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Biomedical subjects

W Seeger

Publications and source records attributed to W Seeger.

At least 289 records · Page 16Linked to original sources
PubMed1990

Altered pulmonary surfactant in uncomplicated and septicemia-complicated courses of acute respiratory failure.

Pulmonary surfactant, which is crucial for alveolar stability, may also be involved in endogenous defense mechanisms of the lungs. Thus, alterations in pulmonary surfactant may promote infections, including pneumonia and septicemia. Because patients who have acute respiratory failure often develop pneumonia, thus septicemia, we investigated when surfactant is altered in these patients and whether there is a specific pattern of changes in surfactant phospholipid composition associated with septicemia in these patients. To answer these questions, we determined the phospholipid content and composition in lung washings obtained from alveolar sites (by bronchoalveolar lavage) and from tracheal sites (by aspiration). Both techniques were performed serially over a period of 18 days in 30 patients who had acute respiratory failure resulting from polytrauma, 18 of whom developed septicemia caused by pneumonia. We found that in lung washings obtained from the alveolar sites from all patients, the phosphatidylglycerol content was decreased and the phosphatidylinositol content was increased as early as 6 hr after trauma and normalized during recovery of the patients. In addition, alveolar phosphatidylcholine content was decreased 24 hr after trauma. In patients who developed septicemia during the observation time, but not in patients who had uncomplicated courses of acute respiratory failure, the concentrations of alveolar phosphatidylethanolamine (normally 4.8% of total phospholipids) and alveolar phosphatidylcholine (normally 62.8%) both approached the proportions found in the trachea (phosphatidylethanolamine 33.4%, phosphatidylcholine 35.6%), suggesting that surfactant phospholipid pool size had progressively decreased. Our results indicate that in patients who have acute respiratory failure, pulmonary surfactant is altered very early, and that when septicemia complicates the course of acute respiratory failure, the surfactant phospholipid pool size decreases progressively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

Effects of Escherichia coli hemolysin on endothelial cell function.

Escherichia coli hemolysin is considered an important virulence factor in extraintestinal E. coli infections. The present study demonstrates that cultured pulmonary artery endothelial cells are susceptible to attack by low concentrations of E. coli hemolysin (greater than or equal to 0.05 hemolytic units/ml; greater than or equal to 5 ng/ml). Sublytic amounts of hemolysin increased the permeability of endothelial cell monolayers in a time- and dose-dependent manner. The hydraulic conductivity increased approximately 30-fold and the reflection coefficient for large molecules dropped from 0.71 to less than 0.05, indicating a toxin-induced loss of endothelial barrier function. The alterations of endothelial monolayer permeability were accompanied by cell retraction and interendothelial gap formation. In addition, E. coli hemolysin stimulated prostacyclin synthesis in endothelial cells. This effect was strictly dependent on the presence of extracellular Ca2+ but not of Mg2+. An enhanced passive influx of 45Ca2+ and 3H-sucrose but not of tritiated inulin and dextran was noted in toxin-treated cells, indicating that small transmembrane pores comparable to those detected in rabbit erythrocytes had been generated in endothelial cell membranes. These pores may act as nonphysiologic Ca2+ gates, thereby initiating different Ca2+-dependent cellular processes. We conclude that endothelial cells are highly susceptible to E. coli hemolysin and that two major endothelial cell functions are altered by very low concentrations of hemolysin.

Animals↗
PubMed1990

Leukotriene and hydroxyeicosatetraenoic acid generation elicited by low doses of Escherichia coli hemolysin in rabbit lungs.

Low doses of Escherichia coli hemolysin cause thromboxane-mediated hypertension and vascular leakage in blood-free perfused rabbit lungs (W. Seeger, H. Walter, N. Suttorp, M. Muhly, and S. Bhakdi, J. Clin. Invest. 84:220-227, 1989). The recirculating buffer medium and bronchoalveolar lavage fluid from lungs exposed to hemolysin (2.5 hemolytic units per ml) in the presence of cyclooxygenase inhibitor were analyzed for leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs) by reverse-phase and straight-phase high-pressure liquid chromatographic techniques combined with UV spectrum analysis and post-high-pressure liquid chromatography radioimmunoassay. A rapid release of large amounts of cysteinyl-LTs and leukotriene B4 (LTB4) into the intravascular space was noted (total sum, approximately 4 to 5 micrograms). Similar quantities have hitherto been elicited only by high concentrations of the artificial calcium ionophore A 23187. Moreover, a marked liberation of 5-HETE and 12-hydroxyheptadecatrienoic acid into the buffer medium occurred, whereas LTB4 represented the predominant compound in the lavage fluid. The hemolysin-induced burst of LT and HETE generation preceded the onset of vascular leakage. The outstanding capacity of E. coli hemolysin to produce the liberation of potent lipid mediators is probably relevant to the pathways of vascular injury and amplification of inflammatory events during severe infection with hemolytic E. coli strains.

Animals↗
PubMed1990

Inhibition of norepinephrine and acetylcholine release from human neocortex by omega-conotoxin GVIA.

Superfused slices of human neocortex, prepared from surgically removed tissue (to gain access to subcortical tumors) and prelabeled selectively with [3H]norepinephrine (NE) or [3H]choline, were stimulated electrically to evoke tritium overflow. This tritium overflow was abolished by the sodium channel blocker tetrodotoxin and by withdrawal of extracellular Ca++. Thus, the action potential-induced, exocytotic tritium overflow supports the assumption of a quasiphysiological release of NE from noradrenergic and of acetylcholine (ACh) from cholinergic nerve terminals, respectively. In addition, the modulation of NE release by adrenoceptor ligands displayed the appropriate pharmacology of alpha-2 autoreceptors; ACh release was modulated by muscarinic ligands. Both NE and ACh release decreased with the age of the patients. The effects of drugs on NE and ACh release were not age-related. The peptide modulator of the N-type voltage sensitive Ca++ channel, omega-conotoxin GVIA, inhibited NE release with an IC50 of about 14 nM and ACh release with an IC50 of about 3 nM, whereas L-type modulators were ineffective. The binding of [125I]omega-conotoxin GVIA to human neocortical membranes was of high affinity (KD = 1.3 pM) to one site (nH = 0.97) of substantial density (maximum binding = 878 fmol/mg of protein); the binding of the L-type modulator [3H]isradipine to these membranes was also of high affinity (KD = 89 pM) to one site (nH = 1.03) of lesser density (maximum binding = 429 fmol/mg of protein). In conclusion, Ca++ entry through N-type Ca++ channels, rather then L-type Ca++ channels, predominates in subserving NE and ACh release from noradrenergic and cholinergic nerve terminals, respectively, of human neocortex.

Acetylcholine↗
PubMed1990

[4-way immunosuppression in pre-sensitized recipients of allogenic cadaver kidney transplants].

As a result of introduction of quadruple immunosuppression using cyclosporine, antithymocyte globulin, azathioprine and prednisone in immunological high-risk patients with a presensitization greater than or equal to 80% and/or multiple grafts the rate of immediate graft function could significantly increased, the frequency of rejection and graft rupture was reduced and the patient survival rate could improved to 100%. The problem of vascular rejection should resolved by a more aggressive biopsy approach.

Antilymphocyte Serum↗
PubMed1990

Staphylococcal alpha-toxin-induced vascular leakage in isolated perfused rabbit lungs.

alpha-Toxin, the major, pore-forming exotoxin of Staphylococcus aureus, caused acute hypertension when perfused through blood-free rabbit lungs (21). This reaction is mediated by pulmonary thromboxane generation, for which toxin-induced calcium flux into target cells with subsequent stimulation of arachidonic acid metabolism is predominantly responsible. In the present study, we investigated the effects of alpha-toxin on the integrity of the lung microvasculature. Thromboxane generation was inhibited in all experiments to suppress the development of pulmonary hypertension. Application of low alpha-toxin concentrations (5 to 40 ng/ml) induced protracted, severe vascular leakage in a dose-dependent manner. After a lag period of 40 to 120 minutes, gravimetrically determined capillary filtration coefficients progressively increased to greater than 10-fold values, and this was followed by pronounced weight gain of the isolated organs. These physiologic alterations were paralleled by dose- and time-dependent structural changes documented by electron microscopic examination of perfusion-fixed lungs. Increasing electron density of microvascular endothelial cell nuclei and subsequently of their cytoplasma was noted, followed by detachment of these cells from the mutual endoepithelial basal lamina. Edema was localized in the blood-gas exchange area, in contrast to hydrostatically induced lung fluid accumulation. These results identify pulmonary microvascular endothelium cells as highly susceptible targets for attack by alpha-toxin. Given a similar sensitivity of human endothelial cells, alpha-toxin might directly contribute to the pathogenesis of acute respiratory failure under conditions of severe infection with Staphylococcus aureus.

Animals↗
PubMed1989

Microsurgical unilateral approaches for spinal tumour surgery: eight years' experience in 256 primary operated patients.

A series of 256 consecutive patients suffering from spinal tumours was studied with respect to the value of bilateral or unilateral surgical approaches. The case material included 152 extradural, 87 intradural, extramedullary and 17 intramedullary tumours. The cervical spinal cord was involved in 43, the thoracic in 152 and the lumbosacral region in 61 cases. Hemilaminectomy was chosen mainly for juxtamedullary tumours, while laminectomy was used for intramedullary tumours. No remarkable difference regarding the choice of approaches was found in extradural tumours. More than 60% of cervical or lumbosacral tumours were managed using unilateral procedures. A higher rate of surgical radicality but fewer complications, shorter stay in hospital and better early results were achieved using hemilaminectomy especially in patients with juxtamedullary tumours. From the observations it may be concluded that the results do not depend on the type of surgical approach but are closely related to the histology and location of tumours. Under the prerequisite of exact pre-operative definition of tumour location, unilateral approaches are advantageous for all kinds of spinal tumours especially for juxtamedullary benign tumours.

Adolescent↗
PubMed1989

Local complement activation, thromboxane-mediated vasoconstriction, and vascular leakage in isolated lungs. Role of the terminal complement sequence.

In situ complement activation was induced in isolated, ventilated, and blood-free perfused rabbit lungs. Six to 11% human serum (vol/vol) was repeatedly admixed to the recirculating Krebs Henseleit buffer during 10-min periods, interrupted by rinsing phases with serum-free medium. This caused dose-dependent, reversible, and reproducible pulmonary artery pressor responses with pressure peaks or plateaus of 8 to 22 mm Hg. Pressor responses were paralleled by a marked release of thromboxane (TxA2) and prostaglandin I2 into the medium. Heat-inactivated serum, purified fluid-phase SC5b-9, and serum that had been activated with inulin in the absence or presence of a carboxypeptidase inhibitor all failed to elicit pressor responses. Both pressor response and prostanoid release were strictly dependent on complement factor C8, and evidence for C8 binding was obtained with the use of 125I-C8. Inhibitor studies collectively indicated that TxA2 was the predominant vasoconstrictive agent. Although repetitive short-term application of human serum induced no major lung weight gain, prolonged exposure to serum (40 to 80 min) without intermittent rinsing phases caused a delayed increase in the capillary filtration coefficient to maximally 3- to 4-fold values, with marked lung edema formation. We conclude that in situ activation of complement in the rabbit lung vasculature causes immediate intrapulmonary prostanoid generation and thromboxane-mediated vasoconstriction, independent of circulating leukocytes, but dependent on the formation of terminal membrane-complement complexes. Continuous complement activation results in a delayed increase in lung vascular permeability.

Animals↗
PubMed1989

Surfactant abnormalities in patients with respiratory failure after multiple trauma.

We present a prospective study, designed to evaluate surfactant abnormalities in severely injured patients during the course of post-traumatic pulmonary dysfunction. Serially obtained bronchoalveolar lavage fluids from noncontused lung areas (in total, 132 samples from 17 patients) were analyzed for alveolar phospholipid composition and surfactant function in vitro during the first 14 days after trauma. The data were compared with those of 29 lavage samples obtained from 10 healthy control subjects and correlated to severity of respiratory failure. In the traumatized patients, the total lavage phospholipid content was unchanged, but there was a progressive decrease in the relative amounts of phosphatidylcholine (%PC) and phosphatidylglycerol and an increase in phosphatidylinositol, phosphatidylethanolamine, and sphingomyelin. These alterations were paralleled by a marked decrease in the hysteresis area of the surface tension isotherm. The decrease in %PC and reduction of hysteresis area were significantly correlated. The alterations in alveolar phospholipid composition and in vitro surfactant function were more pronounced in patients with severe respiratory failure. There was a significant inverse correlation between severity of respiratory dysfunction and %PC or hysteresis area for all traumatized patients. Protein leakage into the alveolar space was significantly higher in patients with severe respiratory failure and appeared to precede surfactant abnormalities in such patients. The neutrophil content in the alveolar space was markedly increased in all patients with multiple injuries however, no significant correlation with the noted alterations in alveolar phospholipid composition or surfactant function was found. We concluded that surfactant abnormalities occur during the course of post-traumatic pulmonary dysfunction and are correlated with the severity of respiratory failure.

Adolescent↗
PubMed1989

Thromboxane-mediated hypertension and vascular leakage evoked by low doses of Escherichia coli hemolysin in rabbit lungs.

Escherichia coli hemolysin has been implicated as a pathogenicity factor in extraintestinal E. coli infections including sepsis. In the present study the effects of intravascular administration of hemolysin were investigated in isolated blood-free perfused rabbit lungs. Low concentrations of the toxin in the perfusate (0.05-5 hemolytic units/ml, corresponding to approximately 5-500 ng/ml), caused a dose- and time-dependent release of potassium, thromboxane A2, and prostaglandin I2, but not of lactate dehydrogenase, into the recirculating medium, as well as a dose-dependent liberation of the prostanoids into the bronchoalveolar space. These events were paralleled by a dose-dependent pulmonary hypertension, and studies with different inhibitors collectively indicated that the vasoconstrictor response was mediated predominantly by pulmonary thromboxane generation. In addition, E. coli hemolysin elicited a protracted, dose-dependent increase in the lung capillary filtration coefficient, which was independent of the prostanoid-mediated pressor response and resulted in severe pulmonary edema formation. We conclude that E. coli hemolysin can elicit thromboxane-mediated pulmonary hypertension combined with severe vascular leakage in isolated lungs in the absence of circulating inflammatory cells and humoral mediator systems, mimicking the key events in the development of acute respiratory failure in states of septicemia.

Animals↗
PubMed1989

Role of Ca2+ and Mg2+ for endothelial permeability of water and albumin in vitro.

The permeability of endothelial monolayers grown on a polycarbonate filter membrane and continuously exposed to a hydrostatic pressure of 10 cm H2O was studied. The ionophores A23187 and ionomycin dose dependently (0.1-10 microM) enhanced the hydraulic conductivity of sealed endothelial cell monolayers 10 to 15-fold, at the same time the reflection coefficient of albumin dropped from 0.75 to 0.2. The effects of A23187 were dependent on extracellular Ca2+. In the absence of Ca2+, however, Mg2+ could substitute for Ca2+. Phase contrast- and scanning electron-microscopy showed that the A23187-induced effects were accompanied by gap-formation in the intercellular clefts. These gaps probably are the sites which allowed enhanced fluid exchange. Ionophore-induced effects on permeability could be modified by antagonists of calmodulin function and of arachidonate liberation and metabolism. The data suggest that alterations of endothelial Ca2+-homeostasis induce metabolic events which result in an increased permeability of an endothelial monolayer.

Albumins↗