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ABSTRACT: We report the case of a 72-year-old woman with signs of pulmonary embolism and right heart failure. Echocardiographic imaging and computed tomography revealed a mass within the inferior vena cava reaching from the head of the pancreas to the right ventricle. From standard imaging procedures and clinical findings alone, differentiation of a cardiac thrombus from a metastatic tumor mass was difficult. After resection of the intravascular tumor, histopathologic analysis confirmed a metastasis of primary ductal pancreatic adenocarcinoma. This is a report of a case of mucinous adenocarcinoma of the pancreas reaching the heart by continuous intravascular spreading.
The Annals of thoracic surgery 02/2013; 95(2):706-7. · 3.74 Impact Factor
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Markus Velten,
Georg D Duerr,
Thilo Pessies,
Julia Schild,
Ralph Lohner,
Jan Mersmann,
Oliver Dewald,
Kai Zacharowski,
Sven Klaschik,
Tobias Hilbert,
Andreas Hoeft,
Georg Baumgarten,
Rainer Meyer,
Olaf Boehm, Pascal Knuefermann
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ABSTRACT: AIMS: Inflammation and Toll-like receptor (TLR) signalling have been linked to the development of cardiac hypertrophy following transverse aortic constriction (TAC). In the present study, we investigated whether pre-treatment with the synthetic TLR9 ligands 1668-thioate or 1612-thioate modulates the progression of TAC-induced cardiac inflammation and hypertrophy. METHODS AND RESULTS: C57BL/6N-mice were pre-treated with 1668-thioate, 1612-thioate (0.25 nmol/g, i.p.), or phosphate-buffered saline 16 h prior to TAC or sham surgery. Heart-weight/body-weight ratio (HW/BW), cardiomyocyte cell size, cellular macrophage accumulation, myofibroblast differentiation, and collagen deposition were investigated for up to 28 days. Cardiac function was monitored using a pressure-volume catheter and M-mode echocardiography. Inflammatory gene expression in the heart was analysed via gene array, while the time course of mRNA expression of key inflammatory mediators was assessed via RT-qPCR. TAC increased the HW/BW ratio and cardiomyocyte cell size and induced macrophage accumulation, myofibroblast differentiation, and collagen deposition. These changes were accompanied by cardiac inflammation and a significant loss of left ventricular function. Pre-treatment with cytosine-phosphate-guanine (CpG)-containing 1668-thioate attenuated the inflammatory response, the progression of cardiac hypertrophy, and cardiac remodelling, which resulted in a prolonged preservation of left ventricular function. These changes were induced to a smaller extent by the use of the non-CG-containing oligodeoxynucleotide 1612-thioate. CONCLUSION: Pre-treatment with 1668-thioate attenuated cardiac hypertrophy following pressure overload, possibly by modifying the hypertrophy-induced inflammatory response, thereby reducing cardiac growth and fibrosis as well as delaying loss of cardiac function.
Cardiovascular research 09/2012; · 5.80 Impact Factor
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ABSTRACT: Aim was to elucidate the specific role of pattern recognition receptors in vascular dysfunction during polymicrobial sepsis (colon ascendens stent peritonitis, CASP).
Vascular contractility of C57BL/6 (wildtype) mice and mice deficient for Toll-like receptor 2/4/9 (TLR2-D, TLR4-D, TLR9-D) or CD14 (CD14-D) was measured 18 h following CASP. mRNA expression of pro- (Tumor Necrosis Factor-α (TNFα), Interleukin (IL)-1β, IL-6) and anti-inflammatory cytokines (IL-10) and of vascular inducible NO-Synthase (iNOS) was determined using RT-qPCR. Wildtype mice exhibited a significant loss of vascular contractility after CASP. This was aggravated in TLR2-D mice, blunted in TLR4-D animals and abolished in TLR9-D and CD14-D animals. TNF-α expression was significantly up-regulated after CASP in wildtype and TLR2-D animals, but not in mice deficient for TLR4, -9 or CD14. iNOS was significantly up-regulated in TLR2-D animals only. TLR2-D animals showed significantly higher levels of TLR4, -9 and CD14. Application of H154-ODN, a TLR9 antagonist, attenuated CASP-induced cytokine release and vascular dysfunction in wildtype mice.
Within our model, CD14 and TLR9 play a decisive role for the development of vascular dysfunction and thus can be effectively antagonized using H154-ODN. TLR2-D animals are more prone to polymicrobial sepsis, presumably due to up-regulation of TLR4, 9 and CD14.
PLoS ONE 01/2012; 7(9):e44531. · 4.09 Impact Factor
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ABSTRACT: Severe sepsis and septic shock are often accompanied by acute cardiovascular depression. Lipopolysaccharide (LPS) signaling via Toll-like receptor 4 (TLR4) can induce septic organ dysfunction. The aim of this study was to elucidate the in vivo impact of pharmacological TLR4 antagonism on LPS-induced cardiovascular depression using eritoran tetrasodium (E5564). To simulate sepsis, C3H/HeN mice were challenged i.p. with 2 mg/kg body weight LPS. With the intent to antagonize the LPS effects, eritoran was administered i.v. (4 mg/kg body weight). Physical activity, peripheral blood pressure, and heart frequency were recorded before and after LPS and eritoran injection. In addition, intracardiac hemodynamic parameters were analyzed with a pressure conductance catheter. After 2 and 6 h of LPS stimulation ± eritoran treatment, the hearts and aortae were harvested, and TLR as well as inflammatory mediator expression was measured using reverse transcription-quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. Lipopolysaccharide significantly decreased arterial blood pressure over time. Administration of eritoran partially prevented the LPS-dependent reduction in blood pressure and preserved cardiac function. In addition, LPS increased the expression of CD14 and TLR2 in cardiac and aortic tissue. In aortic tissue, eritoran attenuated this increase, whereas no significant reduction was observed in the heart. Furthermore, cardiac and aortic inducible nitric oxide synthetase mRNA levels were significantly increased 6 h after LPS application. This effect was reduced in the presence of eritoran. In summary, the beneficial influence of eritoran on cardiovascular function in vivo seems to rely mainly on reduction of LPS-induced inducible nitric oxide synthetase expression as well as on attenuated cytokine expression in the vascular wall.
Shock (Augusta, Ga.) 12/2011; 36(6):613-20. · 2.87 Impact Factor
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Journal of the American College of Cardiology 09/2011; 58(12):e23. · 14.16 Impact Factor
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ABSTRACT: In this report, we describe a patient who developed severe headache following epidural analgesia for labor and delivery. Although the epidural puncture had been reported to be uneventful, headache was initially suspected to result from an accidental dural puncture. After the headache worsened, a sinus venous thrombosis was suspected and subsequently confirmed by magnetic resonance imaging. This case highlights the difficulty of differential diagnosis of headache in the postnatal period in patients after EDA and stresses the necessity of considering alternative pathologies.
Archives of Gynecology 07/2011; 285(1):93-7. · 0.91 Impact Factor
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ABSTRACT: Toll-like receptor 4 (TLR4) recognizes lipopolysaccharides and endogenous ligands released after organ injury. Deficiency of TLR4 attenuates the development of left ventricular hypertrophy after transverse aortic constriction (TAC) in mice. We hypothesized that application of the TLR4 antagonist eritoran may also reduce cardiac hypertrophy after TAC surgery.
A catheter was implanted into the jugular vein of C57BL/6 mice to allow repeated administration of eritoran (5 mg/kg body weight) or placebo. Three days after TAC or sham surgery, heart weights were determined and cardiac tissue underwent mRNA and protein quantification. The TAC placebo group exhibited a significant increase in left ventricular weight, left ventricular weight/tibia length, and left ventricular/body weight ratio compared with the sham and TAC eritoran groups. Natriuretic peptide mRNA was elevated significantly only in TAC placebo mice. Transverse aortic constriction surgery led to a distinct increase in interleukin (IL)-1β and IL-6 mRNA and protein expression in the placebo but not the eritoran group. In contrast, IL-10 was significantly increased in both eritoran groups independent from TAC. Matrix metalloproteinase zymographic activity was highest in TAC placebo animals.
Application of the TLR4 antagonist eritoran attenuates the development of cardiac hypertrophy possibly by a reduction in inflammatory and increase in anti-inflammatory cytokines.
European Journal of Heart Failure 06/2011; 13(6):602-10. · 4.90 Impact Factor
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ABSTRACT: The induction of the heat shock (HS) response is accepted to be a protective response, reducing injury and improving cell survival. However, when inflammation precedes HS, there is an unexpected increase in injury, known as the HS paradox, which is hypothesized to be a mechanism underlying multiorgan dysfunction. We hypothesized that the HS paradox would occur in adult cardiac myocytes and that HS factor (HSF) 1 would contribute to injury. Heat shock at 42°C and TNF (10 ng/mL) were used as the HS and the inflammatory insult, respectively. The combination of TNF followed by HS (TNF/HS) caused the greatest amount of apoptosis in adult rat cardiac myocytes. TNF/HS resulted in an increase in HS protein (HSP) 60, compared with untreated cells, those receiving HS/TNF, or TNF alone. There was no increase in heme oxygenase 1 in any of the groups. Heat shock protein 72 increased in all the groups, with the greatest levels with TNF/HS. Nuclear factor κB activation was greatest with TNF/HS. Pretreatment with a DNA-binding decoy for HSF-1 prevented the increase in HSPs and decreased apoptosis in all groups. However, the increase in iNOS, seen in all treatment groups, was unaffected by the HSF-1-binding decoy. We conclude that the HS paradox occurs in adult cardiac myocytes, that HSP60 is increased as part of the HS paradox, and that HSF-1 activation contributes to injury.
Shock (Augusta, Ga.) 12/2010; 35(5):478-84. · 2.87 Impact Factor
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Critical care medicine 09/2008; 36(8):2468-9. · 6.37 Impact Factor
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Pascal Knuefermann,
Markus Schwederski,
Markus Velten,
Peter Krings,
Heidi Ehrentraut,
Myriam Rüdiger,
Olaf Boehm,
Klaus Fink,
Ulrike Dreiner,
Christian Grohé,
Andreas Hoeft,
Georg Baumgarten,
Alexander Koch,
Kai Zacharowski,
Rainer Meyer
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ABSTRACT: Myocardial function is severely compromised during sepsis. Several underlying mechanisms have been proposed. The innate immune system, i.e. toll-like receptor (TLR) 2 and 4, significantly contributes to cardiac dysfunction. Little is known regarding TLR9 and its pathogenic ligand bacterial DNA in the myocardium. We therefore studied the role of TLR9 in myocardial inflammation and cardiac contractility.
Wild-type (WT, C57BL/6) and TLR9-deficient (TLR9-D) mice and isolated cardiomyocytes were challenged with synthetic bacterial DNA (CpG-ODN). Myocardial contractility as well as markers of inflammation/signalling were determined. Isolated cardiomyocytes incorporated fluorescence-marked CpG-ODN. In WT mice, CpG-ODN caused a robust response in hearts demonstrated by increased levels of tumour necrosis factor (TNF-alpha), interleukin (IL)-1beta, IL-6, inducible nitric oxide synthase (iNOS), and nuclear factor kappaB activity. This inflammatory response was absent in TLR9-D mice. Under similar conditions, contractility measurements of isolated ventricular cardiomyocytes demonstrated a TLR9-dependent loss of sarcomeric shortening after CpG-ODN exposure. This observation was iNOS dependent as the application of a specific iNOS inhibitor reversed sarcomeric shortening to normal levels.
Our data suggest that bacterial DNA contributes to myocardial cytokine production and loss of cardiomyocyte contractility via TLR9.
Cardiovascular Research 05/2008; 78(1):26-35. · 6.06 Impact Factor
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ABSTRACT: Proliferation of vascular smooth muscle cells (VSMC) plays an important role in the pathogenesis of atherosclerosis and restenosis. Recent studies have demonstrated that the transcription factor gut-enriched Krüppel-like factor (GKLF, KLF4) is involved in redox-sensitive growth arrest of VSMC. We investigated the role of GKLF in VSMC proliferation and differentiation and the potentially important interaction with the tumor suppressor gene p53. Cultured rat aortic VSMC were transfected with GKLF sense and antisense constructs by electroporation. GKLF enhanced the mRNA expression of the differentiation marker SM22-alpha, but had no effect on the expression of alpha-smooth muscle actin (real-time RT-PCR, Western blot). Overexpression of GKLF significantly reduced VSMC proliferation (cell count, BrdU FACS analysis). Because p53 is essential for proliferation processes, the effect of GKLF on p53 gene expression was investigated. GKLF overexpression led to an enhanced p53 promoter activity and increased p53 mRNA and protein expression (luciferase reporter assay, real-time PCR, Western blot). Consistently, GKLF overexpression induced an enhanced expression of the p53 target genes p21(WAF1/Cip1) and Mdm2. Co-transfection experiments revealed that the growth arrest induced by GKLF sense transfection was completely abolished by co-transfection of p53 antisense constructs, whereas the reduced proliferation exerted by p53 sense transfection was not inhibited by GKLF antisense transfection, suggesting that p53 induction is essential for the interference of GKLF with VSMC proliferation. Finally, stimulation of VSMC with hydroxyl radicals increased expression of GKLF and p53 and reduced cell proliferation. The transcription factor GKLF induces inhibition of proliferation of VSMC which is mechanistically linked to a GKLF-induced enhancement of the expression of the tumor suppressor gene p53.
Journal of Molecular and Cellular Cardiology 10/2007; 43(3):301-7. · 5.17 Impact Factor
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Nguyen Tran,
Alexander Koch,
Reinhard Berkels,
Olaf Boehm,
Paula A Zacharowski,
Georg Baumgarten, Pascal Knuefermann,
Matthias Schott,
Waldemar Kanczkowski,
Stefan R Bornstein,
Stafford L Lightman,
Kai Zacharowski
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ABSTRACT: Sepsis is a leading cause of death in the Western world and can be associated with failure of the hypothalamic-pituitary-adrenal axis. A coordinated response of the adrenal and immune system is of vital importance for survival during sepsis. Within the immune response, Toll-like receptors (TLRs) play a crucial role by recognizing pathogen-associated molecules such as bacterial DNA. TLR-9 can detect motifs of unmethylated cytosine-phosphate-guanine (CpG) dinucleotides (CpG-DNA) being present in bacterial DNA.
We investigated whether TLR-9 is expressed in human and murine adrenal glands and whether its activation is associated with an adrenal response.
Human fetal and adult adrenal glands; wild-type, C57BL/6 and TLR-9 deficient (TLR-9-/-) mice; and in vitro cell line models were used in the study.
The study took place at a university hospital.
TLR-9 is expressed in human and murine adrenal glands, as well as in in vitro cell lines (Y-1 and NCI-H295R cells). CpG-oligodeoxynucleotide challenge caused a 3-fold increase in plasma levels of corticosterone in wild-type mice. This effect was not observed in TLR-9-/- mice. Furthermore, CpG-oligodeoxynucleotide challenge resulted in a strong release of several inflammatory cytokines, such as TNF-alpha, and IL-1beta, -6, -10, and -12 in vivo as well as in vitro. Again, this effect was not present in TLR-9-/- mice.
TLR-9 is present in both murine and human adrenal glands. TLR-9 stimulation led to a corticosterone and inflammatory cytokine response. TLR-9 may play a role in the regulation of the hypothalamic-pituitary-adrenal axis during conditions in which bacterial DNA is present.
Journal of Clinical Endocrinology & Metabolism 08/2007; 92(7):2773-83. · 6.50 Impact Factor
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Pascal Knuefermann,
Georg Baumgarten,
Alexander Koch,
Markus Schwederski,
Markus Velten,
Heidi Ehrentraut,
Jan Mersmann,
Rainer Meyer,
Andreas Hoeft,
Kai Zacharowski,
Christian Grohé
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ABSTRACT: Bacterial DNA containing motifs of unmethylated CpG dinucleotides (CpG-ODN) initiate an innate immune response mediated by the pattern recognition receptor Toll-like receptor 9 (TLR9). This leads in particular to the expression of proinflammatory mediators such as tumor necrosis factor (TNF-alpha) and interleukin-1beta (IL-1beta). TLR9 is expressed in human and murine pulmonary tissue and induction of proinflammatory mediators has been linked to the development of acute lung injury. Therefore, the hypothesis was tested whether CpG-ODN administration induces an inflammatory response in the lung via TLR9 in vivo.
Wild-type (WT) and TLR9-deficient (TLR9-D) mice received CpG-ODN intraperitoneally (1668-Thioat, 1 nmol/g BW) and were observed for up to 6 hrs. Lung tissue and plasma samples were taken and various inflammatory markers were measured.
In WT mice, CpG-ODN induced a strong activation of pulmonary NFkappaB as well as a significant increase in pulmonary TNF-alpha and IL-1beta mRNA/protein. In addition, cytokine serum levels were significantly elevated in WT mice. Increased pulmonary content of lung myeloperoxidase (MPO) was documented in WT mice following application of CpG-ODN. Bronchoalveolar lavage (BAL) revealed that CpG-ODN stimulation significantly increased total cell number as well as neutrophil count in WT animals. In contrast, the CpG-ODN-induced inflammatory response was abolished in TLR9-D mice.
This study suggests that bacterial CpG-ODN causes lung inflammation via TLR9.
Respiratory research 02/2007; 8:72. · 3.36 Impact Factor
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ABSTRACT: Abstract
Backgound
It has been reported that Toll-like receptor 4 (TLR4) deficiency reduces infarct size after myocardial ischemia/reperfusion (MI/R). However, measurement of MI/R injury was limited and did not include cardiac function . In a chronic closed-chest model we assessed whether cardiac function is preserved in TLR4-deficient mice (C3H/HeJ) following MI/R, and whether myocardial and systemic cytokine expression differed compared to wild type (WT).
Results
Infarct size (IS) in C3H/HeJ assessed by TTC staining after 60 min ischemia and 24h reperfusion was significantly smaller than in WT. Despite a smaller infarct size, echocardiography showed no functional difference between C3H/HeJ and WT. Left-ventricular developed pressure measured with a left-ventricular catheter was lower in C3H/HeJ (63.0 ± 4.2 mmHg vs. 77.9 ± 1.7 mmHg in WT, p < 0.05). Serum cytokine levels and myocardial IL-6 were higher in WT than in C3H/HeJ (p < 0.05). C3H/HeJ MI/R showed increased myocardial IL-1β and IL-6 expression compared to their respective shams (p < 0.05), indicating TLR4-independent cytokine activation due to MI/R.
Conclusion
These results demonstrate that, although a mutant TLR4 signaling cascade reduces myocardial IS and serum cytokine levels, it does not preserve myocardial function . The change in inflammatory response, secondary to a non-functional TLR-4 receptor, may contribute to the observed dichotomy between infarct size and function in the TLR-4 mutant mouse.
BMC Physiology. 01/2007;
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ABSTRACT: It has been reported that Toll-like receptor 4 (TLR4) deficiency reduces infarct size after myocardial ischemia/reperfusion (MI/R). However, measurement of MI/R injury was limited and did not include cardiac function. In a chronic closed-chest model we assessed whether cardiac function is preserved in TLR4-deficient mice (C3H/HeJ) following MI/R, and whether myocardial and systemic cytokine expression differed compared to wild type (WT).
Infarct size (IS) in C3H/HeJ assessed by TTC staining after 60 min ischemia and 24h reperfusion was significantly smaller than in WT. Despite a smaller infarct size, echocardiography showed no functional difference between C3H/HeJ and WT. Left-ventricular developed pressure measured with a left-ventricular catheter was lower in C3H/HeJ (63.0 +/- 4.2 mmHg vs. 77.9 +/- 1.7 mmHg in WT, p < 0.05). Serum cytokine levels and myocardial IL-6 were higher in WT than in C3H/HeJ (p < 0.05). C3H/HeJ MI/R showed increased myocardial IL-1beta and IL-6 expression compared to their respective shams (p < 0.05), indicating TLR4-independent cytokine activation due to MI/R.
These results demonstrate that, although a mutant TLR4 signaling cascade reduces myocardial IS and serum cytokine levels, it does not preserve myocardial function. The change in inflammatory response, secondary to a non-functional TLR-4 receptor, may contribute to the observed dichotomy between infarct size and function in the TLR-4 mutant mouse.
BMC Physiology 01/2007; 7:5.
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ABSTRACT: Toll-like receptor 4 (TLR4) mediates innate immune responses following endotoxemia and myocardial ischaemia-reperfusion (I/R) injury. Pre-treatment with the major TLR4 ligand lipopolysaccharide (LPS) reduces infarct size. Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) play a crucial role in endotoxemia possibly also determining I/R injury.
We investigated the influence of TLR4 on infarct size and assessed the influence of MMP and TIMP regulation on I/R injury.
Left anterior descending artery (LAD) occlusion was performed on wild-type (C3H/HeN) and TLR4-deficient (C3H/HeJ) mice. Animals were stimulated with LPS (1 mg/kg) or PBS 16 h ahead of 60 min LAD ligation. After 24 h of reperfusion, triphenyltetrazolium chloride staining was performed and infarct size was measured by planimetry. MMP- and TIMP-mRNA expression were determined by RPA after 3 h of reperfusion. MMP zymographic activity was monitored 6 h after occlusion.
TLR4-deficient mice and LPS-treated wild-type mice showed significantly reduced infarct areas. LPS-stimulation significantly increased the overall MMP/TIMP mRNA expression ratio due to elevated MMP-3, -8, -9, and TIMP-1 in wild-type mice. I/R overall reduced the MMP/TIMP ratio due to increased MMP-1, TIMP-1, and -3 mRNA expression.
LPS pre-treatment and TLR4-deficiency led to a decreased infarct size. However, infarct area and MMP/TIMP ratio were not correlated. This means that in TLR4-deficient mice MMP/TIMP ratios are not determining the infarct size.
European Journal of Heart Failure 12/2006; 8(7):665-72. · 4.90 Impact Factor
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ABSTRACT: Transverse aortic constriction (TAC) results in a transient increase of proinflammatory cytokines, which return to baseline levels within 3 d. In contrast to cytokine baseline levels, the myocardium remains capable to respond even stronger to a new stimulus. As the molecular mechanisms for this phenomenon are unknown, we tested whether TAC modulates the innate immune system in mice and changes the inflammatory reaction to a new stimulus.
Following 3 d of TAC or sham-operation procedure (SOP), LPS (20 mg/kg) or PBS (control) were administered intraperitoneal for 10 min as well as for 6 h. Hemodynamic parameters were recorded to measure the effects of TAC and LPS. After TAC/SOP alone CD14 expression was monitored and after additional 6 h of LPS/PBS the expression of CD14, TLR4 and proinflammatory cytokines were determined by western-blot, ELISA and RNase protection assay, respectively. Following TAC/SOP and 10 min of LPS/PBS, NFkappaB activation was investigated by EMSA.
TAC induced cardiac hypertrophy and elevated blood pressure. LPS application led to hypotension and other symptoms of sepsis. CD14 expression increased after TAC alone and even further after additional LPS challenge. However, we did not detect changes of TLR4 expression. Also NFkappaB activation increased after LPS challenge higher in the TAC than in the SOP group. LPS-stimulation induced also higher cytokine expression in the TAC than in the SOP group.
TAC modulates innate immunity by regulating the expression of CD14 and changes the myocardial tissue to respond more powerful to LPS.
Archiv für Kreislaufforschung 10/2006; 101(5):427-35. · 7.35 Impact Factor
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Kai Zacharowski,
Paula A Zacharowski,
Alexander Koch,
Aida Baban,
Nguyen Tran,
Reinhard Berkels,
Claudia Papewalis,
Klaus Schulze-Osthoff, Pascal Knuefermann,
Ulrich Zähringer,
Ralf R Schumann,
Valeria Rettori,
Samuel M McCann,
Stefan R Bornstein
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ABSTRACT: Sepsis and septic shock are leading killers in the noncoronary intensive care unit, and they remain worldwide health concerns. The initial host defense against bacterial infections involves Toll-like receptors (TLRs), which detect and respond to microbial ligands. In addition, a coordinated response of the adrenal and immune systems is crucial for survival during severe inflammation. Previously, we demonstrated a link between the innate immune system and the endocrine stress response involving TLR-2. Like TLR-2, TLR-4 is also expressed in human and mouse adrenals. In the present work, by using a low dose of LPS to mimic systemic inflammatory response syndrome, we have revealed marked cellular alterations in adrenocortical tissue and an impaired adrenal corticosterone response in TLR-4-/- mice. Our findings demonstrate that TLR-4 is a key mediator in the crosstalks between the innate immune system and the endocrine stress response. Furthermore, TLR polymorphisms could contribute to the underlying mechanisms of impaired adrenal stress response in patients with bacterial sepsis.
Proceedings of the National Academy of Sciences 05/2006; 103(16):6392-7. · 9.68 Impact Factor
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ABSTRACT: The myotrophin/V-1 protein was originally found to be elevated in failing heart tissues and was described as an exogenously acting hypertrophy-inducing factor. However, several studies have proposed only intracellular functions for this protein. We investigated whether this protein is an exogenously acting hypertrophy-inducing trophin or an intracellular nuclear factor of kappa B (NFkappaB) regulatory protein. In the current report, immunofluorescence and cell fractionation studies showed that myotrophin is present only in the cytoplasm and is not actively released into the extracellular environment in response to hypertrophy-inducing stimuli. Moreover, in response to ischemia/reperfusion injury, an active release of myotrophin from adult rat myocardium was not observed. Furthermore, protein synthesis studies in rat neonatal myocytes indicated that exogenous myotrophin did not induce hypertrophy. On the other hand, myotrophin stimulates the generation of NFkappaB dimers in vitro and thus regulates the NFkappaB-mediated transcription in cardiac myocytes. Taken together, these studies suggest that myotrophin is a strictly cytosolic protein that regulates the NFkappaB-mediated transcriptional process.
Texas Heart Institute journal / from the Texas Heart Institute of St. Luke's Episcopal Hospital, Texas Children's Hospital 02/2006; 33(3):281-9. · 0.65 Impact Factor
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Georg Baumgarten, Pascal Knuefermann,
Gerrit Schuhmacher,
Volker Vervölgyi,
Joscha von Rappard,
Ulrike Dreiner,
Klaus Fink,
Chryso Djoufack,
Andreas Hoeft,
Christian Grohé,
A A Knowlton,
Rainer Meyer
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ABSTRACT: The molecular mechanisms that mediate gram-negative sepsis-associated myocardial dysfunction remain elusive. Myocardial expression of inflammatory mediators is Toll-like receptor 4 (TLR4) dependent. However, it remains to be elucidated whether TLR4, expressed on cardiac myocytes, mediates impairment of cardiac contractility after lipopolysaccharide (LPS) application. Cardiac myocyte contractility, measured as sarcomere shortening of isolated cardiac myocytes from C3H/HeJ (with nonfunctional TLR4) and C3H/HeN (control), were recorded at stimulation frequencies between 0.5 and 10 Hz and after incubation with 1 and 10 mug/mL LPS for up to 8 h. Control cells treated with LPS were investigated with and without a competitive LPS inhibitor (E5564) and a specific inducible nitric oxide synthase (iNOS) inhibitor S-methylisothiourea. In control mice, LPS reduced sarcomere shortening amplitude and prolonged duration of relaxation, whereas sarcomere shortening of C3H/HeJ cells was insensitive to LPS. NFkappaB and iNOS were upregulated after LPS application in control mice compared with C3H/HeJ. Inhibition of TLR4 by E5564 as well as inhibition of iNOS prevented the influence of LPS on contractile activity in control myocytes. LPS-dependent suppression of cardiac myocyte contractility was significantly blunted in C3H/HeJ mice. Competitive inhibition of functional TLR4 with E5564 protects cardiac myocyte contractility against LPS. These findings suggest that TLR4, expressed on cardiac myocytes, contributes to sepsis-induced myocardial dysfunction. E5564, currently under investigation in two clinical phase II trials, seems to be a new therapeutic option for the treatment of myocardial dysfunction in sepsis associated with endotoxemia.
Shock 02/2006; 25(1):43-9. · 2.85 Impact Factor
