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PubMedDate not supplied

Pulmonary insufficiency in the rat after intravascular coagulation and inhibition of fibrinolysis. II. Investigations on oedema formation and morphology.

Solute and fluid compartments in the lungs were investigated following thrombin-induced intravascular coagulation in rats treated with the fibrinolysis inhibitor, Trans-4-(amino-methyl) cyclohexanecarboxalic acid. The lung weight was increased to almost three times normal due to accumulation of extravascular water with albumin and chloride concentrations similar to those in plasma. The blood content and dry weight were doubled. Microscopic sections were characterized by widespread fibrin-rich microemboli, thickened alveolar walls, distension of peribronchiolar and perivascular spaces with fluid, dilated lymph vessels and protein-rich alveolar oedema. An increased microvascular permeability to protein explains the findings. When the dose of thrombin was decreased to a point where no pulmonary oedema developed, supplementary infusion of low molecular weight fibrinogen degradation products induced oedema formation as verified microscopically.

Animals↗
PubMed1987

Role of the clotting system in the pathogenesis of neuroimmunologic disease.

Experimental allergic encephalomyelitis (EAE) is a prototypic neuroautoimmune disease involving sensitization to central nervous system myelin basic protein (MBP). Our studies of the clotting system and ensuing fibrinolysis implicate coagulation and cleavage of fibrin within or on the luminal surface of the cerebrovasculature as events initiating the inflammation characterizing EAE. Among recipient rats injected with MPB-primed, cultured-activated lymph node cells, opening of the blood-brain barrier (BBB) and deposition of perivascular fibrin within the spinal cord occur in parallel 1 day before onset of clinical signs of EAE. Daily treatment of recipient rats with trans-4-(aminomethyl)cyclohexanecarboxylic acid, a synthetic product that specifically inhibits plasminogen activator derived from endothelial cells, results in marked reduction of increased permeability of the BBB and suppression of clinical signs of EAE. We postulate that the critical event precipitating EAE is binding of circulating MBP-reactive immune effector cells to MBP immunodeterminants on the surface of cerebrovascular endothelial cells. Coagulation and ensuing fibrinolysis occur at sites of binding of effector cells to cerebrovascular endothelium. Release of biologically active peptides cleaved from fibrin open the BBB, thereby setting the stage for the cascade of inflammatory events culminating in clinical manifestations of EAE.

Animals↗
PubMed1978

Role of fibrinolysis in development of hyaline membrane disease in newborn rabbits.

The role of fibrinolysis in the pathogenesis of hyaline membrane disease was studied in newborn rabbits at 28- or 29-day gestation. Hyaline membrane was recognized in the lungs of rabbits that were exposed to intrauterine hypoxia and received trans-4-aminomethylcyclohexane carboxylic acid (t-AMCHA), a plasmin inhibitor found to cause a marked decrease in the fibrinolytic activity of lung extracts. In the newborn rabbits subjected to intrauterine hypoxia alone, surface activity of lung extracts was reduced, but hyaline membrane was not seen. By immunofluorescent examination the hyaline membrane was found to be rich in fibrinogen and its derivatives. Electron microscopic examination revealed that they contained various amounts of cellular debris, bundles of fibrils and electron-dense, finely granular deposits and polymerized fibrin with 230 A periodicity. Disintegration of pulmonary epithelial cells was also seen. These findings indicate that diminished fibrinolytic activity of lung tissue contributes to intra-alveolar accumulation of fibrinogen, fibrin and their degradation products, thereby bringing about morphological and physiological disintegration of the terminal airways.

Animals↗
PubMed1996

Effect of 1,6-dihydro-2[2-(2-methylpropoxy)anilino]-6-oxo-5-pyrimidineca rboxyli c acid on ethanol-induced microvascular injury in rats.

To disclose the cytoprotective mechanism of 1,6-dihydro-2[2-(2-methyoxypropoxy)anilino]-6-oxo-5-pyrimidinecarb oxylic acid (CAS 98772-05-5, MAR-99), the effect of this compound on the microvascular injury in gastric mucosa induced by 99.5% ethanol in rats was studied. In this experiment, it was found that the elevation of vascular permeability observed at the early state of ethanol-induced gastric mucosal injury was closely correlated with the combined action of histamine and slow reacting substance (leukotriene C4, LTC4). MAR-99 (0.3-10 mg/kg p.o.) prevented dose-dependently the increase in vascular permeability. Furthermore, MAR-99 (10 mg/kg p.o.) improved the decrease in the number of histamine containing cells and histamine content, and prevented the production of LTC4. These results suggest that MAR-99 exerts its anti-microvascular injury effect by regulating the release of histamine and the production of LTC4 in glandular stomach against ethanol, and this effect may contribute to the anti-lesion effect of this compound.

Animals↗
PubMed2002

Successful treatment of acute promyelocytic leukaemia during pregnancy.

A case is reported of a pregnant 16-year-old-woman diagnosed with Acute promyelocytic leukaemia (APL) at 25 weeks gestation and treated with all-trans retinoic acid (ATRA) (45 mg/m2) for 25 days in combination with chemotherapy. She achieved a complete cytogenetic and molecular remission. Clinical course was complicated, with an intracerebral bleed, respiratory failure requiring ventilation and prolonged pancytopenia following initial chemotherapy. A live female infant was born at 28 weeks gestation who survived to discharge with significant pulmonary complications. She remains oxygen dependent at 6 months of age. ATRA has been used from the 3rd week of gestation, but fetal malformations are common during the first trimester. In contrast it seems to be safe in the second and third trimesters with regard to teratogenesis but can cause other side-effects. Most successful outcomes in treatment of APL during pregnancy are seen after treatment with ATRA and delivery of the baby at as late a stage as possible. Pregnancies terminated before remission has been obtained or those treated in the first trimester have a poor maternal outcome.

Adolescent↗
PubMed1986

1H-NMR spectroscopic manifestations of ligand binding to the kringle 4 domain of human plasminogen.

Structural aspects of the binding of the linear ligands N alpha-acetyl-L-lysine (AcLys) and epsilon-aminocaproic acid (epsilon ACA) and of the cyclic analogs trans-(aminomethyl)-cyclohexanecarboxylic acid (AMCHA) and p-benzylaminesulfonic acid (BASA) to the intact plasminogen kringle 4 domain have been investigated by 1H-NMR spectroscopy at 300 and 600 MHz. Ligand binding results in consistent shifts of the His-II (His31), Trp-I (Trp25?), Trp-II (Trp62?), Trp-III (Trp72), Tyr-II (Tyr50), and Phe64 ring signals. BASA tends to induce larger shifts than elicited by the aliphatic ligands, most noticeably on Trp-II and on Trp72, suggesting that the ligand aromatic ring interacts with the two indole groups. Trp-II and, to lesser extent, Trp-I interact with an acidic side chain group, in a manner that is blocked by BASA. BASA binding also perturbs Tyr-II (Tyr50), Tyr-III (Tyr41), and Tyr-IV (Tyr74) over a wide pH range and lowers the pKa* of His31 from approximately 4.8 to approximately 4.6. His-III (His33) responds to BASA and AMCHA but is relatively insensitive to the linear ligands. His33 carries a sterically shielded side chain which, in conjunction with Leu46, Trp-I, Tyr50, and Tyr74, participates in structuring the kringle hydrophobic core, contiguous to the binding site. Pronounced shifts are observed for aliphatic resonances stemming from the kringle-bound molecules of AMCHA, AcLys, and epsilon ACA. It is proposed that the lysine-binding site is mostly supported by the loop that extends from Cys51 through Cys71 and that aromatic residues, which include Trp-II, Trp72, and Phe64, play a major role in interacting with the nonpolar segment of the ligand molecule. The binding site also encompasses Tyr50, Tyr74, His31, and His33 although it is not clear the extent to which these residues interact directly with the ligand.

Benzylamines↗
PubMed1986

Trinitrobenzoylated poly(D-lysine) as a stimulator of interactions between plasminogen, plasmin, and tissue-type plasminogen activator.

Trinitrobenzyl alkylation of poly(D-lysine) provides a novel powerful stimulator of tissue-type plasminogen activator. Its stimulatory effect on plasminogen activation is far greater than that of the original poly(D-lysine), and even surpasses that of fibrin. Its effect on plasmin-catalysed modification of both tissue-type plasminogen activator (t-PA) and native (Glu-1-) plasminogen are also investigated. Cleavage of one-chain t-PA to its two-chain form is monitored by measuring the increase in amidolytic activity which accompanies this transformation. Presupposing apparent first-order reaction kinetics, a theory is developed by which the rate constant, kcat/Km = 1.0 X 10(6) M-1 X s-1 of plasmin cleavage of one-chain t-PA can be calculated. Plasmin-catalysed transformation of 125I-labelled Glu-1- to Lys-77-plasminogen is quantified following separation by polyacrylamide gel electrophoresis at pH 3.2. A rate constant, kcat/Km = 4.4 X 10(3) M-1 X s-1 is obtained for the reaction between plasmin and Glu-1-plasminogen in the presence of 1 mM trans-4-(aminomethyl)cyclohexane-1-carboxylic acid. Both of the above plasmin-catalysed reactions are strongly enhanced by trinitrobenzoylated poly(D-lysine). The mechanism of action of this stimulator is elucidated by studying its binding to both activator and plasmin(ogen), and by direct comparison of the results with measurements of plasminogen activation kinetics in the presence of the stimulator. Binding studies are performed exploiting the observation that an insoluble yellow complex is formed between plasminogen and modified poly(D-lysine). Protein-polymer interactions are also studied with solubilised components in an aqueous two-phase partition system containing dextran and poly(ethylene glycol). The rate enhancement of plasminogen activation is found to be closely correlated to the association of plasminogen to the stimulator. It is proposed that the stimulator effects of this simple polymer on the enzymatic activities of both plasminogen activator and plasmin are brought about by association of the proteinase and its substrate to a common matrix. Similarities between the action of the artificial and the natural stimulator (fibrin) are stressed. These properties of trinitrobenzoylated poly(D-lysine) makes it useful as a model for the study of the regulatory mechanism of the fibrinolytic process at the molecular level.

Alkylation↗
PubMed1999

Demonstration of flow and platelet dependency in a ferric chloride-induced model of thrombosis.

Further to characterize the processes involved in the FeCl3-induced thrombosis model, we determined the effect of aspirin, heparin, hirudin, trans-4-(aminomethyl) cyclohexane carboxylic acid (AMCHA), thrombocytopenia, and flow modifications on time to occlusion (TTO) and thrombus weight (TW) in the rat carotid artery. Aspirin, from 3 to 100 mg/kg, showed no dose-response relation for either TTO or TW and did not significantly affect ex vivo platelet aggregation. Heparin, at doses that significantly increased the activated partial thromboplastin time (APTT), dose-dependently increased the TTO of animals that showed an occlusion during the monitoring period and also reduced the TW. Hirudin required constant infusion to prevent occlusion and reduce the TW, when the APTT was also significantly increased. AMCHA did not affect the TW but reduced the TTO. Animals made thrombocytopenic by the use of antiplatelet serum did not occlude during the monitoring period, and the TW was significantly reduced. Changes in flow showed that the TTO was not affected, but the TW showed an inverse correlation with average flow. The results obtained for platelet depletion and flow modifications expand on previous findings with this model and support the physiological relevance of the model.

Animals↗
PubMed1997

Plasmin is a potent and specific chemoattractant for human peripheral monocytes acting via a cyclic guanosine monophosphate-dependent pathway.

We have previously reported that the serine protease plasmin generated during contact activation of human plasma triggers biosynthesis of leukotrienes (LTs) in human peripheral monocytes (PMs), but not in polymorphonuclear neutrophils (PMNs). We now show that purified plasmin acts as a potent chemoattractant on human monocytes, but not on PMNs. Human plasmin or plasminogen activated with urokinase, but not active site-blocked plasmin or plasminogen, elicited monocyte migration across polycarbonate membranes. Similarly, stimulation of monocytes with plasmin, but not with active site-blocked plasmin or plasminogen, induced actin polymerization. As assessed by checkerboard analysis, the plasmin-mediated monocyte locomotion was a true chemotaxis. The plasmin-induced chemotactic response was inhibited by the lysine analog trans-4-(aminomethyl)cyclohexane-1-carboxylic acid (t-AMCA), which prevents binding of plasmin/ogen to the appropriate membrane binding sites. In addition, active site-blocked plasmin inhibited monocyte migration triggered by active plasmin. Further, plasmin-induced monocyte chemotaxis was inhibited by pertussis toxin (PTX) and 1-O-hexadecyl-2-O-methyl-rac-glycerol (HMG) and chelerythrine, two structurally unrelated inhibitors of protein kinase C (PKC). Plasmin, but not active site-blocked plasmin or plasminogen, triggered formation of cyclic guanosine monophosphate (cGMP) in monocytes. LY83583, an inhibitor of soluble guanylyl cyclase, inhibited both plasmin-induced cGMP formation and the chemotactic response. The latter effect could be antagonized by 8-bromo-cGMP. In addition, KT5823 and (Rp)-8-(p-chlorophenylthio)guanosine-3',5'-cyclic monophosphorothioate [(Rp)-8-pCPT-cGMPs], two structurally unrelated inhibitors of cGMP-dependent protein kinase, inhibited plasmin-mediated monocyte chemotaxis. Thus, beyond being a stimulus for lipid mediator release, plasmin is a potent and specific chemoattractant for human monocytes acting via a cGMP-dependent mechanism. Therefore, plasmin represents a proinflammatory activator for human monocytes.

Alkaloids↗
PubMed1987

Analysis of ligand-binding to the kringle 4 fragment from human plasminogen.

The interaction of the isolated human plasminogen kringle 4 with the four omega-amino acid ligands epsilon-aminocaproic acid (epsilon ACA), N alpha-acetyl-L-lysine (AcLys), trans-aminomethyl(cyclohexane)carboxylic acid (AMCHA) and p-benzylaminesulfonic acid (BASA) has been further characterized by 1H-NMR spectroscopy at 300 and 600 MHz. Pronounced high-field shifts, reaching approximately 3 ppm, are observed for AMCHA resonances upon binding to kringle 4, which underscores the relevance of ligand lipophilic interactions with aromatic side chains at the binding site. Ligand titration curves for the nine His and Trp singlets found in the kringle 4 aromatic spectrum reveal a striking uniformity in the kringle response to the various ligands. The average binding curves exhibit a clear Langmuir absorption isotherm saturation profile and the data were analyzed under the assumption of one (high affinity) binding site per kringle. Equilibrium association constants (Ka) and first order dissociation rate constants (k off) were derived from linearized expressions of the Langmuir isotherm and of the spectral line-shapes, respectively. The results for the four ligands, at approximately 295 K, pH 7.2, indicate that: AMCHA exhibits the strongest binding (Ka = 159 mM-1) and epsilon ACA the weakest (Ka = 21 mM-1) with AcLys and BASA falling in between; epsilon ACA dissociates readily (k off = 5.3 X 10(3) s-1) and AMCHA associates the fastest (k on = 2.0 X 10(8) M-1 s-1) while the kinetics for BASA exchange is relatively slow (k off = 0.8 X 10(3) s-1, k on = 0.6 X 10(8) M-1 s-1); the ligand-binding kinetics is close to diffusion-controlled.

Aminocaproates↗
PubMed1996

Effects of castration on plasminogen activator activities and plasminogen activator inhibitor type 1 in the rat ventral prostate.

The involution of the prostate gland after castration is an active process which requires the induction of new proteins. The plasminogen activator urokinase has been proposed to be a gene repressed by androgen which is activated upon castration and thus participating in the atrophy of the gland. However, urokinase is secreted by the ventral lobe of the rat prostate and this should be positively affected by androgens. The purpose of this study was to examine further the effects of castration upon plasminogen activator (PA) activities in the rat prostate and to determine possible explanations to this apparent dilemma. Castration of young sexually mature adult rats resulted in a substantial increase in PA activities at 4 days after castration in the ventral prostate, but then the activities returned to within the range of untreated animals with a longer duration of castration. Urokinase was the predominant molecular form of PA in the normal ventral prostate and it was the molecular form increased after castration; based upon its sensitivity to amiloride and its molecular size determined in zymograms. In contrast to the effect of castration, there was no increase in PA activities in the ventral prostate with treatment of rats with the antiandrogen flutamide, but rather a decrease when specific activity was expressed per unit DNA. In addition, the effect of castration was specific for the ventral lobe for there was no change in the PA activity in the dorsolateral prostate after androgen ablation. The diminished PA activities in the ventral prostates of rats castrated for 7 days or longer appeared to be due at least in part to an increase in plasminogen activator inhibitor type-1 (PAI-1). Immunoreactive PAI-1 was found predominantly in high molecular weight forms which indicates that the inhibitor was complexed with PA. Daily treatment of rats upon castration with agents known to retard the rate of regression of the involuting prostate gave dichotomous results. Hydrocortisone prevented the increase in PA activity, whereas treatment with actinomycin D, an inhibitor of RNA synthesis, not only did not prevent an increase in PA activity, but actually produced a superinduction in PA activity at 4 days orchiectomy. These data may be interpreted to mean that hydrocortisone stimulated PAI activity and that actinomycin D treatment blocked its induction. However, the actinomycin D data may also indicate that an increase in urokinase protein and mRNA after castration may result from some mechanism to conserve these molecules suggesting that this inhibitor of RNA synthesis prevented the transcription of messages for proteins involved in the degradation of urokinase message.

Amiloride↗
PubMed1987

Acute promyelocytic leukemia. A childhood cluster.

Nine children with acute promyelocytic leukemia (APL) are presented. This series of children represents 7% of all acute leukemias and 21% of acute myelogenous leukemias seen during the same period at the Red Cross War Memorial Children's Hospital. These figures are much higher than the incidence quoted in other series of childhood leukemia. In addition, most of those children came from a confined geographic area. Two of the patients were younger than 2 years of age. The youngest patient with APL previously reported in the literature was 24 months.

Bone Marrow↗
PubMed1995

Methods for cell proliferation analysis by fluorescent image cytometry.

Methods were developed for multimodal microscopic image analysis in order to identify and analyze one cell type under various microscopic conditions. Our purpose was to quantify both total DNA content using propidium iodide (PI) stain and S-phase fraction using the bromodeoxyuridine (BrdUrd) incorporation technique in cell population subsets. The model chosen was plasma cells in bone marrow triply labelled with fluorescein isothiocyanate (FITC) for intracytoplasmic immunoglobulins, with amino-methylcoumarin-acetate (AMCA) for BrdUrd, and with PI for DNA. Image analysis included three phases. First, plasma cells were recognized on FITC images, and the centroid positions were stored. Second, plasma cell nuclei were geodesically reconstructed from these stored positions using PI images in which DNA content was measured, and the nuclear mask outlines were stored. Third, BrdUrd incorporation level of plasma cells was measured on AMCA images inside PI nuclei masks and stored. Image DNA vs. BrdUrd scatterplots were obtained for cells selected according to the expression of intracytoplasmic immunoglobulin. Thus, both ploidy and proliferation could be independently evaluated on a subset of the cellular population.

Animals↗
PubMed1993

Oxyradical generation from leukocytes during endotoxin-induced microcirculatory disturbance in rat mesentery--attenuating effect of cetraxate.

By using the intravital microscope equipped with digital imaging processor, we investigated the granulocyte-mediated oxidative burst during the endotoxin-induced microvascular derangement in rat mesentery. The leukocyte behavior after the injection of acridine orange was detected by using a silicon-intensified target camera, the erythrocyte velocity was measured by using a high-speed video camera system, and the luminol-dependent photoemission was visualized by an ultrasensitive photon-counting camera in lipopolysaccharide (LPS)-treated microvascular beds. At 60 min after the LPS administration, a significant leakage of FITC-labeled albumin was observed along mesenteric venules under a fluorescence microscopy. The number of sticking leukocytes increased in association with the decrease in erythrocyte velocity after starting the LPS infusion. The luminol-dependent chemiluminescence in microvascular beds gradually increased over that recorded prior to LPS exposure and was fourfold higher 60 min after the start of LPS infusion. The distribution of the photoemission clearly corresponded to the venular endothelium, to which leukocytes adhered. In blood samples taken from the mesenteric vein at 60 min after the LPS administration, a decrease in the number of granulocytes and increases of total and individual chemiluminescence activities were observed. These results suggest that LPS induces oxidative burst from granulocytes on the venular endothelium. Cetraxate, an inhibitor of proteases including plasmin, significantly inhibited the leukocyte activation and prevented alterations in microvascular hemodynamics induced by LPS in vivo, whereas it had no effect on the LPS-induced oxyradical generation from adherent leukocytes in vitro. The present study demonstrates that proteases such as plasmin may play an important role in the pathogenesis of endotoxin-induced microvascular disturbances.

Animals↗
PubMed1984

Studies of four Japanese families with hereditary angioneurotic edema: simultaneous activation of plasma protease systems and exogenous triggering stimuli.

Forty-five relatives of 4 families with hereditary angioneurotic edema (HANE) were studied. Twenty-five, including 11 asymptomatic kindreds with the disposition, showed typical changes in complement system compatible with HANE. Follow-up study of HANE patients showed that, even in remission period, complement, coagulation and fibrinolytic systems can be activated. During edema attacks, moderate haemoconcentration and neutrophilia were encountered and kallikrein-kinin system was found to be also activated. Replacement therapy with C 1-inhibitor preparation for an edema attack revealed that clinical improvement paralleled the increase in blood levels of high molecular weight kininogen. Thus, HANE attack is considered to be elicited in kindreds with the hereditary disposition by activation of plasma protease systems, particularly by that of kallikrein-kinin system. On the other hand, exogenous triggers that can initiate activation of the protease systems can be classified into 2, neuro-humoral (sympathetic nerve response) and physico-chemical, categories. Hence, the edema attack of kindreds with the hereditary disposition can at least be modified by the biosynthesis of plasma factors and the individual susceptibility to the liberated catecholamines. These two different reaction processes are considered to be linked by the release of plasminogen activator and/or Hageman factor activating enzyme.

Angioedema↗