scholarly journals Low-grade endotoxaemia enhances artery thrombus growth via Toll-like receptor 4: implication for myocardial infarction

2020 ◽  
Vol 41 (33) ◽  
pp. 3156-3165 ◽  
Author(s):  
Roberto Carnevale ◽  
Sebastiano Sciarretta ◽  
Valentina Valenti ◽  
Flavio di Nonno ◽  
Camilla Calvieri ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Escherichia Coli ◽  
Platelet Activation ◽  
Cathepsin G ◽  
Low Grade ◽  
Toll Like Receptor ◽  
Gut Permeability ◽  
Toll Like Receptor 4 ◽  
E Coli ◽  
St Elevation

Abstract Aims Low-grade endotoxaemia is detectable in human circulation but its role in thrombosis is still unclear. Methods and results We measured serum lipopolysaccharide (LPS) concentration, soluble P-selectin (sP-selectin), a marker of platelet activation, and zonulin, a marker of gut permeability, in peripheral circulation, coronary thrombi, and intracoronary blood of patients with ST-elevation myocardial infarction (STEMI, n = 50) and stable angina (SA) (n = 50), respectively, and in controls (n = 50). Experimental study was carried out in mice to assess if Escherichia coli-LPS (E. coli-LPS) possess thrombotic property. Coronary thrombi from STEMI showed higher concentrations of LPS, sP-selectin vs. intracoronary blood of SA and peripheral blood of controls (P < 0.001). Zonulin was higher in STEMI compared to the other two groups [4.57 (3.34–5.22); 2.56 (0.41–4.36); 1.95 (1.22–2.65) ng/mL; P < 0.001] and correlated with LPS (Rs = 0.585; P < 0.001). Escherichia coli DNA was positive in 34% of STEMI vs. 12% of SA and 4% of controls (P < 0.001). In a subgroup of 12 STEMI, immunohistochemical analysis of coronary thrombi showed positivity for leucocyte Toll-like receptor 4 (TLR4), cathepsin G, and LPS from E. coli in 100%, 80%, and 25% of samples, respectively. E. coli-LPS injected in mice to reach LPS concentrations like those detected in coronary thrombi was associated with enhanced artery thrombosis and platelet activation, an effect blunted by TLR4 inhibitor co-administration. In vitro study demonstrated that LPS from E. coli enhanced platelet aggregation via TLR4-mediated leucocyte cathepsin G activation. Conclusion ST-elevation myocardial infarction patients disclose an enhanced gut permeability that results in LPS translocation in human circulation and eventually thrombus growth at site of artery lesion via leucocyte–platelet interaction.

scholarly journals Toll-Like Receptor 4/Stem Cell Antigen 1 Signaling Promotes Hematopoietic Precursor Cell Commitment to Granulocyte Development during the Granulopoietic Response to Escherichia coli Bacteremia

2013 ◽  
Vol 81 (6) ◽  
pp. 2197-2205 ◽  
Author(s):  
Xin Shi ◽  
Robert W. Siggins ◽  
William L. Stanford ◽  
John N. Melvan ◽  
Marc D. Basson ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Bone Marrow ◽  
Stem Cell ◽  
Precursor Cell ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Content Type ◽  
E Coli ◽  
Hematopoietic Precursor

ABSTRACTIn response to severe bacterial infection, bone marrow hematopoietic activity shifts toward promoting granulopoiesis. The underlying cell signaling mechanisms remain obscure. To study the role of Toll-like receptor 4 (TLR4)/stem cell antigen-1 (Sca-1) signaling in this process, bacteremia was induced in mice by intravenous injection ofEscherichia coli. A subgroup of animals also received intravenous 5-bromo-2-deoxyuridine (BrdU). In a separate set of experiments, bone marrow lineage-negative (lin−) stem cell growth factor receptor-positive (c-kit+) Sca-1−cells containing primarily common myeloid progenitors were culturedin vitrowithout or withE. colilipopolysaccharide (LPS). In genotypic background control mice, bacteremia significantly upregulated Sca-1 expression by lin−c-kit+cells, as reflected by a marked increase in BrdU-negative lin−c-kit+Sca-1+cells in the bone marrow. In mice with the TLR4 gene deletion, this bacteremia-evoked Sca-1 response was blocked.In vitro, LPS induced a dose-dependent increase in Sca-1 expression by cultured marrow lin−c-kit+Sca-1−cells. LPS-induced upregulation of Sca-1 expression was regulated at the transcriptional level. Inhibition of c-Jun N-terminal kinase/stress-activated protein kinase (JNK) activity with the specific inhibitor SP600125 suppressed LPS-induced upregulation of Sca-1 expression by marrow lin−c-kit+Sca-1−cells. Engagement of Sca-1 with anti-Sca-1 antibodies enhanced the expression of Sfpi1 spleen focus-forming virus (SFFV) proviral integration 1 (PU.1) in marrow lin−c-kit+Sca-1−cells cultured with LPS. Sca-1 null mice failed to maintain the marrow pool of granulopoietic cells following bacteremia. These results demonstrate that TLR4/Sca-1 signaling plays an important role in the regulation of hematopoietic precursor cell programming and their enhancement of granulocyte lineage commitment in response toE. colibacteremia.

scholarly journals The lipopolysaccharide from Escherichia coli O127:B8 induces inflammation and motility disturbances in rabbit ileum

2017 ◽  
Vol 25 (2) ◽  
pp. 185
Author(s):  
Laura Grasa ◽  
Sergio Gonzalo ◽  
Alba De Martino ◽  
María Divina Murillo
Keyword(s):  
Escherichia Coli ◽  
Mrna Expression ◽  
Intestinal Inflammation ◽  
Organ Bath ◽  
Toll Like Receptor ◽  
Rabbit Ileum ◽  
Toll Like Receptor 4 ◽  
E Coli ◽  
Mucosal Layer ◽  
Spontaneous Contractions

<p>The aim of this work was to evaluate the effects of lipopolysaccharide (LPS) from <em>Escherichia coli </em>O127:B8 on the expression of toll-like receptor 4 (TLR4), the histology, and motor function in rabbit ileum. Rabbits were injected intravenously with saline or LPS (100 μg/kg, 2 h). The mRNA expression and localization of TLR4 were determined by reverse transcriptase-PCR and immunofluorescence, respectively. Histological damage induced by LPS was evaluated in sections of ileum stained with haematoxylin and eosin. Contractility studies of ileum were performed in an organ bath. The mRNA expression of TLR4 decreased in the muscular but not in the mucosal layer of rabbits treated with LPS. TLR4 was localised in both the mucosal and muscular layers of rabbit ileum. LPS induced intestinal inflammation and altered the spontaneous contractions and the serotonin-, acetylcholine- and KCl-induced contractions. In conclusion, LPS from <em>E. coli </em>O127:B8 induced a decrease in the mRNA expression of TLR4, an inflammatory response, and changes in the contractility of rabbit ileum.</p>

Differential expression of Toll-like receptor 4 signaling pathway genes in Escherichia coli F18-resistant and – sensitive Meishan piglets

2016 ◽  
Vol 19 (2) ◽  
pp. 303-308 ◽  
Author(s):  
Y. Liu ◽  
L.N. Gan ◽  
W.Y. Qin ◽  
S.Y. Sun ◽  
G.Q. Zhu ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Lymph Nodes ◽  
Signaling Pathway ◽  
Expression Profiles ◽  
Mrna Levels ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
E Coli ◽  
Significant Difference ◽  
Spleen And Lymph Nodes

Abstract The Toll-like receptor 4 (TLR4) signaling pathway is an important inflammatory pathways associated with the progression of numerous diseases. The aim of the present study was to investigate the relationship between TLR4 signaling and resistance to Escherichia coli F18 in locally weaned Meishan piglets. Using a real-time PCR approach, expression profiles were determined for key TLR4 signaling pathway genes TLR4, MyD88, CD14, IFN-α, IL-1β and TNF-α in the spleen, thymus, lymph nodes, duodenum and jejunum of E. coli F18-resistant and -sensitive animals. TLR4 signaling pathway genes were expressed in all the immune organs and intestinal tissues, and the expression was generally higher in the spleen and lymph nodes. TLR4 transcription was higher in the spleen of sensitive piglets (p<0.05), but there was no significant difference in TLR4 mRNA levels in other tissues. Similarly, CD14 transcription was higher in lymph nodes of sensitive animals (p<0.05) but not in other tissues. IL-1β expression was higher in the spleen and in the duodenum of resistant piglets (p<0.05, p<0.01, respectively), and there were no significant differences in other tissues. There were also no significant differences in the expression of MyD88, TNF-α and IFN-α between sensitive and resistant piglets (p>0.05). These results further confirm the involvement of the TLR4 signaling pathway in resistance to E. coli F18 in Meishan weaned piglets. The resistance appeared to be mediated via downregulation of TLR4 and CD14, and upregulation of MyD88 that may promote the release of cytokines TNF-α, IL-1β, IFN-α and other inflammatory mediators which help to fight against E. coli F18 infection.

scholarly journals Francisella tularensis LPS induces the production of cytokines in human monocytes and signals via Toll-like receptor 4 with much lower potency than E. coli LPS

2006 ◽  
Vol 18 (5) ◽  
pp. 785-795 ◽  
Author(s):  
Ana I Dueñas ◽  
Mónica Aceves ◽  
Antonio Orduña ◽  
Ramón Díaz ◽  
Mariano Sánchez Crespo ◽  
...  
Keyword(s):  
Francisella Tularensis ◽  
Human Monocytes ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
E Coli

Role of the toll-like receptor 4 polymorphism Asp299Gly in longevity and myocardial infarction in German men

2007 ◽  
Vol 128 (5-6) ◽  
pp. 409-411 ◽  
Author(s):  
Almut Nebel ◽  
Friederike Flachsbart ◽  
Arne Schäfer ◽  
Michael Nothnagel ◽  
Susanna Nikolaus ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4

Abstract 39: Platelet Reactivity to Prostaglandin E2 is a Novel Modifiable Risk Factor for St-Elevation Myocardial Infarction

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Eitan A Friedman ◽  
Elias V Haddad ◽  
Valentinas Joksas ◽  
Shi Huang ◽  
Meng Xu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiovascular Risk ◽  
Platelet Activation ◽  
Platelet Reactivity ◽  
Platelet Rich Plasma ◽  
Coronary Intervention ◽  
Prostaglandin E ◽  
Platelet Response ◽  
Increased Risk ◽  
St Elevation

Background: Patients with lower thresholds for platelet activation are at increased risk for primary and recurrent myocardial infarction (MI) and overall cardiovascular (CV) mortality. We have demonstrated that there are two phenotypes of platelet response to Prostaglandin E 2 (PGE 2 ), such that it increases threshold for aggregation in 45% of individuals (inhibitory) and lowers threshold for aggregation in 55% (potentiating). As PGE 2 is present in atherosclerotic plaques, and its receptors are present on platelets, biologic variability in PGE 2 responses may have clinical implications. We hypothesized that patients with higher thresholds for platelet activation would have a lower risk of thrombotic CV events, specifically ST-Elevation MI (STEMI). Methods: 85 patients undergoing percutaneous coronary intervention for stable or unstable coronary disease were phenotyped for PGE 2 response. Platelet rich plasma was treated with various concentrations of U46,619 (thromboxane agonist) with or without PGE 2 100 nM, and phenotype determined by light aggregometry. Analysis of the maximum PGE 2 effect (maximum aggregation with PGE 2 minus maximum aggregation without it) was performed using linear and non-linear statistical methods. Results: Traditional cardiovascular risk factors were similar between groups. A higher percentage of patients with the potentiating phenotype had a history of STEMI than those with the inhibitory phenotype. Logistic regression using restricted cubic spline showed that the predicted probabilities of STEMI increased from 0.04 (at the strongest inhibitory phenotype) to 0.43 (at the median phenotype). The OR of phenotype at the median relative to that at the 10th quantile was 7.4 (95 % CI=1.6, 34.8). Conclusions: PGE 2 inhibitory phenotype confers a decreased lifetime risk of STEMI in individuals at high risk for CV events. We have previously shown that an EP3 receptor antagonist converts the potentiating to the inhibitory phenotype. Thus, the PGE2 phenotype may be a novel marker of cardiovascular risk that may also identify patients who would benefit from an EP3 antagonist.

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