scholarly journals Hypersensitivity of Aryl Hydrocarbon Receptor-Deficient Mice to Lipopolysaccharide-Induced Septic Shock

2009 ◽  
Vol 29 (24) ◽  
pp. 6391-6400 ◽  
Author(s):  
Hiroki Sekine ◽  
Junsei Mimura ◽  
Motohiko Oshima ◽  
Hiromi Okawa ◽  
Jun Kanno ◽  
...  
Keyword(s):  
Septic Shock ◽  
Aryl Hydrocarbon Receptor ◽  
Plasminogen Activator Inhibitor ◽  
Dependent Manner ◽  
Wild Type ◽  
Toxicological Effects ◽  
Aryl Hydrocarbon ◽  
Polycyclic Aromatic ◽  
Deficient Mice ◽  
Activator Inhibitor

ABSTRACT Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, is known to mediate a wide variety of pharmacological and toxicological effects caused by polycyclic aromatic hydrocarbons. Recent studies have revealed that AhR is involved in the normal development and homeostasis of many organs. Here, we demonstrate that AhR knockout (AhR KO) mice are hypersensitive to lipopolysaccharide (LPS)-induced septic shock, mainly due to the dysfunction of their macrophages. In response to LPS, bone marrow-derived macrophages (BMDM) of AhR KO mice secreted an enhanced amount of interleukin-1β (IL-1β). Since the enhanced IL-1β secretion was suppressed by supplementing Plasminogen activator inhibitor-2 (Pai-2) expression through transduction with Pai-2-expressing adenoviruses, reduced Pai-2 expression could be a cause of the increased IL-1β secretion by AhR KO mouse BMDM. Analysis of gene expression revealed that AhR directly regulates the expression of Pai-2 through a mechanism involving NF-κB but not AhR nuclear translocator (Arnt), in an LPS-dependent manner. Together with the result that administration of the AhR ligand 3-methylcholanthrene partially protected mice with wild-type AhR from endotoxin-induced death, these results raise the possibility that an appropriate AhR ligand may be useful for treating patients with inflammatory disorders.

Intra-airway administration of small interfering RNA targeting plasminogen activator inhibitor-1 attenuates allergic asthma in mice

2011 ◽  
Vol 301 (6) ◽  
pp. L908-L916 ◽  
Author(s):  
Shintaro Miyamoto ◽  
Noboru Hattori ◽  
Tadashi Senoo ◽  
Yojiro Onari ◽  
Hiroshi Iwamoto ◽  
...  
Keyword(s):  
Small Interfering Rna ◽  
Plasminogen Activator Inhibitor ◽  
Healthy Controls ◽  
Wild Type ◽  
Plasminogen Activator Inhibitor 1 ◽  
Asthma Model ◽  
Interfering Rna ◽  
Deficient Mice ◽  
Activator Inhibitor ◽  
Pai 1

Recent studies suggest that plasminogen activator inhibitor-1 (PAI-1), a major inhibitor of the fibrinolytic system, may promote the development of asthma. To further investigate the significance of PAI-1 in the pathogenesis of asthma and determine the possibility that PAI-1 could be a therapeutic target for asthma, this study was conducted. First, PAI-1 levels in induced sputum (IS) from asthmatic subjects and healthy controls were measured. In asthmatic subjects, IS PAI-1 levels were elevated, compared with that of healthy controls, and were significantly higher in patients with long-duration asthma compared with short-duration asthma. PAI-1 levels were also found to correlate with IS transforming growth factor-β levels. Then, acute and chronic asthma models induced by ovalbumin were established in PAI-1-deficient mice and wild-type mice that received intra-airway administrations of small interfering RNA against PAI-1 (PAI-1-siRNA). We could demonstrate that eosinophilic airway inflammation and airway hyperresponsiveness were reduced in an acute asthma model, and airway remodeling was suppressed in a chronic asthma model in both PAI-1-deficient mice and wild-type mice that received intra-airway administration of PAI-1-siRNA. These results indicate that PAI-1 is strongly involved in the pathogenesis of asthma, and intra-airway administration of PAI-1-siRNA may be able to become a new therapeutic approach for asthma.

scholarly journals Plasminogen Activator Inhibitor-Type I Gene Deficient Mice Show Reduced Influx of Neutrophils in Ventilator-Induced Lung Injury

2011 ◽  
Vol 2011 ◽  
pp. 1-11
Author(s):  
Esther K. Wolthuis ◽  
Alexander P. J. Vlaar ◽  
Jorrit-Jan H. Hofstra ◽  
Joris J. T. H. Roelofs ◽  
Vivian de Waard ◽  
...  
Keyword(s):  
Lung Injury ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Lavage Fluid ◽  
Type I ◽  
Wild Type ◽  
Ventilator Induced Lung Injury ◽  
Deficient Mice ◽  
Activator Inhibitor ◽  
Pai 1

Ventilator-induced lung injury (VILI) is associated with inhibition of the fibrinolytic system secondary to increased production of plasminogen activator inhibitor- (PAI-)1. To determine the role of PAI-1 on pulmonary coagulopathy and inflammation during mechanical ventilation, PAI-1 gene-deficient mice and their wild-type littermates were anesthetized (control), or anesthetized, tracheotomized and subsequently ventilated for 5 hours with either low tidal volumes () or high tidal volumes (). VILI was assessed by pulmonary coagulopathy, lung wet-to-dry ratios, total protein level in bronchoalveolar lavage fluid, neutrophil influx, histopathology, and pulmonary and plasma cytokine levels. Ventilation resulted in pulmonary coagulopathy and inflammation, with more injury following ventilation with as compared to . In PAI-1 gene-deficient mice, the influx of neutrophils in the pulmonary compartment was attenuated, while increased levels of pulmonary cytokines were found. Other endpoints of VILI were not different between PAI-1 gene-deficient and wild-type mice. These data indicate that a defect fibrinolytic response attenuates recruitment of neutrophils in VILI.

Enhanced Fibrinolytic Potential in Mice with Combined Homozygous Deficiency of α2-antiplasmin and PAI-1

2001 ◽  
Vol 86 (08) ◽  
pp. 640-646 ◽  
Author(s):  
D. Collen ◽  
H. R. Lijnen ◽  
M. Dewerchin
Keyword(s):  
Plasminogen Activator Inhibitor ◽  
Fibrin Deposition ◽  
Wild Type ◽  
Plasminogen Activator Inhibitor 1 ◽  
Fibrinolytic Potential ◽  
Fibrinolytic Capacity ◽  
Deficient Mice ◽  
Activator Inhibitor ◽  
Pai 1 ◽  
Combined Deficiency

Summaryα2-antiplasmin (α2-AP) and plasminogen activator inhibitor-1 (PAI-1) are the main physiological inhibitors of the plasminogen/ plasmin system in mammalian plasma. In the present study, the relative importance of both inhibitors was evaluated with the use of mice with single or combined deficiency of α2-AP and PAI-1 in the same genetic background. Mice with combined deficiency (α2-AP–/–:PAI-1–/–) are viable, develop normally and are fertile. After amputation of the tail, bleeding times are prolonged (>15 min) in α2-AP–/–:PAI-1–/– mice, as compared to double wild-type or single deficient mice (4.6 to 10 min). Spontaneous lysis after 4 h of intravenously injected 125I-fibrin labeled plasma clots is significantly higher in mice with α2-AP deficiency both in the PAI-1+/+ background (89 ± 2% versus 42 ± 3%; p = 0.002) and in the PAI-1–/– background (83 ± 4% versus 53 ± 5%; p = 0.002). PAI-1 deletion in the α2-AP+/+ or α2-AP–/– background, however, has no significant effect (p = 0.13 or 0.18, respectively). Four hours after endotoxin injection, fibrin deposition in the kidneys is not significantly affected by PAI-1 deletion in mice with α2-AP+/+ or α2-AP–/– background (p = 0.07 and 0.19, respectively). In contrast, α2-AP deletion causes significantly reduced fibrin deposition in the PAI-1+/+ background (p = 0.01). Endotoxin injection causes a dramatic increase in PAI-1 antigen levels in kidney extracts of PAI-1+/+ animals, without effect on α2-AP levels.Taken together, these data indicate that the higher endogenous fibrinolytic capacity observed in mice with combined deficiency is mainly due to the lack of α2-AP and suggest a less important role for PAI-1.

Abstract 188: Selective Inhibition of Vascular Smooth Muscle Cell Migration by Targeting Plasminogen Activator Inhibitor-1

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Neha Goyal ◽  
Zhen Weng ◽  
Philip Fish ◽  
Tammy Strawn ◽  
Samantha Myears ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Cell Migration ◽  
Plasminogen Activator ◽  
Intimal Hyperplasia ◽  
Differential Effect ◽  
Plasminogen Activator Inhibitor ◽  
Dependent Manner ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor ◽  
Pai 1

Introduction: Plasminogen activator inhibitor-1 (PAI-1) is the primary inhibitor of mammalian plasminogen activators and an important regulator of cell migration. We have shown that tiplaxtinin, a small molecule, specific inhibitor of PAI-1, inhibits intimal hyperplasia in a murine vein graft model. However, little is known about the effects of pharmacological inhibition of PAI-1 on vascular cell migration under physiologically relevant conditions. Methods: We studied the effects of tiplaxtinin on migration of smooth muscle cells (SMCs) and endothelial cells (ECs). Results: Tiplaxtinin significantly inhibited migration of murine SMCs through 3-dimensional (3-D) collagen matrix in a concentration-dependent manner. Tiplaxtinin did not inhibit SMC proliferation, and it did not inhibit migration of PAI-1-deficient SMCs, suggesting that tiplaxtinin’s effect on SMCs was non-toxic and PAI-1-dependent. The anti-migratory effect of tiplaxtinin on SMCs was preserved in collagen 3-D matrix containing vitronectin and other extracellular matrix molecules, further supporting the physiological significance of the effect. In contrast to SMCs, tiplaxtinin did not inhibit migration of human aortic ECs in vitro or murine ECs in vivo, the latter assessed in a murine carotid injury model. To study the basis for the differential effect of tiplaxtinin on SMCs vs. ECs, we compared expression of LDL receptor-related protein 1 (LRP1), a motogenic receptor for PAI-1, between cell types by RT-PCR and found that LRP1 gene expression was significantly lower in ECs than in SMCs. Furthermore, recombinant PAI-1 stimulated the migration of wild-type mouse embryonic fibroblasts (MEFs), but not LRP1-deficient MEFs. Conclusions: Tiplaxtinin, a pharmacological inhibitor of PAI-1, inhibits SMC migration under physiological conditions, while having no inhibitory effect on EC migration. The differential effect of PAI-1 inhibition on SMCs vs. ECs appears to be mediated by LRP1 and may be of clinical significance, as it is advantageous to prevent intimal hyperplasia by inhibiting SMC migration without inhibiting EC migration, which is key to preserving an intact, anti-thrombotic vascular endothelium.

scholarly journals Protection of Plasminogen Activator Inhibitor-1-Deficient Mice from Nasal Allergy

2005 ◽  
Vol 174 (12) ◽  
pp. 8135-8143 ◽  
Author(s):  
Takayuki Sejima ◽  
Seiji Madoiwa ◽  
Jun Mimuro ◽  
Teruko Sugo ◽  
Kiyotaka Okada ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Nasal Allergy ◽  
Plasminogen Activator Inhibitor 1 ◽  
Deficient Mice ◽  
Activator Inhibitor

scholarly journals Endotoxin-induced production of plasminogen activator inhibitor by human monocytes is autonomous and can be inhibited by lipid X

Blood ◽  
1989 ◽  
Vol 73 (8) ◽  
pp. 2188-2195 ◽  
Author(s):  
BS Schwartz ◽  
MC Monroe ◽  
JD Bradshaw
Keyword(s):  
Tissue Factor ◽  
Plasminogen Activator ◽  
Lipid A ◽  
Mononuclear Cells ◽  
Plasminogen Activator Inhibitor ◽  
Dependent Manner ◽  
Peripheral Blood Mononuclear ◽  
Inhibitor Type ◽  
Activator Inhibitor Type ◽  
Activator Inhibitor

Abstract Peripheral blood mononuclear cells (PBMs) produce both tissue factor and plasminogen activator inhibitor type 2 (PAI-2) in response to gram- negative bacterial lipopolysaccharide (LPS). The cellular roles in the tissue factor response have been previously elucidated, and we now report those roles in PAI-2 production. Monocytes are the only cells among LPS-stimulated PBMs that produce PAI-2 as assessed by measurement of PAI-2 activity and antigen. Concomitant immunohistochemistry demonstrated that monocytes contain PAI-2, with a greater number staining positively and more intensely after exposure to LPS. LPS- stimulated monocytes produced increased amounts of PAI-2 with or without addition of lymphocytes. Lymphocytes prestimulated with LPS and then washed did not induce PAI-2 production in monocytes to which they were added. Lipid X, a precursor in the biosynthetic pathway of lipid A and LPS, was able to inhibit LPS induction of monocyte PAI-2 in a dose- dependent manner. This inhibition was not due to cellular toxicity, the phospholipidlike nature of lipid X, interference with the PAI-2 assay, or monocyte production of a substance interfering with PAI-2. Lipid X was an effective inhibitor of PAI-2 production even when added up to 30 minutes after LPS.

scholarly journals Interleukin 33 Expression Induced by Aryl Hydrocarbon Receptor in Macrophages

2019 ◽  
Vol 170 (2) ◽  
pp. 404-414 ◽  
Author(s):  
Yasuhiro Ishihara ◽  
Thomas Haarmann-Stemmann ◽  
Norman Y Kado ◽  
Christoph F A Vogel
Keyword(s):  
Particulate Matter ◽  
Aryl Hydrocarbon Receptor ◽  
Airway Inflammation ◽  
Airborne Particulate Matter ◽  
Response To Treatment ◽  
Luciferase Assay ◽  
Interleukin 33 ◽  
Aryl Hydrocarbon ◽  
Polycyclic Aromatic ◽  
Mrna And Protein Expression

Abstract Polycyclic aromatic hydrocarbons (PAHs) contained in airborne particulate matter have been identified as a contributing factor for inflammation in the respiratory tract. Recently, interleukin-33 (IL-33) is strongly suggested to be associated with airway inflammation. Aryl hydrocarbon receptor (AhR) is a receptor for PAHs to regulate several metabolic enzymes, but the relationships between AhR and airway inflammation are still unclear. In this study, we examined the role of AhR in the expression of IL-33 in macrophages. THP-1 macrophages mainly expressed IL-33 variant 5, which in turn was strongly induced by the AhR agonists 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) and kynurenine (KYN). AhR antagonist CH223191 suppressed the increase in IL-33 expression. Promoter analysis revealed that the IL-33 promoter has 2 dioxin response elements (DREs). AhR was recruited to both DREs after treatment with TCDD or KYN as assessed by gel shift and chromatin immunoprecipitation assays. A luciferase assay showed that one of the DREs was functional and involved in the expression of IL-33. Macrophages isolated from AhR-null mice expressed only low levels of IL-33 even in response to treatment with AhR ligands compared with wild-type cells. The treatment of THP-1 macrophages with diesel particulate matter and particle extracts increased the mRNA and protein expression of IL-33. Taken together, the results show that ligand-activated AhR mediates the induction of IL-33 in macrophages via a DRE located in the IL-33 promoter region. AhR-mediated IL-33 induction could be involved in the exacerbation and/or prolongation of airway inflammation elicited by toxic chemical substances.

Polycyclic Aromatic Hydrocarbons Can Trigger Hepatocyte Release of Extracellular Vesicles by Various Mechanisms of Action Depending on Their Affinity for the Aryl Hydrocarbon Receptor

2019 ◽  
Vol 171 (2) ◽  
pp. 443-462 ◽  
Author(s):  
Nettie van Meteren ◽  
Dominique Lagadic-Gossmann ◽  
Martine Chevanne ◽  
Isabelle Gallais ◽  
Dimitri Gobart ◽  
...  
Keyword(s):  
Cell Death ◽  
Transcription Factor ◽  
Polycyclic Aromatic Hydrocarbons ◽  
Cell Membrane ◽  
Aryl Hydrocarbon Receptor ◽  
Extracellular Vesicles ◽  
Aromatic Hydrocarbons ◽  
Aryl Hydrocarbon ◽  
Polycyclic Aromatic ◽  
Cell Membrane Fluidity

Abstract Extracellular vesicles (EVs) are membrane-enclosed nanostructures released by cells into the extracellular environment. As major actors of physiological intercellular communication, they have been shown to be pathogenic mediators of several liver diseases. Extracellular vesicles also appear to be potential actors of drug-induced liver injury but nothing is known concerning environmental pollutants. We aimed to study the impact of polycyclic aromatic hydrocarbons (PAHs), major contaminants, on hepatocyte-derived EV production, with a special focus on hepatocyte death. Three PAHs were selected, based on their presence in food and their affinity for the aryl hydrocarbon receptor (AhR): benzo[a]pyrene (BP), dibenzo[a,h]anthracene (DBA), and pyrene (PYR). Treatment of primary rat and WIF-B9 hepatocytes by all 3 PAHs increased the release of EVs, mainly comprised of exosomes, in parallel with modifying exosome protein marker expression and inducing apoptosis. Moreover, PAH treatment of rodents for 3 months also led to increased EV levels in plasma. The EV release involved CYP metabolism and the activation of the transcription factor, the AhR, for BP and DBA and another transcription factor, the constitutive androstane receptor, for PYR. Furthermore, all PAHs increased cholesterol levels in EVs but only BP and DBA were able to reduce the cholesterol content of total cell membranes. All cholesterol changes very likely participated in the increase in EV release and cell death. Finally, we studied changes in cell membrane fluidity caused by BP and DBA due to cholesterol depletion. Our data showed increased cell membrane fluidity, which contributed to hepatocyte EV release and cell death.

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