-
Seminars in Thrombosis and Hemostasis Mar 2017Plasmin is the effector protease of the fibrinolytic system, well known for its involvement in fibrin degradation and clot removal. However, plasmin is also recognized... (Review)
Review
Plasmin is the effector protease of the fibrinolytic system, well known for its involvement in fibrin degradation and clot removal. However, plasmin is also recognized as a potent modulator of immunological processes by directly interacting with various cell types including leukocytes (monocytes, macrophages, and dendritic cells) and cells of the vasculature (endothelial cells, smooth muscle cells) as well as soluble factors of the immune system and components of the extracellular matrix. In fact, the removal of misfolded proteins and maintenance of tissue homeostasis seem to be major physiological functions of plasmin. However, a large body of evidence also suggests that excessive plasmin generation frequently contributes to the pathophysiology of acute and chronic inflammatory processes. Hence, one question arising from the broadening effects of plasmin in physiology is whether antifibrinolytic drugs (i.e., tranexamic acid, epsilon aminocaproic acid, or aprotinin) that target plasmin either directly or indirectly and which are commonly used to prevent or treat bleeding might have unintended consequences on the immune response or on other nonfibrinolytic processes in vivo.
Topics: Antifibrinolytic Agents; Fibrinolysin; Fibrinolysis; Humans
PubMed: 27677178
DOI: 10.1055/s-0036-1586227 -
Journal of Leukocyte Biology Sep 2012The serine protease plasmin generated from its zymogen plasminogen is best known for its function as a key enzyme of the fibrinolytic cascade. However, beyond... (Review)
Review
The serine protease plasmin generated from its zymogen plasminogen is best known for its function as a key enzyme of the fibrinolytic cascade. However, beyond fibrinolysis, plasmin has a number of crucial functions in a variety of processes, including inflammation. Various cells can bind plasminogen and plasmin via plasminogen-binding sites exposing a C-terminal lysine. Plasmin, generated as a result of plasminogen activation at the cell surface, is protected from its physiological inhibitors. Apart from its ability to facilitate cell migration in tissues, plasmin is capable of triggering signaling, which depends on cellular binding via its lysine-binding sites and its proteolytic activity. Plasmin-induced signaling affects various functions of monocytes, macrophages, DCs, and others, with the list of affected cells still growing. In vitro and in vivo studies have demonstrated the ability of plasmin to stimulate the production of cytokines, ROS, and other mediators, thereby contributing to inflammation. Plasmin-induced chemotaxis of monocytes and DCs indicates that it is also a potent chemoattractant for immune cells. Therefore, excessive activation of plasmin in chronic inflammatory or autoimmune diseases might exacerbate the activation of inflammatory cells and the pathogenesis of the disease. This review focuses on the available evidence for physiological and pathophysiological roles the serine protease plasmin in inflammatory processes.
Topics: Animals; Fibrinolysin; Humans; Inflammation; Signal Transduction
PubMed: 22561604
DOI: 10.1189/jlb.0212056 -
Transfusion Aug 2022Tranexamic acid (TXA) is a popular antifibrinolytic drug widely used in hemorrhagic trauma patients and cardiovascular, orthopedic, and gynecological surgical patients.... (Review)
Review
Tranexamic acid (TXA) is a popular antifibrinolytic drug widely used in hemorrhagic trauma patients and cardiovascular, orthopedic, and gynecological surgical patients. TXA binds plasminogen and prevents its maturation to the fibrinolytic enzyme plasmin. A number of studies have demonstrated the broad life-saving effects of TXA in trauma, superior to those of other antifibrinolytic agents. Besides preventing fibrinolysis and blood loss, TXA has been reported to suppress posttraumatic inflammation and edema. Although the efficiency of TXA transcends simple inhibition of fibrinolysis, little is known about its mechanisms of action besides the suppression of plasmin maturation. Understanding the broader effects of TXA at the cell, organ, and organism levels are required to elucidate its potential mechanisms of action transcending antifibrinolytic activity. In this article, we provide a brief review of the current clinical use of TXA and then focus on the effects of TXA beyond antifibrinolytics such as its anti-inflammatory activity, protection of the endothelial and epithelial monolayers, stimulation of mitochondrial respiration, and suppression of melanogenesis.
Topics: Antifibrinolytic Agents; Blood Coagulation Disorders; Fibrinolysin; Fibrinolysis; Hemorrhage; Humans; Tranexamic Acid
PubMed: 35834488
DOI: 10.1111/trf.16976 -
Progress in Cardiovascular Diseases 1991
Review
Topics: Fibrinolysin; Humans; Molecular Structure; Plasminogen
PubMed: 1832499
DOI: 10.1016/0033-0620(91)90010-j -
Blood Jul 2021
Topics: Fibrinolysin; Liver
PubMed: 34292330
DOI: 10.1182/blood.2021011853 -
FASEB Journal : Official Publication of... Jan 2020Tannerella forsythia is a periodontopathogen that expresses miropin, a protease inhibitor in the serpin superfamily. In this study, we show that miropin is also a...
Tannerella forsythia is a periodontopathogen that expresses miropin, a protease inhibitor in the serpin superfamily. In this study, we show that miropin is also a specific and efficient inhibitor of plasmin; thus, it represents the first proteinaceous plasmin inhibitor of prokaryotic origin described to date. Miropin inhibits plasmin through the formation of a stable covalent complex triggered by cleavage of the Lys-Thr (P2-P1) reactive site bond with a stoichiometry of inhibition of 3.8 and an association rate constant (k) of 3.3 × 10 Ms. The inhibition of the fibrinolytic activity of plasmin was nearly as effective as that exerted by α-antiplasmin. Miropin also acted in vivo by reducing blood loss in a mice tail bleeding assay. Importantly, intact T. forsythia cells or outer membrane vesicles, both of which carry surface-associated miropin, strongly inhibited plasmin. In intact bacterial cells, the antiplasmin activity of miropin protects envelope proteins from plasmin-mediated degradation. In summary, in the environment of periodontal pockets, which are bathed in gingival crevicular fluid consisting of 70% of blood plasma, an abundance of T. forsythia in the bacterial biofilm can cause local inhibition of fibrinolysis, which could have possible deleterious effects on the tooth-supporting structures of the periodontium.
Topics: Animals; Antifibrinolytic Agents; Bacteria; Catalytic Domain; Female; Fibrinolysin; Fibrinolysis; Humans; Mice, Inbred C57BL; Periodontal Diseases; Protease Inhibitors; Serpins
PubMed: 31914706
DOI: 10.1096/fj.201901490RR -
Translational Vision Science &... Apr 2023We sought to evaluate the efficacy and safety of plasmin injection in the capsular bag during the cataract operation for the prevention of posterior capsule...
PURPOSE
We sought to evaluate the efficacy and safety of plasmin injection in the capsular bag during the cataract operation for the prevention of posterior capsule opacification.
METHODS
Thirty-seven anterior capsular flaps taken from phacoemulsification surgery were immersed in either 1 µg/mL plasmin (plasmin group, n = 27) or phosphate-buffered saline (control group, n = 10) for 2 minutes and photographed after fixation and nuclear staining to compare the numbers of residual lens epithelial cells. In the animal experiments, the plasmin solution was injected into the capsular bag and remained for 5 minutes during hydrodissection or after lens extraction. The degree of posterior capsular opacity of the rabbits at 2 months were photographed by slit lamp biomicroscopy. In HLE-B3 cell culture, the cell detachment rate, proliferation, and apoptosis after the plasmin digestion were analyzed.
RESULTS
The residual lens epithelial cell numbers on the capsule after plasmin treatment were 168 ± 190.7/mm2 in the 1 µg/mL plasmin group, which was significantly lower than that of the control (1012 ± 798.8/mm2; P < 0.0001). In a rabbit model, the treatment of plasmin resulted in a significantly clearer posterior capsule compared with that of the control group at 2 months postoperatively.
CONCLUSIONS
This study suggested that plasmin injection can induce effective lens epithelial cell detachment, which could be a promising adjunctive treatment to further improve the success rate in posterior capsule opacification prevention.
TRANSLATIONAL RELEVANCE
Plasmin injection for lens epithelial cell detachment could significantly decrease the number of residual lens epithelial cells. This approach could be a promising treatment incorporating the current treatment approach to further improve the success rate in posterior capsule opacification prevention.
Topics: Animals; Rabbits; Capsule Opacification; Fibrinolysin; Lens Capsule, Crystalline; Epithelial Cells; Phacoemulsification
PubMed: 37074731
DOI: 10.1167/tvst.12.4.23 -
Thrombosis and Haemostasis Jul 2001Vascular remodeling, defined as lasting structural changes in the vessel wall in response to hemodynamic stimuli, plays a role in many (patho)physiological processes... (Review)
Review
Vascular remodeling, defined as lasting structural changes in the vessel wall in response to hemodynamic stimuli, plays a role in many (patho)physiological processes requiring cell migration and degradation of extracellular matrix (ECM). Two proteolytic systems, the fibrinolytic (plasminogen/plasmin) and matrix metalloproteinase (MMP) systems can degrade most ECM components. The availability of mice models with deficiency of main components of both systems has allowed to study their contribution to vascular remodeling in several biological processes. In mouse models of atherosclerosis, urokinase-mediated plasmin generation plays a role in activation of several macrophage-derived MMPs (MMP-3, -9, -12 and -13), triggering elastolysis and collagenolysis, resulting in media destruction and aneurysm formation. Neointima formation after vascular injury, a process that depends on smooth muscle cell migration, is reduced in mice with plasminogen or urokinase deficiency and enhanced in mice with deficiency of TIMP-1 (type 1 tissue inhibitor of MMPs). Also in allograft transplant arteriosclerosis and in abdominal aortic aneurysm both proteolytic systems contribute to matrix degradation. In a mouse model of myocardial infarction, urokinase deficiency protects totally and MMP-9 deficiency partially against cardiac rupture, but these animals suffer cardiac failure. Thus, the plasminogen/plasmin and MMP systems, in concert, contribute to vascular remodeling in the setting of cardiovascular disease.
Topics: Animals; Blood Vessels; Cardiovascular Diseases; Fibrinolysin; Fibrinolytic Agents; Humans; Matrix Metalloproteinases; Neovascularization, Pathologic
PubMed: 11487021
DOI: No ID Found -
Chembiochem : a European Journal of... Feb 2012The serine protease plasmin is ubiquitously expressed throughout the human body in the form of the zymogen plasminogen. Conversion to active plasmin occurs through... (Review)
Review
The serine protease plasmin is ubiquitously expressed throughout the human body in the form of the zymogen plasminogen. Conversion to active plasmin occurs through enzymatic cleavage by plasminogen activators. The plasminogen activator/plasmin system has a well-established function in the removal of intravascular fibrin deposition through fibrinolysis and the inhibition of plasmin activity; this has found widespread clinical use in reducing perioperative bleeding. Increasing evidence also suggests diverse, although currently less defined, roles for plasmin in a number of physiological and pathological processes relating to extracellular matrix degradation, cell migration and tissue remodelling. In particular, dysregulation of plasmin has been linked to cancer invasion/metastasis and various chronic inflammatory conditions; this has prompted efforts to develop inhibitors of this protease. Although a number of plasmin inhibitors exist, they commonly suffer from poor potency and/or specificity of inhibition that either results in reduced efficacy or prevents clinical use. Consequently, there is a need for further development of high-affinity plasmin inhibitors that maintain selectivity over other serine proteases. This review summarises clearly defined and potential applications for plasmin inhibition. The properties of naturally occurring and engineered plasmin inhibitors are discussed in the context of current knowledge regarding plasmin structure, specificity and function. This includes design strategies to obtain the potency and specificity of inhibition in addition to controlled temporal and spatial distribution tailored for the intended use.
Topics: Drug Design; Fibrinolysin; Humans; Protein Engineering; Serine Proteinase Inhibitors; Structure-Activity Relationship
PubMed: 22238174
DOI: 10.1002/cbic.201100673 -
Trends in Pharmacological Sciences Feb 2004With advances in the field of thrombolytic therapy, whereby clots are routinely treated locally via a catheter, traditional systemic thrombolytics such as plasminogen... (Review)
Review
With advances in the field of thrombolytic therapy, whereby clots are routinely treated locally via a catheter, traditional systemic thrombolytics such as plasminogen activators might not be the best drugs for this task. Plasmin represents a new class of thrombolytic agents that exhibit direct fibrinolytic activity, without the need for either plasminogen or a plasminogen activator. In contrast to plasminogen activators, this independence from plasminogen allows plasmin to efficiently dissolve long, retracted blood clots that are inherently deficient in plasminogen. Preclinical safety studies in rabbits demonstrate that plasmin, in contrast to tissue-type plasminogen activator, does not cause re-bleeding from preformed hemostatic plugs. These results predict that plasmin will prove to be both superior to, and safer than, plasminogen activators in the dissolution of long, retracted blood clots in humans.
Topics: Animals; Fibrinolysin; Fibrinolytic Agents; Humans; Plasminogen Activators; Thrombosis
PubMed: 15102492
DOI: 10.1016/j.tips.2003.12.009