Toll-Like Receptor-Mediated Cardiac Injury during Experimental Sepsis

Lackner, Ina; Weber, Birte; Chakraborty, Shinjini; Braumüller, Sonja; Huber‐Lang, Markus; Gebhard, Florian; Kalbitz, Miriam

doi:10.1155/2020/6051983

Cited by 3 publications

(3 citation statements)

References 87 publications

(113 reference statements)

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“…Furthermore, JAK2/STAT3 signaling pathway had been demonstrated to induce the expression of miR-181b, which could downregulate sphingosine-1-phosphate receptor 1 (S1PR1) and decrease BBB cell adhesion, thereby promoting BBB impairment in rats with sepsis ( Chen et al, 2020 ). TLR signaling was reported to be involved in cardiac redox signaling, calcium handling, energy metabolism, and affecting cardiac structure and gap junction proteins in sepsis mice ( Lackner et al, 2020 ). The high expression of some proteins, such as TLR2, TLR3, and TLR4, have been demonstrated to play a crucial role in sepsis-induced acute injury of the lungs, kidneys, and intestine ( Krivan et al, 2019 ; Kumar, 2020a ).…”

Section: Resultsmentioning

confidence: 99%

“…Comparatively, IL-1Ra, IL-4, IL-6, IL-10, IL-11, IL-13, IL-35, and TGF-β are some anti-inflammatory cytokines ( Chaudhry et al, 2013 ). Furthermore, some signaling pathways have been reported to relate with sepsis closely, such as the JAK/STAT signaling pathway could mediate the myocardial injury of septic rats ( Jin et al, 2020 ); the PI3K-Akt signaling pathway could attenuate apoptosis and improve the survival in animal models of sepsis ( Liu et al, 2019 ; Mizuta et al, 2020 ); the T-cell receptor signaling pathway could release some activated T cells and nuclear factors, CD4 + , CD8 + , and nuclear factor of activated T cells 2 (NFATC2), to take the immune response against sepsis ( Beckmann et al, 2020 ; Kim et al, 2021 ); the JAK2/STAT3 signaling pathway could promote blood–brain barrier (BBB) impairment in rats with sepsis ( Chen et al, 2020 ); the TLR signaling pathway could play a crucial role in sepsis-induced acute cardiac injury and acute injury of the lungs, kidneys, and intestine ( Krivan et al, 2019 ; Kumar, 2020a ; Lackner et al, 2020 ); the NF-κB/TNF-α signaling pathway could regulate inflammatory apoptosis ( Chand et al, 2018 ) and alleviate the injury of lungs and intestinal barrier in sepsis ( Wang et al, 2020 ; Cao et al, 2021 ). NF-κB could activate the cytokine storm by promoting the transcription of some pro-inflammatory cytokines, including IL-1β, IL-12, and TNF-α ( Hotchkiss et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

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Detecting Critical Functional Ingredients Group and Mechanism of Xuebijing Injection in Treating Sepsis

Yin

et al. 2021

Front. Pharmacol.

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Sepsis is a systemic inflammatory reaction caused by various infectious or noninfectious factors, which can lead to shock, multiple organ dysfunction syndrome, and death. It is one of the common complications and a main cause of death in critically ill patients. At present, the treatments of sepsis are mainly focused on the controlling of inflammatory response and reduction of various organ function damage, including anti-infection, hormones, mechanical ventilation, nutritional support, and traditional Chinese medicine (TCM). Among them, Xuebijing injection (XBJI) is an important derivative of TCM, which is widely used in clinical research. However, the molecular mechanism of XBJI on sepsis is still not clear. The mechanism of treatment of “bacteria, poison and inflammation” and the effects of multi-ingredient, multi-target, and multi-pathway have still not been clarified. For solving this issue, we designed a new systems pharmacology strategy which combines target genes of XBJI and the pathogenetic genes of sepsis to construct functional response space (FRS). The key response proteins in the FRS were determined by using a novel node importance calculation method and were condensed by a dynamic programming strategy to conduct the critical functional ingredients group (CFIG). The results showed that enriched pathways of key response proteins selected from FRS could cover 95.83% of the enriched pathways of reference targets, which were defined as the intersections of ingredient targets and pathogenetic genes. The targets of the optimized CFIG with 60 ingredients could be enriched into 182 pathways which covered 81.58% of 152 pathways of 1,606 pathogenetic genes. The prediction of CFIG targets showed that the CFIG of XBJI could affect sepsis synergistically through genes such as TAK1, TNF-α, IL-1β, and MEK1 in the pathways of MAPK, NF-κB, PI3K-AKT, Toll-like receptor, and tumor necrosis factor signaling. Finally, the effects of apigenin, baicalein, and luteolin were evaluated by in vitro experiments and were proved to be effective in reducing the production of intracellular reactive oxygen species in lipopolysaccharide-stimulated RAW264.7 cells, significantly. These results indicate that the novel integrative model can promote reliability and accuracy on depicting the CFIGs in XBJI and figure out a methodological coordinate for simplicity, mechanism analysis, and secondary development of formulas in TCM.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Detecting Critical Functional Ingredients Group and Mechanism of Xuebijing Injection in Treating Sepsis

Yin

et al. 2021

Front. Pharmacol.

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“…Mammalian Toll-like receptors (TLRs) are pattern recognition receptors (PRR) that act as CD-14-associated signal transducers to help cells recognize and differentiate pathogens and initiate appropriate signaling cascades ( Lackner et al, 2020 ). TLRs also bridge innate and adaptive immunity by inducing various costimulatory and effector molecules.…”

Section: Mechanisms Of Immune Regulation and Metabolism In Sepsis-induced Cardiovascular Dysfunctionmentioning

confidence: 99%

Novel Insights Into the Potential Mechanisms of N6-Methyladenosine RNA Modification on Sepsis-Induced Cardiovascular Dysfunction: An Update Summary on Direct and Indirect Evidences

Wang

Peng

et al. 2021

Front. Cell Dev. Biol.

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Sepsis is a life-threatening organ dysfunction caused by a host’s dysfunctional response to infection. As is known to all, septic heart disease occurs because pathogens invading the blood stimulate the activation of endothelial cells, causing a large number of white blood cells to accumulate and trigger an immune response. However, in severe sepsis, the hematopoietic system is inhibited, and there will also be a decline in white blood cells, at which time the autoimmune system will also be suppressed. During the immune response, a large number of inflammatory factors are released into cells to participate in the inflammatory process, which ultimately damages cardiac myocytes and leads to impaired cardiac function. N6-methyladenosine (m6A) is a common RNA modification in mRNA and non-coding RNA that affects RNA splicing, translation, stability, and epigenetic effects of some non-coding RNAs. A large number of emerging evidences demonstrated m6A modification had been involved in multiple biological processes, especially for sepsis and immune disorders. Unfortunately, there are limited results provided to analyze the association between m6A modification and sepsis-induced cardiovascular dysfunction (SICD). In this review, we firstly summarized current evidences on how m6A mediates the pathophysiological process in cardiac development and cardiomyopathy to emphasize the importance of RNA methylation in maintaining heart biogenesis and homeostasis. Then, we clarified the participants of m6A modification in extended inflammatory responses and immune system activation, which are the dominant and initial changes secondary to sepsis attack. After that, we deeply analyzed the top causes of SICD and identified the activation of inflammatory cytokines, endothelial cell dysfunction, and mitochondrial failure. Thus, the highlight of this review is that we systematically collected all the related potential mechanisms between m6A modification and SICD causes. Although there is lack of direct evidences on SICD, indirect evidences had been demonstrated case by case on every particular molecular mechanism and signal transduction, which require further explorations into the potential links among the listed mechanisms. This provides novel insights into the understanding of SICD.

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Role of activating the nuclear factor kappa B signaling pathway in the development of septic cardiomyopathy in rats with sepsis

Xing¹,

Li²,

Li³

et al. 2023

THC

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BACKGROUND: Despite advances in the treatment of sepsis over time, this condition remains both a serious threat and a cause of death among critical patients. OBJECTIVE: This study aimed to explore the role of the nuclear factor kappa B (NF-κB) signaling pathway in the development of septic cardiomyopathy in rats with sepsis. METHOD: A total of 32 Sprague Dawley rats were randomized into a sham operation group and three groups with sepsis, which were tested at one of the following time-points: 3, 6, or 12 h. Each group included eight rats. Sepsis models were created via cecal ligation and puncture procedures. All the study rats had the following cardiac parameters and serum levels measured at either 3, 6, or 12 h after the operation (according to their assigned group): heart rate, left ventricular systolic pressure (LVSP), maximum rate of left ventricular pressure rise (+dP/dtmax) and fall (-dP/dtmax), tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), and cardiac troponin I (cTnI). The myocardium of the left ventricle was collected and subjected to hematoxylin and eosin staining to observe the changes in pathological morphology. The expression of toll-like receptor 4 (TLR4) and NF-κB in the myocardium were detected by western blot analysis. RESULTS: Compared with the sham operation group, the rats in the sepsis subgroups exhibited significantly lower values for all the cardiac parameters measured, including the heart rate (sham operation group = 386.63 ± 18.62 beats per minute [bpm], sepsis 3-h group = 368.38 ± 12.55 bpm, sepsis 6-h group = 341.75 ± 17.05 bpm, sepsis 12-h group = 302.13 ± 21.15 bpm), LVSP (sham operation group = 125.50 ± 11.45 mmHg, sepsis 3-h group = 110.88 ± 7.51 mmHg, sepsis 6-h group = 100.00 ± 15.06 mmHg, sepsis 12-h group = 91.38 ± 14.73 mmHg), +dp/dtmax (sham operation group = 7137.50 ± 276.44 mm Hg/sec, sepsis 3-h group = 5745.00 ± 346.16 mm Hg/sec, sepsis 6-h group = 4360.00 ± 312.04 mm Hg/sec, sepsis 12-h group = 2871.25 ± 443.99 mm Hg/sec), and -dp/dtmax (sham operation group = 6363.75 ± 123.86 mm Hg/sec, sepsis 3-h group = 6018.75 ± 173.49 mm Hg/sec, sepsis 6-h group = 5350.00 ± 337.89 mm Hg/sec, sepsis 12-h group = 4085.00 ± 326.76 mm Hg/sec). They also displayed significantly higher levels of serum cytokines, including TNF-α (sham operation group = 14.72 ± 2.90 pg/mL, sepsis 3-h group = 34.90 ± 4.79 pg/mL, sepsis 6-h group = 24.91 ± 2.57 pg/mL, sepsis 12-h group 22.06 ± 3.11 pg/mL), IL-1β (sham operation group = 42.25 ± 16.91, 3-h group = 112.25 ± 13.77, sepsis 6-h group = 207.90 ± 22.64, sepsis 12-h group = 157.18 ± 23.06), IL-6 (sham operation group = 39.89 ± 5.74, sepsis 3-h group = 78.27 ± 9.31, sepsis 6-h group = 123.75 ± 13.11, sepsis 12-h group = 93.21 ± 8.96), and cTnI (sham operation group = 0.07 ± 0.03 ng/mL, sepsis 3-h group = 0.18 ± 0.06 ng/mL, sepsis 6-h group = 0.67 ± 0.19 ng/mL, sepsis = 12-h group 1.28 ± 0.10 ng/mL). The rats in the sepsis groups exhibited pathological changes in the myocardium, which deteriorated gradually over time. The animals in all the sepsis groups exhibited significantly higher levels of TLR4 and NF-κB protein expression compared with the sham group. The TLR4 protein expressions were 0.376 in the sham operation group, 0.534 in the sepsis 3-h group, 0.551 in the sepsis 6-h group, and 0.719 in the sepsis 12-h group. The NF-κB protein expressions were 0.299 in the sham operation group, 0.488 in the sepsis 3-h group, 0.516 in the sepsis 6-h group, and 0.636 in the sepsis 12-h group. CONCLUSION: Sepsis can lead to myocardial injury and cardiac dysfunction. This may be related to the activation of the NF-κB intracellular signal transduction pathway and the release of inflammatory factors as a result of lipopolysaccharides acting on TLR4 during the onset of sepsis.

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Toll-Like Receptor-Mediated Cardiac Injury during Experimental Sepsis

Cited by 3 publications

References 87 publications

Detecting Critical Functional Ingredients Group and Mechanism of Xuebijing Injection in Treating Sepsis

Detecting Critical Functional Ingredients Group and Mechanism of Xuebijing Injection in Treating Sepsis

Novel Insights Into the Potential Mechanisms of N6-Methyladenosine RNA Modification on Sepsis-Induced Cardiovascular Dysfunction: An Update Summary on Direct and Indirect Evidences

Role of activating the nuclear factor kappa B signaling pathway in the development of septic cardiomyopathy in rats with sepsis

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