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Blood May 2021Plasminogen is an abundant plasma protein that exists in various zymogenic forms. Plasmin, the proteolytically active form of plasminogen, is known for its essential... (Review)
Review
Plasminogen is an abundant plasma protein that exists in various zymogenic forms. Plasmin, the proteolytically active form of plasminogen, is known for its essential role in fibrinolysis. To date, therapeutic targeting of the fibrinolytic system has been for 2 purposes: to promote plasmin generation for thromboembolic conditions or to stop plasmin to reduce bleeding. However, plasmin and plasminogen serve other important functions, some of which are unrelated to fibrin removal. Indeed, for >40 years, the antifibrinolytic agent tranexamic acid has been administered for its serendipitously discovered skin-whitening properties. Plasmin also plays an important role in the removal of misfolded/aggregated proteins and can trigger other enzymatic cascades, including complement. In addition, plasminogen, via binding to one of its dozen cell surface receptors, can modulate cell behavior and further influence immune and inflammatory processes. Plasminogen administration itself has been reported to improve thrombolysis and to accelerate wound repair. Although many of these more recent findings have been derived from in vitro or animal studies, the use of antifibrinolytic agents to reduce bleeding in humans has revealed additional clinically relevant consequences, particularly in relation to reducing infection risk that is independent of its hemostatic effects. The finding that many viruses harness the host plasminogen to aid infectivity has suggested that antifibrinolytic agents may have antiviral benefits. Here, we review the broadening role of the plasminogen-activating system in physiology and pathophysiology and how manipulation of this system may be harnessed for benefits unrelated to its conventional application in thrombosis and hemostasis.
Topics: Animals; Antifibrinolytic Agents; Brain; Conjunctivitis; Enzyme Activation; Fibrin; Fibrinolysin; Fibrinolysis; Fibrinolytic Agents; Humans; Immunity; Infections; Inflammation; Mice; Plasminogen; Radiodermatitis; Receptors, Cell Surface; Skin Diseases, Genetic; Thrombosis; Tranexamic Acid; Wound Healing; Wounds and Injuries
PubMed: 33735914
DOI: 10.1182/blood.2020008951 -
Journal of Thrombosis and Thrombolysis Jan 2017Plasminogen plays an important role in fibrinolysis as well as wound healing, cell migration, tissue modeling and angiogenesis. Congenital plasminogen deficiency is a... (Review)
Review
Plasminogen plays an important role in fibrinolysis as well as wound healing, cell migration, tissue modeling and angiogenesis. Congenital plasminogen deficiency is a rare autosomal recessive disorder that leads to the development of thick, wood-like pseudomembranes on mucosal surfaces, mostly seen in conjunctivas named as ''ligneous conjunctivitis''. Local conjunctival use of fresh frozen plazma (FFP) in combination with other eye medications such as cyclosporin and artificial tear drops may relieve the symptoms. Topical treatment with plasminogen eye drops is the most promising treatment that is not yet available in Turkey.
Topics: Conjunctivitis; Humans; Ophthalmic Solutions; Plasma; Plasminogen; Skin Diseases, Genetic; Turkey
PubMed: 27629020
DOI: 10.1007/s11239-016-1416-6 -
Methods in Enzymology 1981
Review
Topics: Amino Acid Sequence; Fibrinolysin; Humans; Isoelectric Point; Plasminogen
PubMed: 6210827
DOI: 10.1016/s0076-6879(81)80031-6 -
Progress in Cardiovascular Diseases 1991
Review
Topics: Fibrinolysin; Humans; Molecular Structure; Plasminogen
PubMed: 1832499
DOI: 10.1016/0033-0620(91)90010-j -
International Journal of Molecular... Apr 2014The plasminogen activation system (PAS) plays an essential role in tissue proteolysis in physiological and pathological processes. Periodontitis is a chronic infection... (Review)
Review
The plasminogen activation system (PAS) plays an essential role in tissue proteolysis in physiological and pathological processes. Periodontitis is a chronic infection associated with increased proteolysis driven by plasminogen activation. In this comprehensive review, we summarise the effects of PAS in wound healing, tissue remodelling, inflammation, bacterial infection, and in the initiation and progression of periodontal disease. Specifically, we discuss the role of plasminogen activators (PAs), including urokinase PA (uPA), tissue-type PA (tPA), PA inhibitor type 1 (PAI-1) and 2 (PAI-2) and activated plasminogen in periodontal tissue, where their concentrations can reach much higher values than those found in other parts of the body. We also discuss whether PA deficiencies can have effects on periodontal tissue. We conclude that in periodontal disease, PAS is unbalanced and equalizing its function can improve the clinical periodontal tissue condition.
Topics: Animals; Enzyme Activation; Humans; Inflammation; Periodontal Diseases; Periodontium; Plasminogen; Wound Healing
PubMed: 24535478
DOI: 10.3892/ijmm.2014.1653 -
Haemostasis 1988Like a number of the components of the fibrinolytic and coagulation systems, plasminogen (plgn) is a multifunctional molecule. As a proenzyme, a number of its activities... (Review)
Review
Like a number of the components of the fibrinolytic and coagulation systems, plasminogen (plgn) is a multifunctional molecule. As a proenzyme, a number of its activities such as its binding to fibrin, histidine-rich glycoprotein (HRGP) and alpha 2-antiplasmin (AP) are expressed while its major enzymatic activity remains unexpressed. This latter activity has been used as a yardstick of plasminogen potency, despite the fact that no such activity resides in the native plasminogen molecule. Assay procedures usually involve the activation of the plasminogen to plasmin using an activator such as streptokinase (SK) or urokinase (UK) and a major problem involves the establishment of a properly-timed plasminogen-activator ratio to fully express the plasminogen as the active enzyme plasmin (Gaffney, P.J. et al. Activation of plasminogen as a feature of its assay. Haemostasis 1977, 6, 72-78). Substrates such as casein, fibrinogen and fibrin have been used to assess the plasmin activity developed while more recently the tripeptide chromogenic substrate S-2251 has been successfully used. These assays have been standardised using a reference preparation of the active enzyme, plasmin, and both a 1st and 2nd International Reference Preparation (IRP) have been established. These IRP's differed in that the fibrin binding kringle-structures were missing in the 1st IRP yielding differing fibrinolytic and chromogenic activities (Philo, R.D. and Gaffney, P.J. Plasmin potency estimates. Influence of substrate used in assay. Thrombosis and Haemostasis 1981, 45, 107-109). Activation procedures of plasminogen and subsequent assays of plasmin using a variety of substrates have been recently superseded by an assay which involves the formation of a plgn-SK complex which complex has an active site which hydrolyses the chromogenic substrate S-2251. This avoids the problems highlighted above involved in measuring plasminogen activity at the optimum stage during activation. While plasmin standards have been suitable for the standardisation of plasminogen when it is measured by activation-based procedures, a British Standard for glutamic acid-plasminogen has now been established in order to standardise the plgn-SK assay (Gaffney, P.J. and Curtis, A.D. The establishment of a standard for plasminogen (glu-type). Thrombosis and Haemostasis 1984, 51, 376-378). The calibration of this standard using the 2nd IRP for plasmin and the value of this standard in the measurement of plasminogen in plasma is discussed.
Topics: Blood Coagulation Tests; Humans; Plasminogen; Reference Standards; United Kingdom
PubMed: 3280425
DOI: 10.1159/000215837 -
Thrombosis and Haemostasis Apr 2005Breakdown of the extracellular matrix is crucial for cancer invasion and metastasis. It is accomplished by the concerted action of several proteases, including the... (Review)
Review
Breakdown of the extracellular matrix is crucial for cancer invasion and metastasis. It is accomplished by the concerted action of several proteases, including the serine protease plasmin and a number of matrix metalloproteases. The activity of each of these proteases is regulated by an array of activators, inhibitors and cellular receptors. Thus, the generation of plasmin involves the pro-enzyme plasminogen, the urokinase type plasminogen activator uPA and its pro-enzyme pro-uPA, the uPA inhibitor PAI-1, the cell surface uPA receptor uPAR, and the plasmin inhibitor alpha(2)-antiplasmin. Furthermore, the regulation of extracellular proteolysis in cancer involves a complex interplay between cancer cells and non-malignant stromal cells in the expression of the molecular components involved. For some types of cancer, this cellular interplay mimics that observed in the tissue of origin during non-neoplastic tissue remodelling processes. We propose that cancer invasion can be considered as uncontrolled tissue remodelling. Inhibition of extracellular proteases is an attractive approach to cancer therapy. Because proteases have many different functions in the normal organism, efficient inhibition will have toxic side effects. In cancer invasion, like in normal tissue remodelling processes, there appears to be a functional overlap between different extracellular proteases. This redundancy means that combinations of protease inhibitors must be used. Such combination therapy, however, is also likely to increase toxicity. Therefore for each type of cancer, a combination of protease inhibitors that is optimised with respect to both maximal therapeutic effect and minimal toxic side effects need to be identified.
Topics: Humans; Neoplasm Invasiveness; Neoplasms; Plasminogen; Plasminogen Activators; Stromal Cells
PubMed: 15841311
DOI: 10.1160/TH05-01-0054 -
Frontiers in Bioscience : a Journal and... May 2003The urokinase plasminogen activation system is a key modulator of the tissue remodeling processes required for tumor cell invasion and metastasis. Malignant progression... (Review)
Review
The urokinase plasminogen activation system is a key modulator of the tissue remodeling processes required for tumor cell invasion and metastasis. Malignant progression is characterised by inappropriately high cell surface levels of receptor- bound active urokinase. This enhances the rate of plasminogen activation resulting in markedly increased levels of cell surface plasmin. The repercussions of this are significant and include the activation of growth factors and signaling pathways, and the degradation of extracellular matrices, either directly or indirectly, via the activation of matrix metalloproteinases. Native, circulating plasminogen binds in a lysine- and/or carbohydrate-dependent manner to tumor and endothelial cells with low affinity but high capacity and a heterogeneous group of plasminogen receptors have been identified. This heterogeneity underscores the complexity of the mechanisms responsible for the regulation of cell-surface plasminogen binding. This review summarizes the literature on known plasminogen receptor candidates and shows that they can be subdivided into three classes based on their mode of interaction with plasminogen. We also aim to emphasize the notion that in the tumor environment the known intrinsic functional relationship between plasminogen conformation and activation is essentially connected to cellular binding. This allows plasminogen to be co-localised in an activation-susceptible form with the enhanced uPA levels seen in malignancy and together furnishes tumor cells with elevated tissue remodeling capacity. In addition, some of the pitfalls and strategies encountered when conducting plasminogen receptor experiments are also addressed.
Topics: Animals; Humans; Neoplasms; Plasminogen; Protein Binding
PubMed: 12700073
DOI: 10.2741/1044 -
Haemostasis 1988Human plasminogen is a beta-globulin (2% carbohydrate, molecular weight 90 KD), which in its native form has NH2-terminal glutamic acid (Glu-plasminogen) whose primary... (Review)
Review
Human plasminogen is a beta-globulin (2% carbohydrate, molecular weight 90 KD), which in its native form has NH2-terminal glutamic acid (Glu-plasminogen) whose primary structure is known (31, 37, 38). From human plasma plasminogen can easily be isolated by affinity chromatography techniques (10, 25, and Table 1). Plasminogen is synthesized in many organs. The production site of the zymogen may be the liver (21), the eosinophiles (3) or the kidney (15). The plasma-plasminogen level is low in newborns (22) and even lower in the premature infant (2). In healthy adults it is found in plasma or serum in a concentration of 200 mg/l (= 2 microM, 22, 39). The half-life of the native (Glu-) plasminogen is 2.24 +/- 0.29 days (6). Two types of Glu-plasminogen occur in human plasma, which differ in their carbohydrate composition as well as in their content of sialic acid. Genetic variants (see Mayr, 3.1.); of plasminogen have been reported (16) after isoelectric focusing of human plasma in polyacrylamide gels. Three patterns were found, two completely different and the third most likely a mixture of the other two. Characteristical functional properties of plasminogen are related to its molecular structure, e.g. its in vivo specificity for fibrin in contrast to the fairly unspecific in vitro activity of plasmin. Glu-plasminogen is easily converted by limited plasmic digestion to modified forms with NH2-terminal lysine, valine or methionine, which are commonly designated "Lys-plasminogen" displaying a plasma half-life time of 0.8 days.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Carbohydrate Conformation; Humans; Plasminogen; Protein Conformation; Structure-Activity Relationship
PubMed: 3280426
DOI: 10.1159/000215824 -
Frontiers in Bioscience : a Journal and... Jan 2002The plasminogen activation system appears to be widely involved in many biological processes in health and disease, but the regulation of plasmin generation or the... (Review)
Review
The plasminogen activation system appears to be widely involved in many biological processes in health and disease, but the regulation of plasmin generation or the mechanisms of stimulation by cell surface receptors are not well understood. Cell surface plasminogen activation requires binding sites for plasminogen substrate and activator enzyme before enhancement of plasmin generation rate is observed. The cell surface moieties involved in binding these reactants appear to be a mixed group of proteins and other molecules, many of which have been extensively investigated. The binding of plasminogen in particular is characterized by heterogeneous receptor molecules, present in high number but generally with low affinity for plasminogen. The low affinity of the interaction, with Kd values around 10(-6) M, presents considerable technical difficulties when studying and quantitating plasminogen binding to cells or isolated receptors. Studying plasminogen activation kinetics in the presence of cells also presents technical difficulties and raises difficult questions on interpretation of results. However, approaches developed to study enzyme activation systems in other areas of hemostasis may also be applied to the problems associated with pericellular proteolysis. Models should be developed that match In vitro experimental data and help us understand the meaning of kinetic constants derived from these systems. In this way it should be possible to better understand the regulation of plasminogen activation around the cell under normal conditions and in a variety of disease states where cell-associated plasminogen activation is believed to be up-regulated. Ultimately, a sound understanding of theses regulatory mechanisms will enable us to devise strategies for modulating proteolytic activity, test these approaches in well designed In vitro systems and relate these results to the in vivo situation.
Topics: Animals; Cell Membrane; Enzyme Activation; Humans; Membrane Proteins; Plasminogen
PubMed: 11779703
DOI: 10.2741/A724