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Cellular Signalling Nov 2020A fine-tuned activation and deactivation of proteases and their inhibitors are involved in the execution of the inflammatory response. The zymogen/proenzyme plasminogen... (Review)
Review
A fine-tuned activation and deactivation of proteases and their inhibitors are involved in the execution of the inflammatory response. The zymogen/proenzyme plasminogen is converted to the serine protease plasmin, a key fibrinolytic factor by plasminogen activators including tissue-type plasminogen activator (tPA). Plasmin is part of an intricate protease network controlling proteins of initial hemostasis/coagulation, fibrinolytic and complement system. Activation of these protease cascades is required to mount a proper inflammatory response. Although best known for its ability to dissolve clots and cleave fibrin, recent studies point to the importance of fibrin-independent functions of plasmin during acute inflammation and inflammation resolution. In this review, we provide an up-to-date overview of the current knowledge of the enzymatic and cytokine-like effects of tPA and describe the role of tPA and plasminogen receptors in the regulation of the inflammatory response with emphasis on the cytokine storm syndrome such as observed during coronavirus disease 2019 or macrophage activation syndrome. We discuss tPA as a modulator of Toll like receptor signaling, plasmin as an activator of NFkB signaling, and summarize recent studies on the role of plasminogen receptors as controllers of the macrophage conversion into the M2 type and as mediators of efferocytosis during inflammation resolution.
Topics: Animals; Blood Coagulation; COVID-19; Complement Activation; Coronavirus Infections; Cytokine Release Syndrome; Cytokines; Humans; Immune System; Inflammation; Low Density Lipoprotein Receptor-Related Protein-1; NF-kappa B; Pandemics; Plasminogen; Pneumonia, Viral; Tissue Plasminogen Activator
PubMed: 32861744
DOI: 10.1016/j.cellsig.2020.109761 -
Frontiers in Immunology 2022Bovine mycoplasmosis is an important infectious disease of cattle caused by () which poses a serious threat to the breeding industry. Adhesin is involved in the initial... (Review)
Review
Bovine mycoplasmosis is an important infectious disease of cattle caused by () which poses a serious threat to the breeding industry. Adhesin is involved in the initial process of colonization, which is closely related to the infection, cell invasion, immune escape and virulence of this pathogenic microorganism. For the reason that lacks a cell wall, its adhesin is predominantly located on the surface of the cell membrane. The adhesins of are usually identified by adhesion and adhesion inhibition analysis, and more than 10 adhesins have been identified so far. These adhesins primarily bind to plasminogen, fibronectin, heparin and amyloid precursor-like protein-2 of host cells. This review aims to concisely summarize the current knowledge regarding the adhesins of and their target proteins of the host cell. Additionally, the biological characteristics of the adhesin will be briefly analyzed.
Topics: Cattle; Animals; Mycoplasma bovis; Adhesins, Bacterial; Mycoplasma Infections; Cattle Diseases; Plasminogen
PubMed: 36341375
DOI: 10.3389/fimmu.2022.1016641 -
International Journal of... 2021Sepsis has been redefined recently as life-threatening organ dysfunction caused by dysregulated host responses to infection and septic shock. Soluble urokinase... (Observational Study)
Observational Study
BACKGROUND
Sepsis has been redefined recently as life-threatening organ dysfunction caused by dysregulated host responses to infection and septic shock. Soluble urokinase plasminogen activator receptor (SuPAR) and plasminogen activator inhibitor-1(PAI-1) concentration positively correlate to the activation level of the immune system, and are markers of disease severity and aggressiveness.
OBJECTIVE
The study aimed to identify the blood level of plasminogen activator inhibitor-1 (PAI-1) and soluble urokinase plasminogen activator receptor (SuPAR) in sepsis and its association with mortality.
PATIENT AND METHODS
This is an observational prospective study that enrolled 60 adult patients with sepsis (according to SOFA), admitted to Menoufia and Zagazig university hospitals during the period from December 2019 till October 2020. Plasminogen activator inhibitor-1 (PAI-1) and soluble urokinase plasminogen activator receptor (SuPAR) were checked in all participants.
RESULTS
SuPAR and PAI.1 were significant independent predictors of hospital mortality. SuPAR showed sensitivity 100%, specificity 95.9%, and accuracy 94% for prediction of early mortality at a cutoff value of 13.4(pg/ml). While, PAI-1 demonstrated sensitivity 100%, specificity 93.9%, and accuracy of 95% at a cutoff value of 122.5 for predicting mortality.
CONCLUSION
PAI-1 and suPAR were significant predictors of hospital mortality among sepsis patients. The sample size was relatively small, which may have decreased the statistical power of the results of the present study. Hence, additional studies with large sample sizes are required for further validation of the present results.
Topics: Aged; Biomarkers; Female; Hospital Mortality; Humans; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Prognosis; Receptors, Urokinase Plasminogen Activator; Respiratory Rate; Sepsis
PubMed: 34647483
DOI: 10.1177/20587384211048561 -
International Journal of Molecular... Aug 2023Severe hemostatic disturbances and impaired fibrinolysis occur in sepsis. In the most serious cases, the dysregulation of fibrinolysis contributes to septic shock,... (Review)
Review
Severe hemostatic disturbances and impaired fibrinolysis occur in sepsis. In the most serious cases, the dysregulation of fibrinolysis contributes to septic shock, disseminated intravascular coagulation (DIC), and death. Therefore, an analysis of circulating concentrations of pro- and anti-fibrinolytic mediators could be a winning strategy in both the diagnosis and the treatment of sepsis. However, the optimal cutoff value, the timing of the measurements, and their combination with coagulation indicators should be further investigated. The purpose of this review is to summarize all relevant publications regarding the role of the main components of the plasminogen activation system (PAS) in the pathophysiology of sepsis. In addition, the clinical value of PAS-associated biomarkers in the diagnosis and the outcomes of patients with septic syndrome will be explored. In particular, experimental and clinical trials performed in emergency departments highlight the validity of soluble urokinase plasminogen activator receptor (suPAR) as a predictive and prognostic biomarker in patients with sepsis. The measurements of PAI-I may also be useful, as its increase is an early manifestation of sepsis and may precede the development of thrombocytopenia. The upcoming years will undoubtedly see progress in the use of PAS-associated laboratory parameters.
Topics: Humans; Plasminogen; Sepsis; Shock, Septic; Fibrinolysis; Serine Proteases; Biomarkers
PubMed: 37569751
DOI: 10.3390/ijms241512376 -
The Journal of Experimental Medicine Apr 2020Plasminogen and its active form, plasmin, have diverse functions related to the inflammatory response in mammals. Due to these roles in inflammation, plasminogen has... (Review)
Review
Plasminogen and its active form, plasmin, have diverse functions related to the inflammatory response in mammals. Due to these roles in inflammation, plasminogen has been implicated in the progression of a wide range of diseases with an inflammatory component. In this review, we discuss the functions of plasminogen in inflammatory regulation and how this system plays a role in the pathogenesis of diseases spanning organ systems throughout the body.
Topics: Animals; Disease Progression; Fibrinolysin; Humans; Inflammation; Plasminogen
PubMed: 32159743
DOI: 10.1084/jem.20191865 -
International Journal of Molecular... Feb 2023Stressful events trigger a set of complex biological responses which follow a bell-shaped pattern. Low-stress conditions have been shown to elicit beneficial effects,... (Review)
Review
Glucocorticoid-Responsive Tissue Plasminogen Activator (tPA) and Its Inhibitor Plasminogen Activator Inhibitor-1 (PAI-1): Relevance in Stress-Related Psychiatric Disorders.
Stressful events trigger a set of complex biological responses which follow a bell-shaped pattern. Low-stress conditions have been shown to elicit beneficial effects, notably on synaptic plasticity together with an increase in cognitive processes. In contrast, overly intense stress can have deleterious behavioral effects leading to several stress-related pathologies such as anxiety, depression, substance use, obsessive-compulsive and stressor- and trauma-related disorders (e.g., post-traumatic stress disorder or PTSD in the case of traumatic events). Over a number of years, we have demonstrated that in response to stress, glucocorticoid hormones (GCs) in the hippocampus mediate a molecular shift in the balance between the expression of the tissue plasminogen activator (tPA) and its own inhibitor plasminogen activator inhibitor-1 (PAI-1) proteins. Interestingly, a shift in favor of PAI-1 was responsible for PTSD-like memory induction. In this review, after describing the biological system involving GCs, we highlight the key role of tPA/PAI-1 imbalance observed in preclinical and clinical studies associated with the emergence of stress-related pathological conditions. Thus, tPA/PAI-1 protein levels could be predictive biomarkers of the subsequent onset of stress-related disorders, and pharmacological modulation of their activity could be a potential new therapeutic approach for these debilitating conditions.
Topics: Humans; Tissue Plasminogen Activator; Plasminogen Activator Inhibitor 1; Glucocorticoids; Mental Disorders
PubMed: 36901924
DOI: 10.3390/ijms24054496 -
Clinical and Applied... 2022Preeclampsia (PE) is a serious complication of pregnancy. The fibrinolytic system play crucial roles regarding placentation and evolution of PE.
OBJECTIVES
Preeclampsia (PE) is a serious complication of pregnancy. The fibrinolytic system play crucial roles regarding placentation and evolution of PE.
AIM
To study comprehensively components of the fibrinolytic system and fibrin lysability in women with PE.
DESIGN AND METHODS
117 women with PE and matched controls were included. Tissue type plasminogen activator (t-PA), plasminogen, PAI-1, plasmin inhibitor (PI), D-dimer, the fibrinolytic potential of dextran sulphate euglobulin fraction (DEF), PAI-2, polymere PAI-2, fibrin clot lysability, thrombin activatable fibrinolysis inhibitor (TAFI) and fibrinogen were assessed.
RESULTS
Women with PE had significantly increased concentrations of t-PA and PAI-1, whereas the plasma concentration of PAI-2 was significantly lower compared to controls, p < 0.0001. Polymere PAI-2 was detected in both groups. DEF, TAFI and fibrinogen were not different between the groups. D-dimer was significantly increased and plasminogen/PI together with fibrin clot lysability time decreased in the PE-group, p = 0.0004 p = 0.04, p = 0.03, p < 0.0001 respectively.
CONCLUSION
This study demonstrates that PE is associated with an affected t-PA/PAI-1 system, decreased PAI-2 and increased fibrin lysability. Furthermore, PAI-2 has the potential to polymerize during pregnancy.
Topics: Female; Humans; Pregnancy; Antifibrinolytic Agents; Carboxypeptidase B2; Dextran Sulfate; Fibrin; Fibrinogen; Fibrinolysis; Plasminogen; Plasminogen Activator Inhibitor 1; Plasminogen Activator Inhibitor 2; Pre-Eclampsia; Thrombosis; Tissue Plasminogen Activator
PubMed: 36217728
DOI: 10.1177/10760296221126172 -
The Journal of Clinical Investigation Apr 2020BACKGROUNDHBV-related acute-on-chronic liver failure (HBV-ACLF) is hallmarked by high short-term mortality rates, calling for accurate prognostic biomarkers for initial... (Clinical Trial)
Clinical Trial
BACKGROUNDHBV-related acute-on-chronic liver failure (HBV-ACLF) is hallmarked by high short-term mortality rates, calling for accurate prognostic biomarkers for initial risk stratification.METHODSThree tandem mass tag-labeled (TMT-labeled) quantitative proteomic studies were performed on 10 patients with HBV-related acute hepatic decompensation and on 20 patients with HBV-ACLF. Candidate biomarkers were preliminarily verified in a cross-sectional cohort (n = 144) and further confirmed in 2 prospective cohorts (n = 207 and n = 148).RESULTSPlasminogen, a potential prognostic biomarker for HBV-ACLF, was identified by TMT quantitative proteomics and preliminarily verified in the cross-sectional cohort. Further validation with a prospective cohort (n = 207) showed that plasminogen levels at admission were significantly lower (P < 0.001) in HBV-ACLF nonsurvivors than in survivors. The cumulative survival duration of patients with high plasminogen levels was significantly longer (P < 0.001) than that of patients with low plasminogen levels. During hospitalization, plasminogen levels significantly decreased (P = 0.008) in the deterioration group but significantly increased (P < 0.001) in the improvement group. Additionally, plasminogen levels gradually increased in survivors but gradually decreased in nonsurvivors. The P5 score, a prognostic panel incorporating plasminogen levels, hepatic encephalopathy occurrence, age, international normalized ratio (INR), and total bilirubin, was significantly superior to the Child-Pugh, Model for End-stage Liver Disease (MELD), Chronic Liver Failure Consortium ACLF (CLIF-C ACLF), Chinese Group on the Study of Severe Hepatitis B (COSSH), and HINT (a prognostic score based on hepatic encephalopathy occurrence, INR, neutrophil count, and thyroid-stimulating hormone) scores (all P < 0.05). The performances of the plasminogen level and P5 score were validated in a second multicenter, prospective cohort (n = 148).CONCLUSIONSPlasminogen is a promising prognostic biomarker for HBV-ACLF, and sequential plasminogen measurements could profile the clinical course of HBV-ACLF. P5 is a high-performance prognostic score for HBV-ACLF.FUNDINGThe National Key Research and Development Program (2017YFC1200204); the National Natural Science Foundation of China (81400589, 81600497); the Foundation for Innovative Research Groups of the National Natural Science Foundation of China (81121002); the Chinese High-Tech Research and Development Programs (2012AA020204); the National S&T Major Project (2012ZX10002004); and the Zhejiang Provincial Medicine and Health Science and Technology Project (2016147735).
Topics: Acute-On-Chronic Liver Failure; Adult; Biomarkers; Female; Hepatitis B virus; Hepatitis B, Chronic; Humans; Male; Middle Aged; Plasminogen
PubMed: 32175919
DOI: 10.1172/JCI130197 -
Neural Regeneration Research Dec 2020Plasmin is generally known as a promotor of inflammation. Recent advancement suggests that it has a complex role as immunity modulator. Pharmacological inhibition of... (Review)
Review
Plasmin is generally known as a promotor of inflammation. Recent advancement suggests that it has a complex role as immunity modulator. Pharmacological inhibition of plasmin production and activity has been proven to improve neurological outcomes in traumatic brain injury and subarachnoid hemorrhage, most probably by preventing re-bleeding. The immune-modulatory properties of antifibrinolytics, however, suggest that they probably have effects unrelated to fibrinolysis inhibition, which are currently not adequately harnessed. The present work aims to give an account of the existing data regarding antifibrinolytics as agents influencing neuroinflammation. Preclinical and clinical studies on the possible influence of antifibrinolytics on neuroinflammation are scarce. However, the emerging evidence suggests that inhibition of plasmin(ogen) activity can ameliorate neuroinflammation to some extent. This data demonstrate that plasmin(ogen) is not exclusively involved in fibrinolysis, but also has other substrates and can precipitate in inflammatory processes. Investigation on the role of plasmin as the factor for the development of neuroinflammation shows the significant potential of antifibrinolytics as pharmacotherapy of neuroinflammationm, which is worthy of further exploration.
PubMed: 32594031
DOI: 10.4103/1673-5374.284979 -
Diabetology & Metabolic Syndrome Sep 2022Plasminogen activator inhibitor 1 (PAI-1) also known as serpin E1 or endothelial plasminogen activator inhibitor, is produced from endothelial cells and adipose tissue.... (Review)
Review
Plasminogen activator inhibitor 1 (PAI-1) also known as serpin E1 or endothelial plasminogen activator inhibitor, is produced from endothelial cells and adipose tissue. PAI-1 inhibits tissue plasminogen activator (tPA) and urokinase (uPA) preventing activation of plasminogen and fibrinolysis. Gestational diabetes mellitus (GDM) is defined as glucose intolerance and hyperglycemia during pregnancy. The underlying mechanism of GDM is due to the reduction of insulin secretion or the development of insulin resistance (IR). Normal PAI-1 is a crucial mediator for maintaining pregnancy, though aberrantly high PAI-1 promotes inflammation and thrombosis with increased risk of pregnancy loss. Increasing PAI-1 level had been shown to be an early feature of cardio-metabolic derangement in women with GDM. As well, GDM is regarded as an independent predictor for increasing PAI-1 levels compared to normal pregnancy. Taken together, GDM seems to be the causal factor in the increase of PAI-1 via induction of IR, hyperglycemia and hypertriglyceridemia. In conclusion, GDM triggers expression and release of PAI-1 which linked with GDM severity due to exaggerated pro-inflammatory and inflammatory cytokines with the development of IR. High PAI-1 levels in GDM may induce hypofibrinolysis and thrombotic complications.
PubMed: 36076264
DOI: 10.1186/s13098-022-00900-2