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Biomedical subjects

H Neuhof

Publications and source records attributed to H Neuhof.

At least 55 records · Page 3Linked to original sources
PubMed1987

Effects of aprotinin on hemostatic mechanisms during cardiopulmonary bypass.

Cardiopulmonary bypass (CPB) is associated with activation of humoral systems, which results in the release of proteases. These proteases may affect platelets and stimulate granulocytes. In the present study, the protease inhibitor aprotinin was given in high doses to 11 patients to achieve plasma concentrations of more than 150 kallikrein inactivator units per milliliter during CPB. At such concentrations, kallikrein and plasmin are effectively inhibited. This treatment resulted in platelet preservation during CPB. Platelet numbers were virtually unaffected, and thromboxane release was prevented in the aprotinin-treated group in contrast to the control group. Postoperatively, hemostasis was significantly better preserved after aprotinin treatment (blood loss of 357 ml in the treated group versus 674 ml in the untreated group; p less than 0.01). Since tissue-plasminogen activator activity was similar in both groups, the improved hemostasis most likely should be attributed to platelet preservation. Furthermore, aprotinin lessened neutrophilic elastase release, which might contribute to decreased pulmonary dysfunction in patients at risk.

Aprotinin↗
PubMed1987

Endotoxin alters arachidonate metabolism in pulmonary endothelial cells.

Endotoxin and lipid A dose dependently (1 ng/ml to 10 micrograms/ml) and time dependently (6-24 h) stimulated the generation of large amounts of prostacyclin in cultured pig pulmonary artery endothelial cells. This effect occurred in the absence of cell detachment and overt cell damage. The presence of at least 1% serum was required but the activation of the complement cascade was not. Endotoxin-treated endothelial cells generated increased amounts of prostacyclin upon stimulation with A23187 and arachidonic acid. Endotoxin-induced activation of arachidonate metabolism could be reduced by 10(-10) M glucocorticoids but not by progesterone. It was further affected by inhibitors of protein and RNA synthesis and calmodulin function. In addition, exposure of endothelial cells to endotoxin resulted in an enhanced synthesis of cyclooxygenase and in a higher enzymatic capacity of prostacyclin synthase. The data indicate that endotoxin in concentrations occurring in the plasma of patients profoundly alters arachidonic acid metabolism in endothelial cells.

Animals↗
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

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

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↗
PubMed1985

Alteration of surfactant function due to protein leakage: special interaction with fibrin monomer.

In isolated rabbit lungs standardized amounts of edema were induced. Stimulation with the Ca ionophore A23187, leukotriene C4, Pseudomonas aeruginosa cytotoxin and human serum (activated complement) all resulted in protein leakage into the alveolar space with no change in the total phospholipid content. The pressure-volume characteristics of the lungs and the characteristics of the lavage surfactant (Wilhelmy balance) were markedly altered, correlating to the lavage protein content. The surfactant alterations were reproduced by addition of perfusion fluid protein to control surfactant in vitro. All changes were far less expressed or even missing in isolated lungs developing the same amount of edema due to omittance of proteins from the perfusion liquid. Different proteins added to control surfactant in the Wilhelmy balance showed a marked rank order of potency in interfering with surfactant function: immunoglobulins G and M and elastin less than albumin less than fibrinogen less than fibrin monomers. The fibrin monomer effect was reproduced by addition of thrombin to a surfactant fibrinogen mixture and was partly reversed by subsequent incubation with plasmin. In conclusion, high-permeability edema induced by different means results in alterations of lung mechanics and surface activity of lavaged surfactant, presumably due to protein surfactant interaction. Among different proteins, fibrin monomers are especially effective in interfering with surfactant function.

Animals↗
PubMed1985

Activation of granular cells during extracorporeal circulation--comparison between bubble-, membrane and hollowfiber oxygenators.

Summarizing our data we can say, that some hematologic disorders during extracorporeal circulation can be diminished by the use of new oxygenator types like the membrane and the Hollowfiber oxygenator. This correlates to the results of other research teams. In contrast to that the activation of the complement cascade is caused by the three systems in a similar way. Although we know, that the activation of the complement systems is only one of numerous reasons for postoperative pulmonary complications, we still must regard this as an important factor, so that the aim of further investigations should be to reduce complement activation during long term ECC.

Adult↗
PubMed1983

Alteration of pressure-volume characteristics due to different types of edema induction in isolated rabbit lungs.

In a model of isolated, ventilated and perfused rabbit lungs the influence of a fixed amount of edema (standardized at 7 g weight gain/kg body weight) on the pressure-volume characteristics of the isolated lungs was investigated. Periodical stimulation with A 23187 or A 23187 plus indomethacin or A 23187 plus indomethacin plus glutathione evokes an increase in vascular permeability with subsequent severe alterations of the pressure-volume characteristics, reflecting a disturbance in the alveolar surfactant system, which is more extensive the more rapidly the edema develops. The alterations caused this way are markedly more severe than those caused by the same amount of weight gain due to mechanically increased capillary filtration pressure.

Animals↗
PubMed1983

Influence of aprotinin and gabexate mesilate on arachidonic acid release by the Ca-ionophore A 23187 in the lung.

In a model of isolated, ventilated rabbit lungs, perfused with Krebs-Henseleit albumin buffer in a recirculating system, increased availability of free AA (arachidonic acid) results in an increase in pulmonary vascular resistance and permeability. The former can be ascribed to cyclooxygenase products of AA, among which thromboxane A2 is mainly responsible. The increase of vascular permeability is, at least partly, due to lipoxygenase products of AA. Availability of free AA for the different oxygenation pathways can be achieved either by direct application of free AA to the perfusion fluid or by stimulation of AA release from the membrane phospholipid pool by the Ca-ionophore A 23187. The serine proteinase inhibitor gebaxate mesilate in a concentration range between 1 microM and 10 microM and aprotinin in a concentration range between 8 and 200 KIE/ml dose-dependently reduce the increase in vascular resistance after stimulation with A 23187. Correspondingly the increase in vascular permeability due to A 23187 is significantly reduced by gabexate mesilate (5 microM) to 52% and by aprotinin (200 KIE/ml) to 73%. On the contrary the increase in pulmonary vascular resistance and permeability after direct application of free AA to the perfusion fluid is not affected by gabexate mesilate and aprotinin. AA metabolism by cyclooxygenase from ram vesicular gland microsomes is inhibited in vitro by gabexate mesilate and by aprotinin only in very high concentrations (greater than 1mM respectively greater than 2130 KIE/ml). Measurements with porcine pancreas and bee venom phospholipase A2 reveal no influence of aprotinin on these enzymes. Gabexate mesilate inhibits pancreas phospholipase A2 in concentrations more than 10-fold higher than those necessary in the isolated lungs (IC50 = 430 microM), bee venom phospholipase A2 not being affected at all. It is thus apparent that the release of AA from the membrane phospholipid pool rather than any particular step in its oxygenation metabolism is the site of action of these proteinase inhibitors in the pulmonary vascular bed. The possible involvement of an intracellular proteinase is discussed.

Animals↗