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Journal of Thrombosis and Haemostasis :... Jun 2015Fibrinolysis appears in many diverse physiological situations, and the components of the system are well established, along with mechanistic details for the individual... (Review)
Review
Fibrinolysis appears in many diverse physiological situations, and the components of the system are well established, along with mechanistic details for the individual reactions and some high-resolution structures. Key questions in understanding the regulation of fibrinolysis surround mechanisms of initiation and propagation, the localization of fibrinolysis reactions to the fibrin clot, and the influence of fibrin structure and clot composition on thrombolysis. This review covers these key areas with a focus on recent developments on fibrin structure and binding, the effects of a variety of cell types, the consequences of histones and DNA released by neutrophils, and the influence of flow. A complete understanding of the regulation of fibrinolysis will come from the building of detailed mathematical models. Suitable models are at an early stage of development, but may improve as model clots increase in complexity to incorporate the components and interactions listed above.
Topics: Animals; Fibrin; Fibrinolysis; Fibrinolytic Agents; Humans; Plasminogen; Plasminogen Activators; Protein Binding; Thrombolytic Therapy
PubMed: 26149056
DOI: 10.1111/jth.12935 -
Frontiers in Immunology 2019Inflammation resolution is an active process that functions to restore tissue homeostasis. Clearance of apoptotic leukocytes by efferocytosis at inflammatory sites plays...
Inflammation resolution is an active process that functions to restore tissue homeostasis. Clearance of apoptotic leukocytes by efferocytosis at inflammatory sites plays an important role in inflammation resolution and induces remarkable macrophage phenotypic and functional changes. Here, we investigated the effects of deletion of either plasminogen (Plg) or the Plg receptor, Plg-R, on the resolution of inflammation. In a murine model of pleurisy, the numbers of total mononuclear cells recruited to the pleural cavity were significantly decreased in both Plg and Plg-R mice, a response associated with decreased levels of the chemokine CCL2 in pleural exudates. Increased percentages of M1-like macrophages were determined in pleural lavages of Plg and Plg-R mice without significant changes in M2-like macrophage percentages. , Plg and plasmin (Pla) increased CD206/Arginase-1 expression and the levels of IL-10/TGF-β (M2 markers) while decreasing IFN/LPS-induced M1 markers in murine bone-marrow-derived macrophages (BMDMs) and human macrophages. Furthermore, IL4-induced M2-like polarization was defective in BMDMs from both Plg and Plg-R mice. Mechanistically, Plg and Pla induced transient STAT3 phosphorylation, which was decreased in Plg and Plg-R BMDMs after IL-4 or IL-10 stimulation. The extents of expression of CD206 and Annexin A1 (important for clearance of apoptotic cells) were reduced in Plg and Plg-R macrophage populations, which exhibited decreased phagocytosis of apoptotic neutrophils (efferocytosis) and . Taken together, these results suggest that Plg and its receptor, Plg-R, regulate macrophage polarization and efferocytosis, as key contributors to the resolution of inflammation.
Topics: Animals; Cell Movement; Humans; Macrophages; Male; Mice, Transgenic; Neutrophils; Phagocytosis; Phenotype; Plasminogen; Pleurisy; Receptors, Cell Surface
PubMed: 31316511
DOI: 10.3389/fimmu.2019.01458 -
International Journal of Molecular... Mar 2021Fibrinolysis is an important process in hemostasis responsible for dissolving the clot during wound healing. Plasmin is a central enzyme in this process via its capacity... (Review)
Review
Fibrinolysis is an important process in hemostasis responsible for dissolving the clot during wound healing. Plasmin is a central enzyme in this process via its capacity to cleave fibrin. The kinetics of plasmin generation (PG) and inhibition during fibrinolysis have been poorly understood until the recent development of assays to quantify these metrics. The assessment of plasmin kinetics allows for the identification of fibrinolytic dysfunction and better understanding of the relationships between abnormal fibrin dissolution and disease pathogenesis. Additionally, direct measurement of the inhibition of PG by antifibrinolytic medications, such as tranexamic acid, can be a useful tool to assess the risks and effectiveness of antifibrinolytic therapy in hemorrhagic diseases. This review provides an overview of available PG assays to directly measure the kinetics of plasmin formation and inhibition in human and mouse plasmas and focuses on their applications in defining the role of plasmin in diseases, including angioedema, hemophilia, rare bleeding disorders, COVID-19, or diet-induced obesity. Moreover, this review introduces the PG assay as a promising clinical and research method to monitor antifibrinolytic medications and screen for genetic or acquired fibrinolytic disorders.
Topics: Animals; Antifibrinolytic Agents; Blood Chemical Analysis; Disease; Fibrin; Fibrinolysin; Fibrinolytic Agents; Humans; Plasminogen
PubMed: 33803235
DOI: 10.3390/ijms22052758 -
Journal of Thrombosis and Haemostasis :... Dec 2007Plasminogen (plg) deficiency has been classified as (i) hypoplasminogenemia or 'true' type I plg deficiency, and (ii) dysplasminogenemia, also called type II plg... (Review)
Review
Plasminogen (plg) deficiency has been classified as (i) hypoplasminogenemia or 'true' type I plg deficiency, and (ii) dysplasminogenemia, also called type II plg deficiency. Both forms, severe hypoplasminogenemia and dysplasminogenemia, are not causally linked to venous thrombosis. Dysplasminogenemia does not lead to a specific clinical manifestation and probably represents only a polymorphic variation in the general population, mainly in Asian countries. Severe hypoplasminogenemia is associated with compromised extracellular fibrin clearance during wound healing, leading to pseudomembraneous (ligneous) lesions on affected mucous membranes (eye, middle ear, mouth, pharynx, duodenum, upper and lower respiratory tract and female genital tract). Ligneous conjunctivitis is by far the most common clinical manifestation. More than 12% of patients with severe hypoplasminogenemia exhibit congenital occlusive hydrocephalus. In milder cases of ligneous conjunctivitis, topical application of plg-containing eye drops, fresh frozen plasma, heparin, corticosteroids or certain immunosuppressive agents (such as azathioprine) may be more or less effective. Oral treatment with sex hormones was successful in two female patients with ligneous conjunctivitis. In severe cases with possibly life-threatening multi-organ involvement, true therapeutic options are not available at present. The plg-knockout mouse is a useful tool to study the many different properties of plg in a variety of settings, such as wound healing, tissue repair and tissue remodeling, virulence and invasiveness of certain bacteria in the human host, tumor growth and dissemination, as well as arteriosclerosis.
Topics: Amino Acid Sequence; Animals; Blood Coagulation Disorders; Conjunctivitis; Disease Models, Animal; Fibrinolysin; Fibrinolysis; Genetic Predisposition to Disease; Heterozygote; Homozygote; Humans; Mice; Mice, Knockout; Molecular Sequence Data; Mutation; Phenotype; Plasminogen; Protein Conformation; Risk Assessment; Risk Factors; Venous Thrombosis
PubMed: 17900274
DOI: 10.1111/j.1538-7836.2007.02776.x -
Veterinary Research Mar 2022Mycoplasma hyorhinis may cause systemic inflammation of pigs, typically polyserositis and arthritis, and is also associated with several types of human cancer. However,...
Mycoplasma hyorhinis may cause systemic inflammation of pigs, typically polyserositis and arthritis, and is also associated with several types of human cancer. However, the pathogenesis of M. hyorhinis colonizing and breaching the respiratory barrier to establish systemic infection is poorly understood. Glycolytic enzymes are important moonlighting proteins and virulence-related factors in various bacteria. In this study, we investigated the functions of a glycolytic critical enzyme, enolase in the infection and systemic spread of M. hyorhinis. Bacterial surface localization of enolase was confirmed by flow cytometry and colony hybridization assay. Recombinant M. hyorhinis enolase (rEno) was found to adhere to pig kidney (PK-15) cells, and anti-rEno serum significantly decreased adherence. The enzyme was also found to bind host plasminogen and fibronectin, and interactions were specific and strong, with dissociation constant (K) values of 1.4 nM and 14.3 nM, respectively, from surface plasmon resonance analysis. Activation of rEno-bound plasminogen was confirmed by its ability to hydrolyze plasmin-specific substrates and to degrade a reconstituted extracellular matrix. To explore key sites during these interactions, C-terminal lysine residues of enolase were replaced with leucine, and the resulting single-site and double-site mutants show significantly reduced interaction with plasminogen in far-Western blotting and surface plasmon resonance tests. The binding affinities of all mutants to fibronectin were reduced as well. Collectively, these results imply that enolase moonlights as an important adhesin of M. hyorhinis, and interacts with plasminogen and fibronectin. The two lysine residues in the C-terminus are important binding sites for its multiple binding activities.
Topics: Adhesins, Bacterial; Animals; Fibronectins; Mycoplasma hyorhinis; Phosphopyruvate Hydratase; Plasminogen; Swine
PubMed: 35337383
DOI: 10.1186/s13567-022-01041-0 -
Journal of Thrombosis and Haemostasis :... Jul 2011Due to its discovery as initiator of fibrinolysis and its well-studied activation by fibrin, tissue-type plasminogen activator (tPA) and the fibrinolytic system are... (Review)
Review
Due to its discovery as initiator of fibrinolysis and its well-studied activation by fibrin, tissue-type plasminogen activator (tPA) and the fibrinolytic system are generally associated with the dissolution of blood clots. However, it has been demonstrated over the years that (i) tPA can be activated by multiple proteins, (ii) plasmin has many substrates other than fibrin and (iii) tPA and plasmin have biological functions independent of fibrin and distinct from their role in blood clot lysis. We here review the data with respect to the activation of tPA by fibrin and its multiple other cofactors, in relation to tPA's role in pathophysiology, notably fibrinolysis and amyloidosis, with emphasis on Alzheimer's disease. We demonstrate a common structural element, termed cross-β structure, in misfolded proteins that is causal to tPA activation. The implications for protein misfolding diseases that are known to be associated with the deposition of amyloid and for diseases for which this has not (yet) been established are discussed.
Topics: Hemostasis; Humans; Plasminogen; Tissue Plasminogen Activator
PubMed: 21781253
DOI: 10.1111/j.1538-7836.2011.04278.x -
Frontiers in Cellular and Infection... 2013The ability to take advantage of plasminogen and its activated form plasmin is a common mechanism used by commensal as well as pathogenic bacteria in interaction with... (Review)
Review
The ability to take advantage of plasminogen and its activated form plasmin is a common mechanism used by commensal as well as pathogenic bacteria in interaction with their respective host. Hence, a huge variety of plasminogen binding proteins and activation mechanisms exist. This review solely focuses on the genus Streptococcus and, in particular, on the so-called non-activating plasminogen binding proteins. Based on structural and functional differences, as well as on their mode of surface linkaging, three groups can be assigned: M-(like) proteins, surface displayed cytoplasmatic proteins with enzymatic activities ("moonlighting proteins") and other surface proteins. Here, the plasminogen binding sites and the interaction mechanisms are compared. Recent findings on the functional consequences of these interactions on tissue degradation and immune evasion are summarized.
Topics: Animals; Bacterial Proteins; Carrier Proteins; Fibrinolysin; Host-Pathogen Interactions; Humans; Immune Evasion; Plasminogen; Protein Binding; Streptococcus
PubMed: 24319673
DOI: 10.3389/fcimb.2013.00085 -
Cellular and Molecular Life Sciences :... Mar 2011The plasmin-antiplasmin system plays a key role in blood coagulation and fibrinolysis. Plasmin and α(2)-antiplasmin are primarily responsible for a controlled and... (Review)
Review
The plasmin-antiplasmin system plays a key role in blood coagulation and fibrinolysis. Plasmin and α(2)-antiplasmin are primarily responsible for a controlled and regulated dissolution of the fibrin polymers into soluble fragments. However, besides plasmin(ogen) and α(2)-antiplasmin the system contains a series of specific activators and inhibitors. The main physiological activators of plasminogen are tissue-type plasminogen activator, which is mainly involved in the dissolution of the fibrin polymers by plasmin, and urokinase-type plasminogen activator, which is primarily responsible for the generation of plasmin activity in the intercellular space. Both activators are multidomain serine proteases. Besides the main physiological inhibitor α(2)-antiplasmin, the plasmin-antiplasmin system is also regulated by the general protease inhibitor α(2)-macroglobulin, a member of the protease inhibitor I39 family. The activity of the plasminogen activators is primarily regulated by the plasminogen activator inhibitors 1 and 2, members of the serine protease inhibitor superfamily.
Topics: Antifibrinolytic Agents; Binding Sites; Blood Coagulation; Fibrinolysis; Humans; Models, Biological; Models, Molecular; Plasminogen; Plasminogen Activators; Plasminogen Inactivators; Protein Structure, Tertiary; Serine Proteases; Serine Proteinase Inhibitors; alpha-Macroglobulins
PubMed: 21136135
DOI: 10.1007/s00018-010-0566-5 -
Trends in Parasitology Feb 2022Plasmodium and other vector-borne pathogens have evolved mechanisms to hijack the mammalian fibrinolytic system to facilitate infection of the human host and the... (Review)
Review
Plasmodium and other vector-borne pathogens have evolved mechanisms to hijack the mammalian fibrinolytic system to facilitate infection of the human host and the invertebrate vector. Plasmin, the effector protease of fibrinolysis, maintains homeostasis in the blood vasculature by degrading the fibrin that forms blood clots. Plasmin also degrades proteins from extracellular matrices, the complement system, and immunoglobulins. Here, we review some of the mechanisms by which vector-borne pathogens interact with components of the fibrinolytic system and co-opt its functions to facilitate transmission and infection in the host and the vector. Further, we discuss innovative strategies beyond conventional therapeutics that could be developed to target the interaction of vector-borne pathogens with the fibrinolytic proteins and prevent their transmission.
Topics: Animals; Fibrinolysin; Fibrinolysis; Humans; Malaria; Mammals; Plasminogen; Vector Borne Diseases
PubMed: 34649773
DOI: 10.1016/j.pt.2021.09.008 -
Biomolecules Mar 2022The plasminogen activation system regulates the activity of the serine protease, plasmin. The role of plasminogen receptors in cancer progression is being increasingly...
The plasminogen activation system regulates the activity of the serine protease, plasmin. The role of plasminogen receptors in cancer progression is being increasingly appreciated as key players in modulation of the tumor microenvironment. The interaction of plasminogen with cells to promote plasminogen activation requires the presence of proteins exposing C-terminal lysines on the cell surface. Plg-R is a structurally unique plasminogen receptor because it is an integral membrane protein that is synthesized with and binds plasminogen via a C-terminal lysine exposed on the cell surface. Here, we have investigated the expression of Plg-R in human breast tumors and human breast cancer cell lines. Breast cancer progression tissue microarrays were probed with anti-Plg-R mAB and we found that Plg-R is widely expressed in human breast tumors, that its expression is increased in tumors that have spread to draining lymph nodes and distant organs, and that Plg-R expression is most pronounced in hormone receptor (HR)-positive tumors. Plg-R was detected by Western blotting in human breast cancer cell lines. By flow cytometry, Plg-R cell surface expression was highest on the most aggressive tumor cell line. Future studies are warranted to address the functions of Plg-R in breast cancer.
Topics: Breast Neoplasms; Cell Membrane; Female; Humans; Plasminogen; Receptors, Cell Surface; Serine Proteases; Tumor Microenvironment
PubMed: 35454092
DOI: 10.3390/biom12040503