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Biomedical subjects

W Seeger

Publications and source records attributed to W Seeger.

At least 325 records · Page 18Linked to original sources
PubMed1987

Mechanism of leukotriene generation in polymorphonuclear leukocytes by staphylococcal alpha-toxin.

The effects of staphylococcal alpha-toxin on arachidonic acid metabolism in rabbit polymorphonuclear leukocytes (PMNs) were investigated and compared with those of the ionophore A23187 and the chemotactic tripeptide formylmethionyl-leucyl-phenylalanine (fMLP). Sublytic amounts of alpha-toxin stimulated the release of leukotriene B4 (LTB4) in PMNs in a dose-dependent manner. The toxin was several times more potent than fMLP but was not as effective as the ionophore. Preincubation of the toxin with neutralizing antibodies abolished the effect. Extracellular calcium was strictly required for eliciting LTB4 generation. Verapamil, a calcium channel blocker, inhibited fMLP-mediated LTB4 generation but had no effect on alpha-toxin- or A23187-exposed PMNs. Agents such as trifluoperazine and N-6(aminohexyl)-5-chloro-1-naphthalene sulfonamid that interfered with calmodulin activity, however, inhibited LTB4 generation in all cases. One minute after the addition of alpha-toxin, PMNs exhibited a severalfold enhancement in passive permeability to 45Ca2+. In addition, these cells became permeable to sucrose but not to inulin or dextran. The influx pattern was consistent with the previous observation that alpha-toxin creates discrete transmembrane channels in erythrocytes with an effective internal diameter of 2 to 3 nm. The results suggest that alpha-toxin triggers the arachidonic acid pathway in PMNs by facilitating calcium influx into the cells, possibly via transmembrane toxin pores that serve as calcium gates. Generation of arachidonic acid metabolites in PMNs by sublytic amounts of alpha-toxin may represent an important cellular reaction that generally occurs during infections with Staphylococcus aureus.

Animals↗
PubMed1987

Complement complex C5b-8 induces PGI2 formation in cultured endothelial cells.

The effects of the terminal complement sequence on prostacyclin (PGI2) generation in antibody-sensitized pulmonary arterial endothelial cells were examined. Whereas C5b-7 complement complexes induced no PGI2 formation, addition of purified complement component C8 resulted in a time- and dose-dependent burst of PGI2 release in the absence of overt cell damage. Formation of the complete terminal complement complex C5b-9 enhanced PGI2 release but was accompanied by cytolysis. Extracellular Ca2+ was required for C5b-8-dependent PGI2 formation. Three different blockers of physiological calcium channels failed to suppress the observed stimulatory effect. In contrast, W7 [N-(6-amino-hexyl)-5-chloro-1-naphthalene sulfonamide] and trifluoperazine, inhibitors of calmodulin activity, all reduced the C5b-8-dependent PGI2 generation. None of the inhibitors used impaired Ca2+ flux into the cells. One minute after addition of C8 to endothelial cells carrying C5b-7 complexes, a six- to seven-fold enhanced passive influx of 45Ca2+ into the cells was noted. An enhanced passive influx was also observed for 51Cr O4(2-), [3H] aminobutyric acid, and [3H]sucrose, but not for [3H]inulin and [3H]dextran. These data together suggest that complement C5b-8 complexes may serve as Ca2+ bypass gates in endothelial cells, the ensuing influx of Ca2+ leading to subsequent activation of the arachidonic acid pathway.

Animals↗
PubMed1987

Management of ureteropelvic junction obstruction using a microsurgical technique.

The use of microsurgery in the treatment of 20 patients with ureteropelvic junction obstruction is described. The Culp-DeWeerd vertical flap pyeloplasty and the dismembered Anderson-Hynes technique were modified by means of microsurgical instruments, optical magnification and fine absorbable polyglactine sutures, described in detail and used in 11 and 8 cases, respectively. In a further patient a similar modified Kucera pyeloplasty was performed. The advantages of the application of microsurgical technique in reconstructive surgery of the renal pelvis and the ureter are the following: no routine use of urinary diversion; shorter hospitalization time; higher success rate, and a cost-saving therapy.

Adolescent↗
PubMed1987

Arachidonic acid lipoxygenase pathways and increased vascular permeability in isolated rabbit lungs.

Products of arachidonic acid (AA) pathways have repeatedly been implicated in acute lung vascular injury with respiratory distress. In blood-free perfused isolated rabbit lungs, AA endogenously released or exogenously applied causes an acute pressor response, mediated by metabolites of the cyclooxygenase pathway including thromboxane A2. Moreover, bolus application of AA (final concentration, 100 microM in the recirculating buffer) during an acute hydrostatic challenge was recently noted to cause a rapid, severalfold increase in the capillary filtration coefficient (Kf,c), though any significant rise in pulmonary vascular pressure was inhibited by indomethacin. In the present study, we showed that during this mode of AA bolus application in cell-free perfused rabbit lungs, microgram amounts of peptidoleukotrienes (LTE4 greater than LTC4 greater than LTD4) and LTB4 were released into the recirculating buffer within 5 min and continued to be released even after 2 exchanges of the perfusion fluid. In the presence of 2 structurally unrelated lipoxygenase inhibitors (nordihydroguaiaretic acid and AA-861), the leukotriene release was nearly completely inhibited and the AA-induced severe increase in vascular permeability was significantly reduced (2.5- to 3-fold rise in Kf,c, compared to a greater than 10-fold increase in Kf,c in the absence of lipoxygenase inhibition). Exogenous LTC4 caused a dose-dependent, sustained pressure rise in protein-free perfused lungs, apparently mediated via the pulmonary generation of AA cyclooxygenase products. Bolus application of 10 micrograms LTC4 or LTD4 or 7.5 micrograms LTB4 in protein-free perfused lungs during an acute hydrostatic challenge did not, however, mimic the AA bolus-induced severalfold increase in vascular permeability.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Differential influence of calcium channel-blockers on prostanoid generation and thromboxane-mediated vasoconstriction in rabbit lungs.

In blood-free perfused and ventilated rabbit lungs, the influence of calcium channel-blockers on pulmonary prostanoid generation and thromboxane-mediated vasoconstriction was investigated. The specific pathways of arachidonic acid (AA) metabolism were stimulated by repetitive pulmonary artery injection of the calcium-ionophore A 23187, which induces the liberation of endogenous AA, or by repetitive application of exogenous AA. In control lungs, both stimuli provoked reproducible phasic vascular pressor responses, accompanied by the release of thromboxane A2 and prostaglandin I2 into the perfusion fluid. Repeated stimulus application in the presence of increasing concentrations of different calcium antagonists showed a dose-dependent inhibition of the pressor responses by all agents. The rank order of potency was nimodipin greater than LU-40883 (verapamil derivative) greater than diltiazem and D-888 (verapamil derivative) greater than verapamil for the ionophore-induced pressure increase, whereas diltiazem was nearly ineffective in the presence of exogenously applied AA. The prostanoid release after application of A 23187 was influenced differentially by the calcium channel-blockers. It was not affected by nimodipin and verapamil, it was slightly depressed by the verapamil derivatives D-888 and LU-40883 and it was dose-dependently and in higher concentrations nearly inhibited completely by diltiazem. We conclude that the thromboxane-mediated pulmonary vasoconstriction is inhibited by different-type calcium channel-blockers with a marked rank order of potency. The prostanoid generation induced by stimulation of the lung vascular AA metabolism is influenced differentially by these agents.

Animals↗
PubMed1987

Activation of the pulmonary arachidonic acid system and its consequences for hemodynamics and fluid balance.

The pulmonary vasculature and perivascular tissue is able to generate arachidonic acid metabolites with strong effects on vascular tone and permeability. Stimulators of the pulmonary arachidonic acid metabolism, which represents a highly potent mediator system, are components of the classical cascade systems, bacterial toxins, hypoxia, and a variety of other physiological and non-physiological factors. Upon excessive stimulation, the pulmonary circulation responds with vasoconstriction and extravasation. Since granulocytes are always involved, their contribution to the resulting vascular effects has to be considered.

Animals↗
PubMed1986

Fibronectin decreases pulmonary vascular permeability under baseline conditions and after administration of arachidonic acid in rabbit lungs.

In blood- and plasma-free perfused isolated rabbit lungs, the influence of albumin and soluble fibronectin on vascular permeability was investigated. The lungs were perfused with Krebs Henseleit buffer containing no protein (KHB), containing 1 g/100 ml bovine albumin (KHAB) or containing albumin together with 100 micrograms/ml soluble fibronectin. The absence or presence of albumin had no influence on the perfusion pressure, the vascular compliance and the capillary filtration coefficient (CFC), determined by zero time extrapolation of the slope of weight gain which was induced by a sudden venous pressure elevation. Fibronectin caused a slight increase in pulmonary artery pressure, a slight decrease in vascular compliance and an approximately 50% reduction of CFC. In a second set of experiments, KHAB-perfused lungs were stimulated by the administration of 100 microM arachidonic acid (AA) during the second hydrostatic challenge within a sequence of three venous pressure elevations. In the presence of indomethacin, which blocks any significant increase in pulmonary vascular pressure after AA application, this procedure caused an immediate gain in lung weight due to increased pulmonary vascular permeability, with greater than 10-fold increased CFC values subsequent to the AA application. In the presence of 100 micrograms/ml fibronectin, this AA-induced increase in CFC was mitigated to less than 20% of the controls without the glycoprotein, with correspondingly severalfold reduced lung weight gain. In conclusion, the present study provides evidence for a direct influence of circulating soluble fibronectin on lung microvascular integrity and fluid balance under baseline conditions and after stimulation of the pulmonary AA cascade.

Animals↗
PubMed1986

Noncytolytic terminal complement complexes may serve as calcium gates to elicit leukotriene B4 generation in human polymorphonuclear leukocytes.

Complement effects on human polymorphonuclear leukocytes (PMN) have generally been ascribed to the anaphylatoxin C5a, which induces degranulation, superoxide anion generation, migration, and cell aggregation via interaction with membrane receptors. We here report that complement activation on the surface of antibody-sensitized human PMN provokes generation of the potent lipid mediator leukotriene B4 (LTB4) in strict dependence on complement component C8, but in the absence of detectable C9. The kinetics of LT generation are rapid, comparable with those observed after challenge with the calcium-ionophore A23187. LTB4 release is a distinct event that is dissociable from cytotoxicity as assessed by lactate dehydrogenase (LDH) release (dependent on C9) and from superoxide generation (independent of C8 and C9). It is dose dependent on extracellular calcium and is not observed in the absence of calcium. It is inhibited by substances interfering with calcium-calmodulin function (trifluoperazine and W7), but not by blockers of physiologic calcium channels (nimodipine, verapamil, and D 888). Addition of purified C8 to cells bearing C5b-7 induces a severalfold increase in their passive permeability to 45calcium. Sieving experiments with the use of marker molecules of different sizes collectively indicate the existence of small hydrophilic channels consisting exclusively or predominantly of C5b-8 complexes, which allow passive transmembrane flux of small molecules with Mr less than 200. Thus, noncytolytic terminal complement complexes may serve as a biological bypass gate for calcium in PMN membranes, triggering the arachidonic acid cascade with generation of LTB4 at doses well below the threshold required to invoke overt cell damage.

Calcium↗
PubMed1986

Release of leukotrienes into the perfusate of calcium-ionophore stimulated rabbit lungs. Influence of 5-lipoxygenase inhibitors.

UNLABELLED: Arachidonic acid and the calcium ionophore A23187 are known to provoke a pulmonary artery pressor response, edema formation and release of thromboxane B2 (TxB2) and 6-keto prostaglandin-F1 alpha (6-keto PGFl alpha) into the recirculating perfusion fluid of isolated blood-free perfused rabbit lungs. Here we investigated the release of leukotrienes (LTs) by repetitive 0.1 microM A23187 challenge in the presence or absence of cyclooxygenase and 5-lipoxygenase inhibitors. RP-HPLC analysis of perfusion fluid extracts persistently showed peaks with retention times of authentic LTC4, -D4, -E4 and -B4. Fractionated RP-HPLC eluate subjected to radioimmunoassay (RIA) with LTC4 and LTB4 antibodies showed two major peaks of immunoreactivity corresponding to those compounds and minor immunoreactivity with LTD4 and LTE4 in accordance with the stated cross-reactivities of the LTC4 antibody. Good correlation for both LTB4 and LTC4 levels measured by RP-HPLC versus RIA of collected HPLC peaks was found. Five to ten min after A23187 challenge, LTC4, -D4 and -B4 levels ranged from 800 to 1600 pg/ml perfusate. LTC4 reached a maximum level at 20 min whereas LTB4 slightly increased over a 35 min period. Upon repeated A23187 challenge, interrupted by rinsing phases with fresh perfusion fluid, the LT release was reproducible several times with increasing reaction strength. This performed in presence of increasing concentration of the 5-lipoxygenase inhibitors AA-861 or U-60,257 caused a dose-dependent inhibition of the release of all LTs with an IC50 of approximately 10(-8) to 10(-7) M and 10(-6) M, respectively. Cyclooxygenase inhibition with acetylsalicylic acid at doses completely suppressing the A23187 induced pressor response did not inhibit the peptidoleukotriene release and only slightly depressed LTB4 release. CONCLUSION: using a rapid and sensitive extraction and RP-HPLC method isolated lungs are found to release nanomolar amounts of LTs into the perfusate upon repetitive A23187 challenge, suppressed by 5-lipoxygenase inhibition.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Generation of mediators by limited proteolysis during blood coagulation and fibrinolysis--its pathogenetic role in the adult respiratory distress syndrome (ARDS).

Products of blood coagulation and fibrinolysis, which are generated by limited proteolysis are able to effect the pulmonary circulation and gas exchange by biochemically mediated actions. Thrombin, fibrin and its degradation products provoke functional and morphological changes in the vessel wall. Fibrinopeptides, fibrin monomers and fibrin (ogen) degradation products induce vasoconstriction and vascular leakage. The vasoconstricting action of fibrin monomers is mediated by thromboxane A2 (TXA2) which is synthetized in the lung tissue itself. Thromboxane synthesis is stimulated by fibrin monomers only in the pulmonary circulation and not in the systemic circulation. Besides their vascular effects, fibrin monomers disturb the function of the surfactant components and increase the surface tension in surfactant monolayers. Proteinase inhibition as a general prophylactic and therapeutic concept with adult respiratory distress syndrome (ARDS) has to include the system of blood coagulation and fibrinolysis predominantly to prevent or stop the generation of products which are able to induce pulmonary vasoconstriction, vascular leakage and impairment of pulmonary gas exchange.

Animals↗
PubMed1986

Asymptomatic pulmonary embolism following pacemaker implantation.

The aim of this prospective study was to investigate the incidence of pulmonary embolism after pacemaker implantation, and to assess the benefits, if any, of postoperative prophylactic heparin therapy. Twenty of 40 patients were given low-dose heparin therapy; the remaining 20 patients were the control group and were not treated. Assignment to one of these groups was made alternately, in chronological order according to the time of implantation. Only tined leads with silicone insulation were used. All patients were mobilized on their first postoperative day. Pulmonary scintigraphy was performed before implantation, two weeks after implantation and again 12 months later. A pulmonary embolism was defined as evidence of new perfusion defects after implantation. There were no such defects in the group treated with heparin; the control group (20 patients) had three cases of perfusion defects within a 14-day postoperative period. Twelve months later, no further perfusion defects were observed in any patient. Thus, our study revealed a 15% incidence of asymptomatic pulmonary embolism following pacemaker implantation in patients not given prophylactic heparin therapy.

Cardiac Pacing, Artificial↗
PubMed1986

Pulmonary microvascular injury induced by Pseudomonas aeruginosa cytotoxin in isolated rabbit lungs.

The effects of Pseudomonas aeruginosa cytotoxin on the pulmonary microvasculature were studied in blood-free, perfused, isolated rabbit lungs. Cytotoxin was administered to the recirculating Krebs Henseleit albumin (1%) buffer during two consecutive 30-min-perfusion phases (phases 1 and 2) at a concentration of 13 micrograms/ml, followed by a third perfusion phase (phase 3) without toxin. After perfusion phases 2 and 3, the capillary filtration coefficient (Kf,c) and vascular compliance were determined gravimetrically from two-step microvascular pressure increments under zero-flow conditions. Cytotoxin caused a continuous release of K+ and lactate dehydrogenase, which started within the first 5 min and amounted to about 50% of the total lung cellular K+ and 5 to 7% of the total lactate dehydrogenase by the end of the experiment. The toxin caused the continuous generation of prostaglandin I2, which was detectable in the perfusates of all perfusion phases at maximum values five times above the control values and which was measured in the bronchoalveolar lavage fluid at the end of the experiment. Thromboxane generation in toxin-treated lungs did not significantly exceed that of control lungs or of lungs with mechanically induced edema. Cytotoxin caused a gradual increase in pulmonary vascular resistance, to maximum values 2.5 times above the control, starting within 1 min; the increase was partially reversible after washout of the toxin. After a lag period of 20 to 30 min, the lungs gained weight, amounting to a mean gain of 9.1 g at the end of the experiments. After perfusion phases 2 and 3, an almost fourfold increase in Kf,c, which was not reversible after washout of the toxin, was measured, whereas the values of vascular compliance were not altered. We conclude that pseudomonal cytotoxin may be an important factor in the pathogenesis of prolonged microvascular injury, encountered in states of P. aeruginosa sepsis or acute lung failure with secondarily acquired P. aeruginosa pneumonia.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Increased lung vascular permeability after arachidonic acid and hydrostatic challenge.

Arachidonic acid (AA) metabolites are known to be potent vasoactive substances in the pulmonary circulation, whereas their influence on lung vascular permeability is still uncertain. We investigated the effect of AA bolus injection on the capillary filtration coefficient (Kf,C) of isolated rabbit lungs, recirculatingly perfused with Krebs-Henseleit albumin (1%) buffer. Kf,C was measured using repetitive sudden venous pressure elevations (7.5 Torr) and time zero extrapolation of the slope of the weight gain curve. It ranged from 1.3 to 2.4 cm3 X s-1 X Torr-1 X g-1 X 10(-4) in control lungs. Pulmonary arterial injection of AA (100 microM; in presence of 20 microM indomethacin to suppress pulmonary arterial pressure rise) during an acute hydrostatic challenge, but not at zero venous pressure, caused a greater than 10-fold increase in Kf,C. Vascular compliance was not altered. Additional experiments, performed under zero-flow conditions to avoid any ambiguity in microvascular pressure, corroborated the severalfold increase in vascular permeability, detectable within 3 min after AA application during acute hydrostatic challenge.

Animals↗
PubMed1986

The glutathione redox cycle as a defense system against hydrogen-peroxide-induced prostanoid formation and vasoconstriction in rabbit lungs.

Leukocyte-derived oxidants have been described as causing vasoconstriction and edema formation in isolated lungs. In the present study, dose-dependent and reversible pressor responses were achieved reproducibly by injection of hydrogen peroxide (H2O2) into the pulmonary artery of blood-free, perfused, isolated rabbit lungs in a dose-dependent manner. The pressor responses were accompanied by an instantaneous release of thromboxane A2 and a more delayed but quantitatively larger release of prostaglandin I2 into the recirculating perfusion fluid. There was no release of potassium or LDH, indicating the absence of overt cell damage. The H2O2-induced pressor responses were blocked by indomethacin (cyclooxygenase inhibitor), imidazole (inhibitor of thromboxane synthetase), mepacrine (phospholipase inhibitor), and W7 and trifluoperazine (agents that interfere with calcium-calmodulin function). Treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) dose-dependently inhibited the lung glutathione reductase activity and augmented the metabolic (prostanoid release) and functional (vasoconstriction) responsiveness of the pulmonary vascular bed to H2O2. Application of 1-(2-chloroethyl)-1-nitrosourea (CCNU), a control to BCNU, and inhibition of catalase activity by aminotriazole did not increase the sensitivity to externally applied H2O2. We conclude that calcium-calmodium function and thromboxane generation may be involved in the pulmonary vasoconstrictive response to H2O2 and that the lung glutathione redox cycle is active in limiting the responsiveness of the pulmonary vascular bed to externally generated H2O2.

Animals↗
PubMed1985

Influence of the thromboxane antagonist BM 13.177 on the arachidonic acid-induced increase in pulmonary vascular resistance and permeability in rabbit lungs.

UNLABELLED: In blood-free perfused isolated rabbit lungs increased availability of free arachidonic acid (AA), whether exogenously applied or released from the endogenous membrane phospholipid pool after different stimuli, causes an acute pulmonary artery pressor response and an increase in vascular permeability. Previous experiments suggested that the vasoconstriction is caused primarily by the cyclooxygenase product thromboxane (Tx) A2, whereas an increase in the capillary filtration coefficient must be ascribed to non-cyclooxygenase products of AA. The influence of BM 13.177, a non-prostanoic antagonist of TxA2- and endoperoxide-effects in platelets, on the AA-induced vascular effects in isolated rabbit lungs was investigated. BM 13.177 dose-dependently inhibited the pressor responses evoked by repetitive direct application of AA (IC50 approximately 10(-6) M) or by repetitive stimulation of endogenous AA-release with the calcium-ionophore A 23187 (IC50 approximately 10(-7) M), with maximum reduction of the pressor responses to less than 15%. The generation of TxA2 and of prostaglandin (PG) I2 evoked by these stimuli was, however, not altered. At a concentration of 10(-5) M BM 13.177 did not influence the capillary filtration coefficient, measured during venous pressure challenge, under baseline conditions and after stimulation with AA in presence of indomethacin. CONCLUSION: BM 13.177 acts as TxA2/endoperoxide antagonist with dose-dependent inhibition of AA-induced vasoconstriction in the pulmonary vascular bed.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Alteration of alveolar surfactant function after exposure to oxidative stress and to oxygenated and native arachidonic acid in vitro.

UNLABELLED: Alveolar surfactant is known to be impaired after inhalation of various oxidizing agents (NO2, ozone) as well as in inflammatory lung processes, in which leucocyte-derived active oxygen species or arachidonic acid oxygenation products may be involved. The effect of lipid peroxidation, oxygen-free radicals and oxygenated versus native arachidonic acid on the surface tension behaviour of natural surfactant was tested in vitro. The studies were performed on pooled surfactant material, obtained from bronchoalveolar lavage of rabbit lungs, in a Langmuir trough/Wilhelmy balance system. Initiation of lipid peroxidation with FeCl3/ascorbate or UV radiation and the generation of OH.(FeCl2/EDTA/H2O2), O2-. (xanthine/xanthine oxidase) and 1O2 (NaOCl/H2O2) provoked a common profile of changes: delayed reduction of surface tension during compression with an increase in minimal compressibility accelerated decrease of film pressure during expansion, reduction of hysteresis area and markedly augmented monolayer collapse rate. Addition of arachidonic acid resulted in decreased minimal compressibility, stability index and hysteresis area. Incubation with the arachidonic acid cyclooxygenase products, prostaglandin E2, I2, F2 alpha or thromboxane B2, with soybean lipoxygenase or with H2O2 and O2-exposure caused only moderate or no alteration of surfactant behaviour in vitro. CONCLUSION: oxidative stress, but not arachidonic acid oxygenation products, provoked altered surface tension behaviour of natural surfactant in vitro.

Arachidonic Acid↗