Myeloperoxidase instigates proinflammatory responses in a cecal ligation and puncture rat model of sepsis

Using two distinct myeloperoxidase (MPO) inhibitors, we show for the first time that MPO plays an important role in producing increases in free 2-chlorofatty aldehyde (2-ClFALD)—a powerful proinflammatory chlorinated lipid in plasma and intestine—a number of cytokines and other inflammatory mediators, leukocyte and platelet rolling and adhesion in postcapillary venules, and lung injury in a cecal ligation and puncture model of sepsis. In addition, the use of a plasminogen activator inhibitor-1 (PAI-1) inhibitor or a mast cell stabilizer prevented inflammatory responses in CLP-induced sepsis. PAI-1 inhibition also prevented the proinflammatory responses to exogenous 2-ClFALD superfusion. Thus, our study provides some of the first evidence that MPO-derived free 2-ClFA plays an important role in CLP-induced sepsis by a PAI-1- and mast cell-dependent mechanism.

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Atorvastatin Inhibits Endothelial PAI-1-Mediated Monocyte Migration and Alleviates Radiation-Induced Enteropathy

International Journal of Molecular Sciences ◽

10.3390/ijms22041828 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1828

Author(s):

Seo Young Kwak ◽

Sunhoo Park ◽

Hyewon Kim ◽

Sun-Joo Lee ◽

Won-Suk Jang ◽

...

Keyword(s):

Mouse Model ◽

Inflammatory Responses ◽

Umbilical Vein ◽

Plasminogen Activator Inhibitor ◽

Endothelial Damage ◽

Plasminogen Activator Inhibitor 1 ◽

Monocyte Migration ◽

Radiation Induced ◽

Umbilical Vein Endothelial Cells ◽

Pai 1

Intestinal injury is observed in cancer patients after radiotherapy and in individuals exposed to radiation after a nuclear accident. Radiation disrupts normal vascular homeostasis in the gastrointestinal system by inducing endothelial damage and senescence. Despite advances in medical technology, the toxicity of radiation to healthy tissue remains an issue. To address this issue, we investigated the effect of atorvastatin, a commonly prescribed hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor of cholesterol synthesis, on radiation-induced enteropathy and inflammatory responses. We selected atorvastatin based on its pleiotropic anti-fibrotic and anti-inflammatory effects. We found that atorvastatin mitigated radiation-induced endothelial damage by regulating plasminogen activator inhibitor-1 (PAI-1) using human umbilical vein endothelial cells (HUVECs) and mouse model. PAI-1 secreted by HUVECs contributed to endothelial dysfunction and trans-endothelial monocyte migration after radiation exposure. We observed that PAI-1 production and secretion was inhibited by atorvastatin in irradiated HUVECs and radiation-induced enteropathy mouse model. More specifically, atorvastatin inhibited PAI-1 production following radiation through the JNK/c-Jun signaling pathway. Together, our findings suggest that atorvastatin alleviates radiation-induced enteropathy and supports the investigation of atorvastatin as a radio-mitigator in patients receiving radiotherapy.

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Recurrence and Late Sequelae after First-Time Deep Vein Thrombosis: Relationship to Initial Signs

Phlebology The Journal of Venous Disease ◽

10.1177/026835559300800205 ◽

1993 ◽

Vol 8 (2) ◽

pp. 62-67 ◽

Cited By ~ 13

Author(s):

C. Lagerstedt ◽

C.-G. Olsson ◽

B. Fagher ◽

L. Norgren ◽

L. Tengborn

Keyword(s):

Clinical Signs ◽

Plasminogen Activator Inhibitor ◽

University Hospital ◽

Poor Correlation ◽

Plasminogen Activator Inhibitor 1 ◽

Vein Thrombosis ◽

Initial Symptoms ◽

First Time ◽

Pai 1

Objective: To investigate the relation between initial symptoms and long-term sequelae in first-time deep venous thrombosis (DVT). Design: Follow-up study of patients 6 years after an episode of suspected symptomatic DVT. Setting: Vascular laboratory, University Hospital of Lund. Patients: 66 patients, 19 with femoral DVT, 20 with calf DVT and 27 with normal phlebograms at initial investigation. Main outcome measures: Symptoms and signs of chronic venous insufficiency (CVI), foot volumetry and measurement of plasminogen activator inhibitor 1 (PAI-1) activity. Initial clinical signs and results at phlebography were compared with findings at follow-up. Results: Of patients with DVT, 11 (28%) had been treated for a recurrent DVT during follow-up. No relation was found between initial signs of DVT and late signs of CVI. Patients with DVT had significantly more signs of CVI but symptoms did not differ between the groups. Mean levels of PAI-1 activity were similar in the three groups, and patients with recurrent DVT did not differ. Refilling flow was related to the clinical CVI-score, and expelled volume was inversely related to the extension of DVT at phlebography. Conclusion: The recurrence rate is high in first-time DVT, but symptoms are mostly mild as long as after 6 years. There is a poor correlation between symptoms of CVI and objective findings. The late development of CVI cannot be predicted from the clinical signs in the acute phase. Levels of PAI-1 do not correlate with the degree of CVI.

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Yiqi-Huoxue Granule (YQHX) Downregulates Prothrombotic Factors by Modulating KLF2 and NF-κB in HUVECs following LPS Stimulation

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/9425183 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10

Author(s):

Hong Wu ◽

Xinzhou Wang ◽

Shuibo Gao ◽

Liping Dai ◽

Haibin Tong ◽

...

Keyword(s):

Chinese Medicine ◽

Inflammatory Responses ◽

Blood Stasis ◽

Plasminogen Activator Inhibitor ◽

Nuclear Factor ◽

Plasminogen Activator Inhibitor 1 ◽

Antithrombotic Activity ◽

Activator Inhibitor ◽

Pai 1 ◽

Dependent Mechanism

The Yiqi-Huoxue granule (YQHX) is a traditional Chinese medication widely used in the therapy of the traditional Chinese medicine diagnosis “Qi deficiency” or “blood stasis” in China. Both these symptoms are related to inflammation, but the mechanisms of YQHX against inflammation are largely unknown. Thus, our present study investigated the effects of YQHX on regulating inflammatory responses induced by lipopolysaccharides (LPS) in HUVECs. Our data found that YQHX remarkably inhibits the production of prothrombotic factors, plasminogen activator inhibitor-1 (PAI-1) and tissue factor (TF), while it upregulates the protein expression of Kruppel-like factor 2 (KLF2). The increase in PAI-1 and TF was significantly attenuated through a transgenic knockdown in KLF2 with a Lenti-shKLF2 vector. YQHX also decreases the phosphorylation of nuclear factor-κB (NF-κB) p65 and IκB following LPS stimulation, and it effectively suppresses PAI-1 and TF via a NF-κB-dependent mechanism. Taken together, our results suggest that YQHX provides a notable antithrombotic activity via regulating the KLF2 expression and NF-κB signaling pathway in HUVECs. The KLF2 and NF-κB may be potential therapeutic targets for interventions of inflammation associated with atherosclerosis.

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Inhibition of neutrophil apoptosis by PAI-1

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00075.2011 ◽

2011 ◽

Vol 301 (2) ◽

pp. L247-L254 ◽

Cited By ~ 16

Author(s):

Jaroslaw W. Zmijewski ◽

Hong-Beom Bae ◽

Jessy S. Deshane ◽

Cynthia B. Peterson ◽

David D. Chaplin ◽

...

Keyword(s):

Plasminogen Activator ◽

Inflammatory Responses ◽

Apoptotic Cell ◽

Plasminogen Activator Inhibitor ◽

Selective Inhibition ◽

Plasminogen Activator Inhibitor 1 ◽

Urokinase Plasminogen Activator Receptor ◽

G Protein Coupled ◽

Pai 1

Increased circulating and tissue levels of plasminogen activator inhibitor 1 (PAI-1) are often present in severe inflammatory states associated with neutrophil activation and accumulation and correlate with poor clinical outcome from many of these conditions. The mechanisms by which PAI-1 contributes to inflammation have not been fully delineated. In the present experiments, we found that addition of PAI-1 to neutrophil cultures diminished the rate of spontaneous and TNF-related apoptosis-inducing ligand-induced apoptotic cell death. The effects of PAI-1 on cell viability were associated with activation of antiapoptotic signaling pathways, including upregulation of PKB/Akt, Mcl-1, and Bcl-xL. Although urokinase-plasminogen activator receptor, lipoprotein receptor-related protein, and vitronectin are primary ligands for PAI-1, these molecules were not involved in mediating its antiapoptotic properties. In contrast, blocking pertussis toxin-sensitive G protein-coupled receptors and selective inhibition of phosphatidylinositide 3-kinase reversed the ability of PAI-1 to extend neutrophil viability. The antiapoptotic effects of PAI-1 were also evident under in vivo conditions during LPS-induced acute lung injury, where enhanced apoptosis was present among neutrophils accumulating in the lungs of PAI-1−/−compared with PAI-1+/+mice. These results demonstrate a novel antiapoptotic role for PAI-1 that may contribute to its participation in neutrophil-associated inflammatory responses.

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943: Plasminogen Activator Inhibitor 1 (PAI-1) is Increased in Human Peyronie's Disease

The Journal of Urology ◽

10.1016/s0022-5347(18)35099-7 ◽

2005 ◽

Vol 173 (4S) ◽

pp. 255-255 ◽

Cited By ~ 1

Author(s):

Hugo H. Davila ◽

Thomas R. Magee ◽

Freddy Zuniga ◽

Jacob Rajfer ◽

Nestor F. GonzalezCadavid

Keyword(s):

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

Peyronie’S Disease ◽

Plasminogen Activator Inhibitor 1 ◽

Peyronie's Disease ◽

Activator Inhibitor ◽

Pai 1

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Relationship of Plasminogen Activator Inhibitor-1 Levels following Thrombolytic Therapy with rt-PA as Compared to Streptokinase and Patency of Infarct Related Coronary Artery

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614637 ◽

1999 ◽

Vol 82 (07) ◽

pp. 104-108 ◽

Cited By ~ 13

Author(s):

Franck Paganelli ◽

Marie Christine Alessi ◽

Pierre Morange ◽

Jean Michel Maixent ◽

Samuel Lévy ◽

...

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Thrombolytic Therapy ◽

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

Control Group ◽

Plasminogen Activator Inhibitor 1 ◽

Vessel Patency ◽

Activator Inhibitor ◽

Pai 1

Summary Background: Type 1 plasminogen activator inhibitor (PAI-1) is considered to be risk factor for acute myocardial infarction (AMI). A rebound of circulating PAI-1 has been reported after rt-PA administration. We investigated the relationships between PAI-1 levels before and after thrombolytic therapy with streptokinase (SK) as compared to rt-PA and the patency of infarct-related arteries. Methods and Results: Fifty five consecutive patients with acute MI were randomized to strep-tokinase or rt-PA. The plasma PAI-1 levels were studied before and serially within 24 h after thrombolytic administration. Vessel patency was assessed by an angiogram at 5 ± 1days. The PAI-1 levels increased significantly with both rt-PA and SK as shown by the levels obtained from a control group of 10 patients treated with coronary angioplasty alone. However, the area under the PAI-1 curve was significantly higher with SK than with rt-PA (p <0.01) and the plasma PAI-1 levels peaked later with SK than with rt-PA (18 h versus 3 h respectively). Conversely to PAI-1 levels on admission, the PAI-1 levels after thrombolysis were related to vessel patency. Plasma PAI-1 levels 6 and 18 h after SK therapy and the area under the PAI-1 curve were significantly higher in patients with occluded arteries (p <0.002, p <0.04 and p <0.05 respectively).The same tendency was observed in the t-PA group without reaching significance. Conclusions: This study showed that the PAI-1 level increase is more pronounced after SK treatment than after t-PA treatment. There is a relationship between increased PAI-1 levels after thrombolytic therapy and poor patency. Therapeutic approaches aimed at quenching PAI-1 activity after thrombolysis might be of interest to improve the efficacy of thrombolytic therapy for acute myocardial infarction.

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Fibrinolysis in Normal Subjects - Comparison Between Plasminogen Activator Inhibitor and Other Components of the Fibrinolytic System

Thrombosis and Haemostasis ◽

10.1055/s-0038-1642775 ◽

1988 ◽

Vol 59 (02) ◽

pp. 299-303 ◽

Cited By ~ 40

Author(s):

Grazia Nicoloso ◽

Jacques Hauert ◽

Egbert K O Kruithof ◽

Guy Van Melle ◽

Fedor Bachmann

Keyword(s):

Plasminogen Activator ◽

Fibrinolytic Activity ◽

Plasminogen Activator Inhibitor ◽

Venous Occlusion ◽

Venous Stasis ◽

Plasminogen Activator Inhibitor 1 ◽

Plate Assay ◽

Fibrin Plate ◽

Activator Inhibitor ◽

Pai 1

SummaryWe analyzed fibrinolytic parameters in 20 healthy men and 20 healthy women, aged from 25 to 59, before and after 10 and 20 min venous occlusion. The 10 min post-occlusion fibrinolytic activity measured directly in diluted unfractionated plasma by a highly sensitive 125I-fibrin plate assay correlated well with the activity of euglobulins determined by the classical fibrin plate assay (r = 0.729), but pre-stasis activities determined with these two methods did not correlate (r = 0.084). The enhancement of fibrinolytic activity after venous occlusion was mainly due to an increase of t-PA in the occluded vessels (4-fold increase t-PA antigen after 10 min and 8-fold after 20 min venous occlusion). Plasminogen activator inhibitor (PAI) activity and plasminogen activator inhibitor 1 (PAI-1)1 antigen levels at rest showed considerable dispersion ranging from 1.9 to 12.4 U/ml, respectively 6.9 to 77 ng/ml. A significant increase of PAI-1 antigen levels was observed after 10 and 20 min venous occlusion. At rest no correlation was found between PAI activity or PAI-1 antigen levels and the fibrinolytic activity measured by 125I-FPA. However, a high level of PAI-1 at rest was associated with a high prestasis antigen level of t-PA and a low fibrinolytic response after 10 min of venous stasis. Since the fibrinolytic response inversely correlated with PAI activity at rest, we conclude that its degree depends mainly on the presence of free PAI.

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Polymorphisms of the Plasminogen Activator Inhibitor- 1 Gene in Type 1 and Type 2 Diabetes, and in Patients with Diabetic Retinopathy

Thrombosis and Haemostasis ◽

10.1055/s-0038-1642514 ◽

1994 ◽

Vol 71 (06) ◽

pp. 731-736 ◽

Cited By ~ 29

Author(s):

M W Mansfield ◽

M H Stickland ◽

A M Carter ◽

P J Grant

Keyword(s):

Diabetic Retinopathy ◽

Plasminogen Activator Inhibitor ◽

Allelic Frequency ◽

Repeat Sequence ◽

Dinucleotide Repeat ◽

Plasminogen Activator Inhibitor 1 ◽

The Difference ◽

Pai 1

SummaryTo identify whether genotype contributes to the difference in PAI-1 levels in type 1 and type 2 diabetic subjects and whether genotype relates to the development of retinopathy, a Hind III restriction fragment length polymorphism and two dinucleotide repeat polymorphisms were studied. In 519 Caucasian diabetic subjects (192 type 1, 327 type 2) and 123 Caucasian control subjects there were no differences in the frequency of the Hind III restriction alleles (type 1 vs type 2 vs control: allele 1 0.397 vs 0.420 vs 0.448; allele 2 0.603 vs 0.580 vs 0.552) nor in the allelic frequency at either dinucleotide repeat sequence. In 86 subjects with no retinopathy at 15 years or more from diagnosis of diabetes and 190 subjects with diabetic retinopathy there was no difference in the frequency of Hind III restriction alleles (retinopathy present vs retinopathy absent: allele 1 0.400 vs 0.467; allele 2 0.600 vs 0.533) nor in the allelic frequencies at either dinucleotide repeat sequence. The results indicate that there is no or minimal influence of the PAI-1 gene on either PAI-1 levels or the development of diabetic retinopathy in patients with diabetes mellitus.

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A Specific Immunologic Assay for Functional Plasminogen Activator Inhibitor 1 in Plasma – Standardized Measurements of the Inhibitor and Related Parameters in Patients with Venous Thromboembolic Disease

Thrombosis and Haemostasis ◽

10.1055/s-0038-1646305 ◽

1992 ◽

Vol 68 (05) ◽

pp. 486-494 ◽

Cited By ~ 15

Author(s):

Malou Philips ◽

Anne-Grethe Juul ◽

Johan Selmer ◽

Bent Lind ◽

Sixtus Thorsen

Keyword(s):

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

Normal Subjects ◽

Tissue Type ◽

Blood Collection ◽

Plasminogen Activator Inhibitor 1 ◽

Type Plasminogen Activator ◽

Significant Difference ◽

Activator Inhibitor ◽

Pai 1

SummaryA new assay for functional plasminogen activator inhibitor 1 (PAI-1) in plasma was developed. The assay is based on the quantitative conversion of PAI-1 to urokinase-type plasminogen activator (u-PA)-PAI-l complex the concentration of which is then determined by an ELISA employing monoclonal anti-PAI-1 as catching antibody and monoclonal anti-u-PA as detecting antibody. The assay exhibits high sensitivity, specificity, accuracy, and precision. The level of functional PAI-1, tissue-type plasminogen activator (t-PA) activity and t-PA-PAI-1 complex was measured in normal subjects and in patients with venous thromboembolism in a silent phase. Blood collection procedures and calibration of the respective assays were rigorously standardized. It was found that the patients had a decreased fibrinolytic capacity. This could be ascribed to high plasma levels of PAI-1. The release of t-PA during venous occlusion of an arm for 10 min expressed as the increase in t-PA + t-PA-PAI-1 complex exhibited great variation and no significant difference could be demonstrated between the patients with a thrombotic tendency and the normal subjects.

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Relation between Plasminogen Activator Inhibitor-1 and Hepatic Enzyme Concentrations in Hyperlipidemic Patients

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648885 ◽

1994 ◽

Vol 72 (03) ◽

pp. 434-437 ◽

Cited By ~ 10

Author(s):

E Bruckert ◽

A Ankri ◽

P Glral ◽

G Turpin

Keyword(s):

Blood Pressure ◽

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

Tolerance Test ◽

High Plasma ◽

Oral Glucose ◽

Plasminogen Activator Inhibitor 1 ◽

Glutamyl Transferase ◽

Activator Inhibitor ◽

Pai 1

SummaryPlasminogen activator inhibitor type-1 (PAI-1) is a key determinant of the fibrinolytic capacity. Its activity correlates with most of the characteristic features of insulin resistance syndrome, i. e. obesity, high blood pressure and hyperlipidemia.We measured plasma PAI-1 antigen levels in 131 asymptomatic men (aged 44.2 ± 11 years) who had been referred for hyperlipidemia. Those taking medication and those with a secondary hyperlipidemia were excluded.We confirmed the correlation between PAI-1 levels and the following variables: body mass index, blood pressure, triglyceride concentration, and blood glucose and insulin levels before and after an oral glucose tolerance test. We also found a significant and independent correlation between PAI-1 and the concentration of the hepatic enzymes glutamyl transferase, alanine aminotransferase and aspartate aminotransferase.Mild liver abnormalities (presumably steatosis) may thus be one of the factors accounting for high plasma PAI-1 levels in hyperlipidemic patients.

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