Toll-Like Receptor 4, Nitric Oxide, and Myocardial Depression in Endotoxemia

Baumgarten, Georg; Knuefermann, Pascal; Schuhmacher, Gerrit; Vervölgyi, Volker; Rappard, Joscha von; Dreiner, Ulrike; Fink, Klaus; Djoufack, Chryso; Hoeft, Andreas; Grohé, Christian; Knowlton, Anne A; Meyer, Rainer

doi:10.1097/01.shk.0000196498.57306.a6

Cited by 100 publications

(76 citation statements)

References 40 publications

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“…TLR4 is part of a receptor complex recognizing Gram-negative bacterial endotoxin and is required for endotoxin signal transduction (29). Experiments with TLR4 inhibitors demonstrated a reduced myocardial dysfunction in endotoxinaemia (28,30,31). Here, we detected an increase in fetal cardiac TLR2 and 4 mRNA levels after systemic administration of endotoxin corresponding to the observations in the adult.…”

Section: Discussionsupporting

confidence: 52%

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Myocardial Response in Preterm Fetal Sheep Exposed to Systemic Endotoxinaemia

et al. 2011

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Exposure of the fetus to antenatal inflammation can occur from chorioamnionitis, which may progress to a fetal inflammatory response syndrome (FIRS) and to fetal sepsis. We tested whether the fetal myocardium responded to systemic Gram-negative endotoxinaemia. We hypothesized that the myocardium would respond to inflammation by changes in hypoxia-inducible factor-␣ (HIF-1␣), inducible NO-synthase (iNOS), Toll-like receptors 2 and 4 (TLR2 and TLR4), IL-6, and phosphorylated signal transducer and activator of transcription-3 (pSTAT3). To model systemic endotoxinaemia, fetal sheep were exposed to Gram-negative endotoxin or saline i.v. 3 d before preterm delivery at 113 d of gestation (term ϭ 147 d). All endotoxin-exposed animals developed cardiac dysfunction within these 72 h. Cardiac mRNA and protein levels of HIF-1␣ and TLR2 and TLR4 mRNA increased, whereas STAT3 phosphorylation decreased significantly. IL-6 and iNOS mRNA remained unchanged. Fetal systemic endotoxinaemia induced myocardial inflammation by activating TLR2 and 4. The following cardiac dysfunction seems not to be mediated via cardiac iNOS. C ardiovascular dysfunction is a severe consequence of the systemic inflammatory response syndrome (SIRS) (1). A number of experiments in vivo and in vitro have been performed to study the mechanism of endotoxin-induced cardiac dysfunction in the adult (2). According to previous studies, it is mediated by proinflammatory cytokines as IL-6 (3,4) leading to excessive NO production, generated as a result of the induction of inducible NOS (iNOS) (5). These processes are controlled by signal transducer and activator of transcription-3 (STAT-3), which is activated on phosphorylation (6,7).Until now, this sequence has not been studied in the fetus. The proposed fetal counterpart to SIRS, the fetal inflammatory response syndrome (FIRS) results from an infection of the amniotic cavity called chorioamnionitis (8). FIRS is the precursor of neonatal early-onset sepsis and has been associated with fetal death, preterm premature rupture of membranes (PROM), and consequently spontaneous preterm labor, and cardiorespiratory failure, or hypoxic-ischemic brain damage at birth (9,10).Early onset neonatal sepsis remains an important cause of illness and death among very LBW preterm infants. More than one half of early infections caused by Gram-negative organisms (53%), with Escherichia coli the most common organism (41%) (11). Endotoxins from Gram-negative bacteria (lipopolysaccharide) bind to Toll-like receptors 2 and 4 (TLR2 and TLR4), which leads to the activation of nuclear factor (NF)-B, required for transcriptional activation of proinflammatory cytokines and several other inflammatory mediators (12). FIRS may launch a cytokine cascade similar to SIRS (8). Until now, it is not known whether the different fetal microenvironment with a relative lack of oxygen (13) and the more tolerant fetal immune system (14) allows the fetal heart to respond to systemic endotoxinaemia in the same way as the adult heart does. Therefore,...

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Section: Discussionsupporting

confidence: 52%

“…Apart from iNOS, members of the TLR family, TLR4 in particular, are also thought to mediate the endotoxinaemic myocardial dysfunction in adult sepsis patients (28). TLR4 is part of a receptor complex recognizing Gram-negative bacterial endotoxin and is required for endotoxin signal transduction (29).…”

Section: Discussionmentioning

confidence: 99%

Myocardial Response in Preterm Fetal Sheep Exposed to Systemic Endotoxinaemia

et al. 2011

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“…Recently, it has been reported that the binding of LPS to TLR4 on rat CMs clearly contributes to myocardial depression (41). We now provide evidence that similar pathways are activated following thermal injury, leading to impaired cardiac contractility.…”

Section: Discussionmentioning

confidence: 55%

C5a-Blockade Improves Burn-Induced Cardiac Dysfunction

Hoesel

Niederbichler²,

Schaefer

et al. 2007

The Journal of Immunology

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We previously reported that generation of the anaphylatoxin C5a is linked to the development of cardiac dysfunction in sepsis due to C5a interaction with its receptor (C5aR) on cardiomyocytes. Burn injury involves inflammatory mechanisms that can lead to C5a generation as well. In this study, we investigated the effects of C5a blockade on burn-induced cardiac dysfunction. Using a standardized rat model of full thickness scald injury, left ventricular pressures were recorded in vivo followed by in vitro assessment of sarcomere contraction of single cardiomyocytes. Left ventricular pressures in vivo and cardiomyocyte sarcomere contractility in vitro were significantly reduced following burn injury. In the presence of anti-C5a Ab, these defects were greatly attenuated 1, 6, and 12 h after burn injury and completely abolished 24 h after burn. In vitro incubation of cardiomyocytes with bacterial LPS accentuated the impaired contractility, which was partially prevented in cardiomyocytes from burned rats that had received an anti-C5a Ab. Based on Western blot analyses, real-time PCR, and immunostaining of left ventricular heart tissue, there was a significant increase in cardiomyocyte expression of C5aR after burn injury. In conclusion, an in vivo blockade of C5a attenuates burn-induced cardiac dysfunction. Further deterioration of contractility due to the exposure of cardiomyocytes to LPS was partially prevented by C5a-blockade. These results suggest a linkage between C5a and burn-induced cardiac dysfunction and a possible contribution of LPS to these events.

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“…Massive stimulation of the TLRs by N. meningitidis, emphasized by the local septic thrombi and increased concentration of N. meningitidis lipopolysaccharide (LPS) analog due to endothelium adherence of the bacteria, could generate such antigenic stimulation, resulting in strong innate immune signaling and myocardial dysfunction. Polynuclear infiltration of the myocardial muscle has been demonstrated to be of critical importance in the TLR4-mediated contractile dysfunction induced by sepsis (26,27). Polynuclear infiltration is present in almost 20% of the vessels analyzed in our model and may also participate in myocardial dysfunction.…”

Section: Discussionmentioning

confidence: 81%

Experimental Evidence of Bacterial Colonization of Human Coronary Microvasculature and Myocardial Tissue during Meningococcemia

et al. 2016

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h Meningococcal septic shock is associated with profound vasoplegia, early and severe myocardial dysfunction, and extended skin necrosis responsible for a specific clinical entity designated purpura fulminans (PF). PF represents 90% of fatal meningococcal infections. One characteristic of meningococcal PF is the myocardial dysfunction that occurs in the early phase of sepsis. Furthermore, hemodynamic studies have shown that the prognosis of meningococcal sepsis is directly related to the degree of impairment of cardiac contractility during the initial phase of the disease. To gain insight into a potential interaction of Neisseria meningitidis with the myocardial microvasculature, we modified a previously described humanized mouse model by grafting human myocardial tissue to SCID mice. We then infected the grafted mice with N. meningitides. Using the humanized SCID mouse model, we demonstrated that N. meningitidis targets the human myocardial tissue vasculature, leading to the formation of blood thrombi, infectious vasculitis, and vascular leakage. These results suggest a novel mechanism of myocardial injury in the course of severe N. meningitidis sepsis that is likely to participate in primary myocardial dysfunction.

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Toll-Like Receptor 4, Nitric Oxide, and Myocardial Depression in Endotoxemia

Cited by 100 publications

References 40 publications

Myocardial Response in Preterm Fetal Sheep Exposed to Systemic Endotoxinaemia

Myocardial Response in Preterm Fetal Sheep Exposed to Systemic Endotoxinaemia

C5a-Blockade Improves Burn-Induced Cardiac Dysfunction

Experimental Evidence of Bacterial Colonization of Human Coronary Microvasculature and Myocardial Tissue during Meningococcemia

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