Niels Ole Kjeldgaard

Bio: Niels Ole Kjeldgaard is an academic researcher from University of Copenhagen. The author has contributed to research in topics: Urokinase & Xanthine oxidase. The author has an hindex of 7, co-authored 7 publications receiving 493 citations.

Plasminogen activators, tissue degradation, and cancer.

Abstract: Publisher Summary This chapter discusses the role of plasminogen activators in various biological processes. In specific, it describes two types of plasminogen activators—namely, the urokinase-type plasminogen activator (u-PA) and the tissue-type plasminogen activator (t-PA), which are essentially different gene products. The amino acid sequences of these activators and nucleotide sequences of the corresponding cDNAs have largely been determined, and the cDNAs have been cloned using recombinant techniques. A variety of enzymatic as well as immunological assay and detection methods have also been developed that allows a precise quantification of the activators, a distinction between u-PA and t-PA, determination of whether an activator is present in its active or zymogen form, analysis of the kinetics of different steps of the cascade reaction, and immunocytochemical identification of u-PA and t-PA in tissue sections. Much of the studies on plasminogen activators and cancer has been guided by the hypothesis that proteolysis of the components of extracellular matrix, initiated by the release of plasminogen activator from the cancer cells, plays a decisive role for the degradation of normal tissue, and thereby for invasive growth and metastases.

The mechanism of clot dissolution by plasmin

Abstract: Normal human and animal sera contain a glob-ulin, plasminogen, which in the presence of acti-vators is rapidly converted to plasmin, a pro-teolytic enzyme active at neutral hydrogen ion concentrations. Plasmin is an enzyme of wide specificity and will attack such varied substrates as gelatin, casein, certain synthetic esters, accelerator globulin, complement, fibrinogen and most importantly fibrin. Plasminogen activation occurs spontaneously (1), or as a result of contact with activators of tissue (2), body fluid (3, 4), or bacterial origin (5). The conversion of plas-minogen to plasmin involves the loss of a peptide moiety and there is evidence to suggest that the plasmin obtained by different modes of activation may vary in composition (6). Biochemically, considerable species differences exist not only between the plasminogen system of man and animals, but more particularly between the systems of various animals; this variability is most extreme with regard to the differential effectiveness of streptokinase. Rigid kinetic studies (6) reveal that the activation of human plasmino-gen under the influence of streptokinase (an ex-tracellular product of hemolytic streptococcal metabolism), trypsin and urokinase (prepared from human urine) results from a first order enzymatic reaction. Since physiological fibrinolytic phenomena result from activity of the plasminogen system, attempts to use plasmin or plasminogen activators to effect therapeutic thrombolysis have been numerous. Animal experiment, despite the difficulties and confusion of species variability, has yielded striking findings (7, 8, 9). Though the demonstration of experimental thrombolytic action has been of an unequivocal nature, the precise mechanism of its production has hitherto been obscure. experiments and in vivo observations bearing upon thrombolytic' mechanisms in man. The results indicate that since plasminogen is found both in plasma and also as a constituent of thrombi, clot lysis occurs by a dual mechanism. The chief and primary mechanism of thrombolysis involves the diffusion or adsorption of plasminogen acti-vator to the thrombus, activation of intrinsic clot plasminogen and thrombolysis. The secondary mechanism involving digestion of the thrombus by extrinsic plasmin action appears to be of little quantitative importance. MATERIALS AND METHODS Streptokinase2 was a highly purified preparation, bio-physically though not immunochemically homogenous; the specific activity was 600 to 700 streptokinase units per lug. nitrogen. Human plasminogen (1) contained 100 to 150 casein units per mg. tyrosine. Plasmin was prepared by autocatalytic activation of plasminogen in glycerol (1) and contained 95 casein units per mg. tyrosine (see Casein assay). Epsilon amino caproic acid2 (6-amino hexanoic acid) had …