Leukotriene antagonists prevent endotoxin lethality.
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Animals↗
Biomedical subjects
W Hagmann
Publications and source records attributed to W Hagmann.
Cell adhesion-dependent differences in endogenous protein phosphorylation on the surface of various cell lines.
Endogenous phosphorylation of intact cells was studied with four mouse, hamster and human cell lines using [gamma-32P]ATP and [gamma-32P]GTP as exogenous substrates. With all four cell lines distinct differences in the phosphoprotein patterns could be demonstrated for cells grown in suspension culture compared to cells grown in monolayers. Two major, apparently ubiquitous phosphoproteins with molecular weights of 135 000 (128 000 in HeLa cells) and 105 000, representing up to 60% of total phosphorylation, were phosphorylated only in cells grown in suspension. These phosphoproteins and the kinase(s) were located on the surface of the suspension cells. Evidence showed that phosphorylation was apparently not a true endogenous reaction, that rather it occurred by cell-cell collision, showing exponentially increasing 32P incorporation with increasing cell population density. Phosphorylation of pp135 and pp105 was established with ATP as well as with GTP and was not dependent on cyclic nucleotides cyclic AMP, cyclic GMP and cyclic CMP. The substrate-attached cells of all four cell lines have protein kinases on the cell surface. The lack of pp135 and pp105 phosphorylation may be due to the fact that these phosphoproteins are not expressed at all on the surface of substrate-attached cells or that these phosphoproteins are already fully phosphorylated.
Adenosine Triphosphate↗
[The effectiveness of various micropore blood filters (author's transl)].
Recently so-called micropore blood transfusion filters have been introduced. They should decrease the number of microemboli produced by blood transfusion and thus decrease the incidence of postoperative and posttraumatic pulmonary insufficiency. Since these filters are rather expensive and several types and models are offered, it seemed to us important to review their properties and the results obtained with the most commonly used models (Pall, fenwal, Swank and Bentley). The efficacy of the various filters is apparently quite different. Depending on the indication, the use of different filters is possible. There is no filter which fulfils all prerequisites which must be made for an ideal micropore filter. On the basis of our literature review we conclude that filters made of Dacron wool are best suited for all purposes. There are no good reasons to use these micropore filters routinely for all blood transfusions. However, when large amounts of blood must be given rapidly and pulmonary function is already reduced, the use of micropore filters routinely for all blood transfusions. However, when large amounts of blood must be given rapidly and pulmonary function is already reduced, the use of micropore filters seems reasonable.
Blood↗
[Is there an indication for the use of "micropore-blood filters"? (AUTHOR'S TRANSL)].
Recently "micropore" blood transfusion sets have been advocated to replace the traditional transfusion sets. Because of the higher cost it is important to review critically the data which would justify their clinical use. The filters eliminate microaggregates as they occur during blood storage. The question is wether micropore filters are able to reduce the incidence of posttraumatic or postoperative respiratory insufficiency. We have analysed all controlled in vivo studies. We found only one clinical study where in massively transfused polytrauma patients a decrease in the number of cases of respiratory insufficiency was documented. However, due to the small number of patients investigated, a significant difference in favour of the micropore filters could not be demonstrated. Animal experiments reveal more: Exchange transfusions carried out in dogs through micropore filters do not lead to functional or morphological pulmonary changes. Using traditional transfusion sets, a significant increase in pulmonary artery pressure and resistance was found together with a decrease in arterial pO2, pH and oxygen consumption. All these results correlate well with morphological changes in the lung. On the basis of our literature review, we conclude that there are no clear data which would make it mandatory to use micropore filters in clinical practice. On the other hand, there are several indirect hints than large amounts of microaggregates are not ideal for pulmonary function. The expensive micropore filters could therefore perhaps be used with advantage in massive tranfusions.
Animals↗
The relation of leukotrienes to liver injury.
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Animals↗
Leukotrienes as mediators in frog virus 3-induced hepatitis in rats.
The role of leukotrienes was investigated in frog virus 3-induced hepatitis in rats. Frog virus 3 elicited an enhanced generation of cysteinyl leukotrienes in vivo as monitored by measurement of N-acetyl-leukotriene E4 as the major endogenous metabolite of cysteinyl leukotrienes secreted into rat bile. N-Acetyl-leukotriene E4 concentrations were elevated for more than 4 hr after frog virus 3 injection. In vitro experiments using cultured rat liver Kupffer cells of high purity indicated that these cells can produce and metabolize leukotrienes and are thus a possible source of leukotrienes elicited in vivo by frog virus 3. The selective 5-lipoxygenase inhibitor AA 861 and the dual inhibitor of arachidonate lipoxygenase and cyclooxygenase, BW 755C, reduced the hepatocellular injury after a high dose of frog virus 3 by about 50 and 80%, respectively, as judged from plasma activities of ALT and sorbitol dehydrogenase at 24 hr after frog virus 3 administration. Our in vivo and in vitro studies argue in favor of an important role of leukotrienes as mediators in frog virus 3 hepatitis in rats.
4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
Role of leukotrienes in endotoxin action in vivo.
The cysteinyl leukotrienes LTC4, LTD4, and LTE4 play an important role within the network of mediators of endotoxin shock since they are capable of eliciting the generation of other lipid mediators of shock. Three lines of evidence support the conclusion that the cysteinyl leukotrienes are involved in the lethal shock-inducing action of endotoxin. (1) Endotoxin elicits the systemic production of cysteinyl leukotrienes in vivo. (2) Injection of these leukotrienes into sensitive species causes shock-like reactions, myocardial depression, and extravasation of plasma. (3) Cysteinyl leukotriene receptor antagonists and inhibitors of leukotriene synthesis prevent experimental endotoxin shock. Moreover, endotoxin induces a strong inhibition of the hepatobiliary elimination of cysteinyl leukotrienes, which normally represents the major pathway for deactivation of these mediators. This dual action of endotoxin, comprising enhanced synthesis and simultaneously impaired deactivation of potent mediators, points to a novel type of toxin action. The role of cysteinyl leukotrienes in endotoxin action does not exclude the involvement of additional shock-inducing factors released by endotoxin and their possible contribution to the formation of lipid mediators, including leukotrienes.
Animals↗
Human mast cells secreting leukotriene C4 express the MRP1 gene-encoded conjugate export pump.
Mast cells are known to secrete endogenously synthesized leukotriene C4 (LTC4), but the identity of the responsible export pump in human mast cells was unknown. The multidrug resistance proteins MRP1 and MRP2 have been identified as primary-active ATP-dependent export pumps for various amphiphilic anions including the glutathione conjugate LTC4. We therefore studied the expression at the RNAand protein levels of both MRP1 and MRP2 as well as the ATP-dependent LTC4 transport in the human mast cell line HMC-1. Upon stimulation by 1 microM ionomycin, intact HMC-1 cells generated 26 pmol LTC4/10(8) cells within 20 min. Transport experiments using inside-out HMC-1 membrane vesicles demonstrated an ATP-dependent LTC4 transport amounting to 1.4 pmol x (mg protein)(-1) x min(-1). Reverse transcription PCR indicated that HMC-1 cells express mRNA of MRP1, but not of MRP2 or MRP3. Cloning and sequencing of the amplified PCR fragment confirmed its identity with the human MRP1 sequence. Immunoblots using antibodies against MRP1 and MRP2 demonstrated that HMC-1 cells contain the MRP1 but not the MRP2 protein. Our results indicate that the 190 kDa integral membrane glycoprotein MRP1 mediates the ATP-dependent export of LTC4 from human mast cells to the extracellular space.
Adenosine Triphosphate↗
[Synovial level of interleukin 1 and C3a in chronic polyarthritis, psoriatic arthritis and activated arthritis].
Concentrations of interleukin-1 (IL-1), C3a des Arg and immune complexes (IC) were investigated in knee effusions of patients with rheumatoid arthritis (RA; n = 36), psoriatic arthritis (Ps.A., n = 19) and osteoarthritis (n = 7). Maximal concentrations of IC and C3a des Arg were found in RA patients, high IL-1-activities could be demonstrated in patients with Ps.A. and seropositive RA. We found significant correlations between IL-1 and C3a des Arg, IL-1 and IC and C3a des Arg, and IC in Ps.A. patients, but not in RA or osteoarthritis patients. The role of IL-1 in the chronic inflammatory response and joint destruction in inflammatory joint diseases is discussed.
Adult↗
[Pneumonia in cyclosporin A-treated chronic polyarthritis (a case report)].
A 71 year old patient with seropositive rheumatoid arthritis developed rapidly progressive pneumonitis with bilateral pulmonary infiltrations and severe hypoxemia. At this time the patient was treated with cyclosporin A, indomethacin, chlorthalidone, amitriptyline and chlordiazepoxide. After these medicaments were discontinued and prednisone therapy was initiated a rapid remission of the pneumopathy was observed. It is probable that the reversible pneumopathy was induced by the treatment with cyclosporin A. Among the other medicaments which were stopped at the same time as cyclosporin A no comparable side effects are known.
Aged↗
Aminoterminal propeptide of type III procollagen: a marker of hepatic fibrosis after bile duct obstruction in the monkey.
BACKGROUND/AIMS: In an experimental study in monkeys, liver fibrosis development after segmental bile duct obstruction was investigated and correlated with the aminoterminal propeptide of type III procollagen (PIIINP). MATERIALS AND METHODS: Segmental bile duct obstruction was produced by ligation and section of the left hepatic bile duct in all monkeys. Fibrosis induction was examined by intravenous leukotriene C4 (LTC4, 5 nmol/kg) application, endogenous LT-production stimulated by endotoxin (LPS,salmonella abortus equi, 50 ng/kg), fibrosis inhibition by dexamethasone (1 mg/kg) intramuscularly and subsequent endogenous LT-production stimulation by LPS (50 ng/kg). Ligated and unligated liver lobe biopsies were taken 3, 7 and 12 weeks after ligation. All portal areas were measured morphometrically. PIIINP was measured by a specific radioimmunoassay each week and correlated with the morphometric results. RESULTS: Bile duct obstruction leads to secondary sclerosing cholangitis with bile duct vanishing and subsequent biliary cirrhosis combined with perivenous sclerosis and cavernous transformation of the terminal vein. The collagen concentration increased in the nonligated lobe from mean +/-SEM 1.05 +/- 0.03% to 1.53 +/- 0.19% only after LTC4 and with no difference in the other groups. In the ligated lobe collagen concentration increased significantly in all groups continuously from 1.05 +/- 0.03% up to: controls 6.1 +/- 0.9%, dexamethasone 5.9 +/- 0.8%, LPS 8.2 +/- 0.8%, LTC4 9.075 +/- 1.4%. PIIINP concentration rose within 6 weeks in the controls with hepatic bile duct obstruction from 34.43 +/- 15 ng/ml up to 57 +/- 13.27 ng/ml, after dexamethasone to 48.5 +/- 18.23 ng/ml, after LPS to 57 +/- 13.27 ng/ml, after LTC4 to 80.25 +/- 16.04 ng/ml. After 12 weeks, PIIINP decreased in the controls resp. after dexamethasone to 41.25 +/- 6.94 ng/ml resp. 33.5 +/- 7.72 ng/ml and increased after LPS resp. LTC4 up to 64.25 +/- 17.07 ng/ml resp.104 +/- 22.46 ng/ ml. The correlation of collagen deposition and PIIINP was in the controls r = 0.83, after dexamethasone r = 0.71, after LPS r = 0.83 after LTC4 r = 0.91. CONCLUSION: PIIINP determination after segmental bile duct obstruction correlates with collagen deposition and allows evaluation of hepatic fibrosis activity.
Animals↗