The inhibitory effect of numerous analogues of PO-16, an hexadecadeoxyribonucleotide antisense to sequences -22 to -17 of PAI-1 mRNA coding for a fragment of the signal peptide, on the expression of PAI-1 in endothelial cells, and physiological consequences of the subsequently reduced PAI-1 activity tested in vitro and in vivo, were described in our previous studies. Of particular interest was PO-16 5'-O-conjugated with menthyl phosphorothioate (MPO-16R). In this work, tissue localisation of MPO-16R labelled with [35S] phosphorothioate at the 3'-end, was determined. [35S]MPO-16R and control [35S]MPO-16R-SENSE oligonucleotides were administered intravenously into 22 rats and organ distribution of the labelled bioconjugates was assessed after 24 and 48 h. For this purpose, tissue sections were subjected to autoradiography, and quantitated by liquid scintillation after solubilisation. Overall clearance of radioactivity was already seen after 24 h, with the radioactivity recovered mainly in the kidney and liver. A smaller fraction of radioactivity was also retained in the spleen and heart. The kidney concentration of the labelled probe was higher than that of liver by 50%. The distribution of PAI-1 mRNA in untreated rat kidney, liver, spleen and heart established by two independent techniques: Ribonuclease Protection Assay and Real-Time PCR, shows the same pattern as that observed for [35S]MPO-16R antisense.
Praca mówi o nie zbadanych dotychczas dokładnie powiązaniach choroby dekompresyjnej z zagadnieniami hemostazy a szczególnie fibrynolizy. Badany był wpływ ekspozycji hiperbarycznej na główne składniki systemu fibrynolizy. Dwie grupy młodych mężczyzn poddawane były ekspozycjom hierbarycznym do ciśnienia 400 kPa - grupa I - i 700 kPa - grupa II. Stosowano dekompresję powietrzna. Po ekspozycji badano nurków na obecność objawów choroby dekompresyjnej, a także poszukiwano pęcherzyków gazu w naczyniach żylnych metoda Dopplera. 15 minut po zakończeniu dekompresji pobierano krew do badań koagulologicznych. Badano stężenie i aktywność t-PA i PAI-1, stężenie PAP i alfa2-antyplazminy. W grupach badawczych nie stwierdzono wykładników choroby dekompresyjnej ani nadmiernej ilości pęcherzyków wewnątrznaczyniowych. Stwierdzono miedzy innymi spadek poziomu alfa2-antyplazminy, spadek stężenia i aktywności PAI-1. Nie zaobserwowano zmian w zakresie czynnika XII jak i t-PA. Ekspozycja hiperbaryczna i dekompresja indukuje fibrynolize, nawet bez obecności pęcherzyków gazowych.
EN
There are a number of reported cases of decompression sickness (DCS) with haemorrhages. These cases have not been sufficiently investigated and thus bleeding complications could not be directly correlated to the enhanced fibrinolysis. The effect of hyperbaric exposition and decompression on the main components of fibrynolitic system have been measured. Two groups of 25 male divers each, were subjected to hyperbaric exposures to the pressure of either 400 kPa - group I - or 700 kPa - group II followed by a staged decompression. The divers were monitored for clinical symptoms of DCS and checked for Doppler-detected venous gas bubbles. Venous blood was drawn from divers before exposition and 15 minutes after decompression. The concentrations and activities of t-PA and PAI-1 as well as concentrations of PAP and alpha2-antiplasmin and activity of factor XIIa were measured. In all groups of divers no cases of DCS as well as detectable gas bubbles were noted. We observed elevated concentration of PAP, decreased concentration of alpha2-AP, decreased PAI-1 concentration and activity. There were no significant changes in factor XIIa activity as well a of t- PA concentration and activity. Hyperbaric exposition and decompression induce activation of fibrynolisis, even in the absence of detectable gas bubbles. Fibrynolitic activity increases mainly due to decrease of PAI-1 concentration and activity. Further clinical trials are necessary for the estimation of the importance of activation of fibrynolisis with decreased level of PAI-1 and alpha2-AP as possible risk factor for bleeding in divers.
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The proteins of the fibrinolytic system - urokinase plasminogen activator(uPA), tissue plasminogen activator (tPA)and plasminogen activator inhibitor type IPAI-I) - play important roles in fibrotization in various organs and including peritoneum. To study the cellular localization of PAI-1, tPA and uPA within the adipose tissue of the peritoneal membrane in patients at the onset of peritoneal dialysis(PD) we determined the initial expression of these proteins in relationship to multiple clinical variables. Methods: routinely performed parietal peritoneal biopsies in 12 patients undergoing peritoneal catheter implantation were examined. We used formalinfixed, paraffin-embedded specimens for immunohistochemical localization of these proteins along with the stereological pointcounting method for quantification of their expression within the peritoneal adipose tissue. Results: strong positive mutual correlation between the expression of PAI-1 and both uPA (SpearmanR=0.66) and tPA (R=0.59) as well as between the expression of uPA and tPA (R=0.77) was found without any relatioship to BMI, age, peritoneal transport characteristic or diabetes status. Conclusion: Adipose tissue within the peritoneum is capable of producing fibrinolysis regulators (independently on clinical parameters) thus possibly affecting the fibrotization and function of peritoneum as dialysis membrane. The effect of dialysis solution dosing, composition and other dialysis related factors should be clarified in future studies.
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