduced the cerebrospinal fluid (CSF) pleocytosis from 12767+/-2520 to 8376+/-2450 cells/microl (P<0.05) and the intracranial pressure from 11.6+/-3.0 to 4.3+/-1.2 mm Hg (P<0.05). Coadministration of oxonic acid, an inhibitor of urate oxidase, increased the blood uric acid levels to 355.0+/-79.6 microM and further reduced the CSF pleocytosis (4190+/-1749 cells/microl, P<0.05) and the intracranial pressure (1.4+/-2.4 mm Hg). Uric acid+oxonic acid also had a beneficial effect when administered 2 or 4 h after the induction of meningitis. We demonstrate a dose-dependent anti-inflammatory effect of uric acid at blood levels in the human physiological range.

Animals↗

PubMed2001

Aspirin, but not the more selective cyclooxygenase (COX)-2 inhibitors meloxicam and SC 58125, aggravates postischaemic cardiac dysfunction, independent of COX function.

Inhibition of cyclooxygenase (COX) might favour non-enzymatic formation of cardiodepressive isoprostanes from arachidonic acid by radicals generated during reperfusion. This could explain deleterious effects of acetylsalicylic acid (ASA) on cardiac function. We examined the influence of COX inhibition on myocardial function after low-flow ischaemia and reperfusion, employing either ASA (100 micromol/l), the partially selective COX-2 inhibitor meloxicam (0.3 micromol/l and 3.0 micromol/l), or the highly selective COX-2 inhibitor SC 58125 (1.0 micromol/l and 3.0 microgmol/l). Isolated, buffer-perfused guinea pig hearts, performing pressure-volume work before and after consecutive low-flow ischaemia and reperfusion, were used for the study. Measurement of coronary and aortic flow, ejection time and heart rate served to calculate external heart work (EHW), before and after ischaemia. Additionally, release of prostacyclin and thromboxane A2, production of lactate, consumption of pyruvate and tissue concentration of the isoprostane 8-iso-PGF2alpha were measured. ASA significantly reduced recovery of EHW (46+/-18% vs. 82+/-15% for controls), whereas meloxicam and SC 58125 did not (64+/-15% and 74+/-13% recovery, respectively). Paradoxically, ASA increased reactive hyperaemia and consumption of pyruvate in the early reperfusion phase in comparison to all other groups, while lactate production did not differ. Prostacyclin production did not increase during reperfusion and was not significantly different between groups at any time point. In contrast, thromboxane A2 release increased about fivefold in the 2nd min of reperfusion under control conditions and in the presence of SC 58125, but was inhibited by ASA and by meloxicam in both concentrations. Isoprostane content of heart tissue was not detectably influenced under the mild reperfusion conditions used here. We conclude that ASA can aggravate postischaemic cardiac dysfunction, independent of COX inhibition. The deleterious effect in the present model might be due to uncoupling of mitochondrial oxidative phosphorylation rather than to direct effects of reduced eicosanoid release or radical induced formation of isoprostanes.

Animals↗

PubMed2001

Evidence for inflammatory responses of the lungs during coronary artery bypass grafting with cardiopulmonary bypass.

OBJECTIVE: The occurrence of a systemic inflammatory reaction during cardiac surgery with cardiopulmonary bypass (CPB) has been well established, and the heart itself has been shown to release inflammatory mediators after ischemia. The hypothesis of the present study was that the lungs are also a site of inflammatory responses during early reperfusion. METHODS: In 20 consecutive patients undergoing coronary artery bypass grafting, blood was simultaneously drawn from the right atrium (RA) and the pulmonary vein (PV) before CPB and at 1 min, 10 min, and 20 min of reperfusion. The levels of interleukin (IL)-6, IL-8, IL-10, and tumor necrosis factor (TNF)-alpha were determined, as well as the adhesion molecules CD41 and CD62 on platelets and CD11b and CD41 on leukocytes. As a measure of the pulmonary release, ratios of PV and RA levels were calculated. RESULTS: Before CPB, the concentrations of cytokines tended to be lower in the PV compared with the RA. At 1 min of reperfusion, no significant concentration increases were found in the PV. At 10 min of reperfusion, the PV/RA ratio (mean +/- SEM) for IL-6 was 2.06 +/- 0.37 and 1.24 +/- 0.15 for IL-8 (p = 0.02 and p = 0.04, respectively, compared with the pre-CPB ratios of 0.89 +/- 0.4 and 0.99 +/- 0.2). At 20 min of reperfusion, PV/RA ratios for IL-6 (1.95 +/- 0.37) and IL-10 (0.99 +/- 0.4) were higher than before CPB (0.89 +/- 0.04, p = 0.05 and 0.85 +/- 0.06, p = 0.03, respectively). Adhesion molecule counts on platelets and polymorphonuclear neutrophils (PMNs) tended to be higher in the PV than in the RA before CPB. At 1 min of reperfusion, the PV/RA ratio of CD41 on monocytes (0.89 +/- 0.04) and of CD41 on PMNs (1.05 +/- 0.05) was less than before CPB (1.24 +/- 0.08, p = 0.0002 and 1.55 +/- 0.14, p = 0.0002). At 10 min and 20 min of reperfusion, similar changes were found. CONCLUSIONS: The observed changes indicate an inflammatory response of the lungs. Proinflammatory cytokines are increased in pulmonary venous blood. At the same time, activated blood cells are retained in the pulmonary circulation. This may contribute to pulmonary dysfunction almost routinely observed after CPB.

Aged↗

PubMed2000

Endothelial function and hemostasis.

The vascular endothelium influences not only the three classically interacting components of hemostasis: the vessel, the blood platelets and the clotting and fibrinolytic systems of plasma, but also the natural sequelae: inflammation and tissue repair. Two principal modes of endothelial behaviour may be differentiated, best defined as an anti- and a prothrombotic state. Under physiological conditions endothelium mediates vascular dilatation (formation of NO, PGI2, adenosine, hyperpolarizing factor), prevents platelet adhesion and activation (production of adenosine, NO and PGI2, removal of ADP), blocks thrombin formation (tissue factor pathway inhibitor, activation of protein C via thrombomodulin, activation of antithrombin III) and mitigates fibrin deposition (t- and scuplasminogen activator production). Adhesion and transmigration of inflammatory leukocytes are attenuated, e.g. by NO and IL-10, and oxygen radicals are efficiently scavenged (urate, NO, glutathione, SOD). When the endothelium is physically disrupted or functionally perturbed by postischemic reperfusion, acute and chronic inflammation, atherosclerosis, diabetes and chronic arterial hypertension, then completely opposing actions pertain. This prothrombotic, proinflammatory state is characterised by vaso-constriction, platelet and leukocyte activation and adhesion (externalization, expression and upregulation of von Willebrand factor, platelet activating factor, P-selectin, ICAM-1, IL-8, MCP-1, TNF alpha, etc.), promotion of thrombin formation, coagulation and fibrin deposition at the vascular wall (expression of tissue factor, PAI-1, phosphatidyl serine, etc.) and, in platelet-leukocyte coaggregates, additional inflammatory interactions via attachment of platelet CD40-ligand to endothelial, monocyte and B-cell CD40. Since thrombin formation and inflammatory stimulation set the stage for later tissue repair, complete abolition of such endothelial responses cannot be the goal of clinical interventions aimed at limiting procoagulatory, prothrombotic actions of a dysfunctional vascular endothelium.

Arteriosclerosis↗

PubMed2000

Endothelial activation--a strategic event during postischemic myocardial inflammation.

Reperfusion after limited ischemia increases leukocyte adhesion, which may contribute to postischemic myocardial and endothelial stunning. Leukocyte adhesion is enhanced immediately after the onset of reperfusion, indicating rapid regulatory mechanisms. In addition, de novo synthesis of, e.g., adhesion molecules induced by reperfusion has been described, providing a prolonged postischemic inflammatory reaction. Enhanced transcription of adhesion molecules involves NF kappa B activation which appears as an essential transcription factor for reperfusion-induced subacute endothelial activation. Both, acute and subacute endothelial activation seem to contribute to the final extent of leukocyte-dependent reperfusion injury and successive treatment of both appears to be a promising therapeutic strategy for postischemic myocardial inflammation and its detrimental effects.

Animals↗

PubMed2000

Reactive oxygen species and nitric oxide in myocardial ischemia and reperfusion.

Oxygen radicals and reactive oxygen species (ROS) are known to be generated in large amounts under inflammatory conditions and in the first few minutes of postischemic organ reperfusion. Due to the interaction of ROS with nitric oxide (NO), formed constitutively by endothelial cells, two alternatives are feasible. On the one hand, reaction with superoxide radicals may induce toxification (formation of peroxynitrite), and, on the other hand, by reacting with superoxide and hydroxyl radicals, NO can serve as a radical scavenger (formation of the innocuous anions, nitrate and nitrite, respectively). However, NO is considered to play a pivotal role in numerous physiological and pathophysiological processes, with effects arising from both lack and surfeit of this easily diffusible and chemically very reactive molecule. Physiologic contributions to vascular dilatation and inhibition of platelet and leukocyte activation, e.g., are infringed by enhanced inactivation of NO. Such inactivation occurs readily due to spontaneous reaction of NO with the superoxide radical, formed, e.g., by stressed endothelial cells and activated leukocytes. Conversely, overproduction of NO by induced NO synthase (iNOS) may lead to circulatory shock, cell apoptosis or even cell necrosis. Caution would, thus, seem to be warranted when attempting to interfere with homeostasis of NO. We have investigated the ability of NO to act as a radical scavenger during myocardial reperfusion in experimental and clinical settings. In the former, inhibition of angiotensin converting enzyme was employed to generate more endogenous NO (via bradykinin), in the latter, low-dose sodium nitroprusside was used as the donor of exogenous NO in patients undergoing coronary bypass grafting. Inhibition of leukocyte adhesion, attenuation of platelet activation and mitigation of redox-stress and inflammation were observed in both instances. Accordingly, modest enhancement of NO levels should afford cardioprotection during reperfusion.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2000

Sodium nitroprusside in patients with compromised left ventricular function undergoing coronary bypass: reduction of cardiac proinflammatory substances.

OBJECTIVE: The aim of the present study was to investigate whether the nitric oxide donor sodium nitroprusside can reduce the cardiac inflammatory response during coronary artery bypass grafting in patients with severely compromised left ventricular function. METHODS: Patients (n = 30) were assigned to receive placebo or sodium nitroprusside (0.5 microg. kg(-1). min(-1)) for the first 60 minutes of reperfusion. Interleukin 6, interleukin 8, and tumor necrosis factor alpha levels; platelet adhesion molecule CD41 and CD62 levels; and CD11b on leukocytes were determined in the radial artery and coronary sinus before cardiopulmonary bypass and during reperfusion (1, 5, 10, 35, and 75 minutes). RESULTS: At 1 minute of reperfusion, coronary venous levels of CD41-positive polymorphonuclear leukocytes were 8% lower than arterial levels in the placebo group and 18% higher in the sodium nitroprusside group (P =.021). At 5 minutes of reperfusion, the respective levels were 29% and 1% for interleukin 6 (P =.015), -5% and 20% for CD41-positive monocytes (P =.032), and -2% and 16% for CD11b-positive monocytes (P =.038). At 10 minutes of reperfusion, these levels were -14% and 21% for CD41-positive monocytes (P =.006). At 35 minutes of reperfusion, these levels were -13% and 7% for CD41-positive monocytes (P =.017), -41% and 23% for CD11b-positive monocytes (P =.001), and 7% and 25% for CD62-positive platelets (P =. 041). At 75 minutes of reperfusion, the levels were 15% and -7% for tumor necrosis factor alpha (P =.025) and -10% and 10% for CD62-positive platelets (P =.041). CONCLUSIONS: Transcardiac production of proinflammatory cytokines is reduced in patients undergoing coronary artery bypass grafting treated with the nitric oxide donor sodium nitroprusside. At the same time, less activated leukocytes and platelets are retained in the coronary circulation.

Aged↗

PubMed2000

Reduction of pro-inflammatory cytokine levels and cellular adhesion in CABG procedures with separated pulmonary and systemic extracorporeal circulation without an oxygenator.

OBJECTIVE: We have recently shown that a considerable amount of pro-inflammatory cytokines is released during pulmonary passage after aortic declamping in patients undergoing coronary artery bypass grafting. The present study was performed to investigate whether bilateral extracorporeal circulation with the lungs as oxygenators can reduce the inflammatory responses of the lungs. METHODS: Eighteen consecutive patients undergoing coronary artery bypass grafting were randomly assigned to routine extracorporeal circulation with cannulation of right atrium and aorta (routine circulation, ten patients) or to a bilateral extracorporeal circulation with additional cannulation of left atrium and pulmonary artery (bilateral circulation, eight patients). Blood was simultaneously drawn from right atrium and pulmonary vein at 1, 10 and 20 min reperfusion. The levels of interleukin (IL)-6 and IL-8 and the adhesion molecules CD41 and CD62 on platelets and CD11b and CD41 on leukocytes were determined. Because of considerable interindividual scatter, the pulmonary venous levels are normalized to percent of the respective right atrial value at each time point. RESULTS: At 1 min reperfusion pulmonary venous levels of IL-6 and IL-8 in routine circulation were +44+/-15% and +43+/-28% of the respective right atrial values. The respective values in bilateral circulation were -3+/-4% and -6+/-7% (P=0.02 and P=0.05 vs. respective right atrium). Similar increments were found after 10 and 20 min. Platelet-monocyte coaggregates were retained during pulmonary passage at 1 min reperfusion in routine circulation (-21+/-6%), but washed out in bilateral circulation (+5+/-8%, P=0. 007). At 20 min reperfusion, activated polymorphonuclear neutrophils (PMN) were retained in routine circulation (-16+/-9%) but washed out in bilateral circulation (+19+/-29%, P=0.05; all data given as mean+/-SEM). CONCLUSIONS: Bilateral extracorporeal circulation without an artificial oxygenator significantly reduces the inflammatory responses during pulmonary passage after aortic declamping.

Aged↗

PubMed2000

Endothelial preconditioning by transient oxidative stress reduces inflammatory responses of cultured endothelial cells to TNF-alpha.

Brief episodes of ischemia can render an organ resistant to subsequent severe ischemia. This 'ischemic preconditioning' is ascribed to various mechanisms, including oxidative stress. We investigated whether preconditioning exists on an endothelial level. Human umbilical vein endothelial cells (HUVECs) were transiently confronted with oxidative stress (1 mM H(2)O(2), 5 min). Adhesion molecules ICAM-1 and E-selectin and release of cytokines IL-6 and IL-8 to subsequent stimulation with TNF-alpha (2.5 ng/ml, 4 h) were measured (flow cytometry and immunoassay), as were nuclear translocation of the transcription factor NFkappaB (Western blotting, confocal microscopy) and redox status of HUVECs (quantification of glutathione by HPLC). TNF-alpha elevated IL-6 in the cell supernatant from 8.8 +/- 1 to 41 +/- 3 pg/ml and IL-8 from 0.5 +/- 0. 03 to 3 +/- 0.2 ng/ml. ICAM-1 was increased threefold and E-selectin rose eightfold. Oxidative stress (decrease of glutathione by 50%) reduced post-TNF-alpha levels of IL-6 to 14 +/- 3 and IL-8 to 1 +/- 0.2; the rise of ICAM-1 was completely blocked and E-selectin was only doubled. The anti-inflammatory effects of preconditioning via oxidative stress were paralleled by reduction of the translocation of NFkappaB on stimulation with TNF-alpha, and antagonized by the intracellular radical scavenger N-acetylcysteine. 'Anti-inflammatory preconditioning' of endothelial cells by oxidative stress may account for the inhibitory effects of preconditioning on leukocyte adhesion in vivo.

Apoptosis↗

PubMed2000

Sevoflurane and isoflurane do not enhance the pre- and postischemic eicosanoid production in guinea pig hearts.

UNLABELLED: Eicosanoids and volatile anesthetics can influence cardiac reperfusion injury. Accordingly, we analyzed the effects of sevoflurane and isoflurane applied in clinically relevant concentrations on the myocardial production of prostacyclin and thromboxane A2 (TxA2) and on heart function. Isolated guinea pig hearts, perfused with crystalloid buffer, performed pressure-volume work. Between two working phases, hearts were subjected to 15 min of global ischemia followed by reperfusion. The hearts received no anesthetic, 1 minimum alveolar anesthetic concentration (MAC) isoflurane (1.2 vol%), or 0.5 and 1 MAC sevoflurane (1 vol% and 2 vol%), either only preischemically or pre- and postischemically. In additional groups, cyclooxygenase function was examined by an infusion of 1 microM arachidonic acid (AA) in the absence and presence of sevoflurane. The variables measured included the myocardial production of prostacyclin, TxA2 and lactate, consumption of pyruvate, coronary perfusion pressure, and the tissue level of isoprostane 8-iso-PGF2alpha. External heart work, determined pre- and postischemically, served to assess recovery of heart function. Volatile anesthetics had no impact on postischemic recovery of myocardial function (50%-60% recovery), perfusion pressure, lactate production, or isoprostane content. Release of prostacyclin and TxA2 was increased in the early reperfusion phase 5-8- and 2-4-fold, respectively, indicating enhanced AA liberation. Isoflurane and sevoflurane did not augment the eicosanoid release. Only 2 vol% sevoflurane applied during reperfusion prevented the increased eicosanoid formation in this phase. Infusion of AA increased prostacyclin production approximately 200-fold under all conditions, decreased pyruvate consumption irreversibly, and markedly attenuated postischemic heart work (25% recovery). None of these effects were mitigated by 2 vol% sevoflurane. In conclusion, only sevoflurane at 2 vol% attenuated the increased liberation of AA during reperfusion. Decreased eicosanoid formation had no effect on myocardial recovery in our experimental setting while excess AA was deleterious. Because eicosanoids influence intravascular platelet and leukocyte adhesion and activation, sevoflurane may have effects in reperfused tissues beyond those of isoflurane. IMPLICATIONS: In an isolated guinea pig heart model, myocardial eicosanoid release was not increased by isoflurane or sevoflurane, either before or after ischemia. Sevoflurane (2 vol%) but not isoflurane attenuated the increased release of eicosanoids during reperfusion.

Anesthetics, Inhalation↗

PubMed2000

Nonuniform behavior of intravenous anesthetics on postischemic adhesion of neutrophils in the guinea pig heart.

UNLABELLED: Adhesion of polymorphonuclear neutrophils (PMN) to the coronary endothelium is a crucial step in the development of ischemic myocardial injury. We tested the possible effects of six widely used IV anesthetics on non- and postischemic coronary adhesion of PMN in isolated perfused guinea pig hearts. Hearts (n = 5-11/group) were perfused under conditions of constant coronary flow. After 15 min global warm ischemia, PMN (10(6)) were infused in the second minute of reperfusion. The number of cells reemerging in the coronary effluent within 2 min was expressed as a percentage of the total number of administered PMN. Anesthetics were given 20 min before ischemia and during reperfusion. In addition, the ability of the drugs to influence the oxidative burst reaction of PMN was assessed by measuring luminol-enhanced chemiluminescence in response to 0.1 microM N-formyl-L-methionyl-L-leucyl-L-phenylalanine. Under nonischemic conditions, 26.3% +/- 0.5% of the injected PMN did not acutely reemerge from the coronary system. Subjecting the hearts to ischemia augmented retention to 40.0% +/- 1.6% (P < 0.05). This postischemic stimulation of adhesion was fully prevented by ketamine (10 microM: 22.8% +/- 1.6%, 20 microM: 26.6% +/- 0.7%), thiopental (25 microM: 24.0% +/- 1.7%, 50 microM: 24.0% +/- 1.4%), and midazolam (1.5 microM: 29.0% +/- 0.9%, 3 microM: 26.4% +/- 1.4%). Propofol also inhibited the augmented postischemic retention at 25 microM (28.7% +/- 2.4%). However, 50 microM propofol, etomidate (0.5 and 1 microM), and fentanyl (1 microM) all had no effect. Only thiopental reduced the nonischemic adhesion value (14.0% +/- 3.7%). This may be linked to the direct antioxidative action of thiopental (50% reduction in oxidative burst activity). Whereas ketamine, midazolam, and propofol did not significantly influence oxidant production by PMN, etomidate and the lipid solvent Intralipid enhanced the burst reaction. This activating effect of the lipid component could explain the biphasic behavior of propofol emulsion. Despite some possible differences in efficacy, several IV anesthetics may protect the heart from PMN-mediated reperfusion injury. IMPLICATIONS: Ketamine, thiopental, and midazolam, but not etomodate or fentanyl, reduce postischemic adhesion of neutrophils in the coronary system of isolated perfused guinea pig hearts, suggesting a role in mitigating myocardial reperfusion injury.

Anesthetics, Intravenous↗