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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 63  |  Issue : 6  |  Page : 276-285

Helium Protects Against Lipopolysaccharide-Induced Cardiac Dysfunction in Mice via Suppressing Toll-Like Receptor 4-Nuclear Factor κB-Tumor Necrosis Factor-Alpha/ Interleukin-18 Signaling


1 Department of Traditional Chinese Medicine, The Third Affiliated Hospital; Institute of Integrated Traditional Chinese and Western Medicine, Sun Yat-sen University, Guangzhou, China
2 Biofeedback Laboratory; School of Biomedical Engineering, Xinhua College of Sun Yat-sen University, Guangzhou, China
3 Biofeedback Laboratory, Xinhua College of Sun Yat-sen University; Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
4 Research Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

Date of Submission11-Aug-2020
Date of Decision13-Oct-2020
Date of Acceptance23-Oct-2020
Date of Web Publication26-Dec-2020

Correspondence Address:
Prof. Hongzhi Yang
600 Tianhe Road, Guangzhou 510630, Guangdong
China
Associate Prof. Min Dai
600 Tianhe Road, Guangzhou 510630, Guangdong
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CJP.CJP_66_20

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  Abstract 


The nonanesthetic noble gas helium (He) can protect many organs against ischemia and reperfusion injury, such as liver and heart. However, the role of He on cardiac dysfunction during sepsis is not clear. In this study, we established a lipopolysaccharide (LPS)-induced cardiac dysfunction mouse model to examine the influence of He on the impaired cardiac function, and further investigated the possible innate immune mechanisms that may be involved. LPS induced left ventricular dysfunction and cavity enlargement, as indicated by decreased percent ejection fraction, percent fractional shortening, left ventricular anterior wall thickness in systole, and left ventricular posterior wall thickness in systole, while increased left ventricular end-systolic diameter and left ventricular end-systolic volume. He improved the impaired left ventricular function and cavity enlargement in a dose-dependent manner, and it was beneficial at 1.0 mL/100 g. Mechanistically, He inhibited toll-like receptor 4 (TLR4) expression, reduced the phosphorylation of nuclear factor κB (NF-κB), and subsequently alleviated tumor necrosis factor-alpha (TNF-α) and interleukin-18 (IL-18) expression in heart. Therefore, He protects against LPS-induced cardiac dysfunction in mice partially via inhibiting myocardial TLR4-NF-κB-TNF-α/IL-18 signaling.

Keywords: Helium, interleukin-18, lipopolysaccharide, nuclear factor-κB, septic cardiomyopathy, toll-like receptor 4, tumor necrosis factor-alpha


How to cite this article:
Zhang Y, Zhang J, Xu K, Chen Z, Xu X, Xu J, Zheng S, Dai M, Yang H. Helium Protects Against Lipopolysaccharide-Induced Cardiac Dysfunction in Mice via Suppressing Toll-Like Receptor 4-Nuclear Factor κB-Tumor Necrosis Factor-Alpha/ Interleukin-18 Signaling. Chin J Physiol 2020;63:276-85

How to cite this URL:
Zhang Y, Zhang J, Xu K, Chen Z, Xu X, Xu J, Zheng S, Dai M, Yang H. Helium Protects Against Lipopolysaccharide-Induced Cardiac Dysfunction in Mice via Suppressing Toll-Like Receptor 4-Nuclear Factor κB-Tumor Necrosis Factor-Alpha/ Interleukin-18 Signaling. Chin J Physiol [serial online] 2020 [cited 2021 Jun 22];63:276-85. Available from: https://www.cjphysiology.org/text.asp?2020/63/6/276/304859




  Introduction Top


Helium (He), which has the lowest melting and boiling points of all elements, belongs to the family of noble gases, a group of chemical elements characterized by filled valence orbitals, carrying a maximum amount of electrons in the outer shell of the atom, rendering them “inert” with very low chemical reactivity.[1] He is the second-most abundant element in the known universe, after hydrogen (H2).[2] Moreover, with a molecular weight of 4 g/mol, He is the lightest noble gas, and the second least dense gas, behind H2.[1],[2] Due to the much lower solubility than nitrogen in body tissues, and the lower density and viscosity, the mixture of He and oxygen (Heliox) decreases the formation of nitrogen bubbles and therefore slowing the onset of decompression illness in deep-sea divers, and heliox also improves the flow of oxygen in patients with upper airway obstruction and asthma exacerbation.[1],[2],[3]

In recent years, serious studies from Nina C. Weber group and others have indicated that He has profound cellular protective effects in vitro and in vivo: He applied before, during, or after an ischemic event reduced cellular damage, known as “organ conditioning,” in some tissues, for example, the myocardium, brain, and endothelium.[1],[4],[5],[6],[7],[8],[9],[10],[11] Moreover, He has the ability to decrease the expression of pro-inflammatory marker CD11b and ICAM-1 on leukocytes and attenuate the expression of pro-coagulant markers CD42b and PSGL-1 on platelets in humans in vivo.[12] Sepsis-related cardiac dysfunction, which is a kind of inflammatory heart disease resulting from a maladaptive host response to infection, represents a severe form of multi-organ anomalies in sepsis, leading to unfavorable changes in cardiac structure and function including dilated ventricles, impaired cardiac contractility, and dampened cardiac output.[13],[14],[15] Mechanistically, the endotoxin lipopolysaccharide (LPS) released from Gram-negative bacteria has a major role in the disrupted inflammatory response and cardiovascular homeostasis in sepsis.[15] Given that inflammation is among the most prominent responses to trigger a wide range of behavior and organ damage in sepsis, LPS is used to establish animal model to provoke transient toll-like receptor 4 (TLR4)-mediated inflammation mimicking sepsis.[15],[16] We have previously revealed that hydrogen gas (H2) can improve LPS-induced cardiac dysfunction via inhibiting excessive activation of innate immune signaling.[13] However, as an inflammatory modulator, the effects of He on the impaired cardiac function during sepsis are not clear. Therefore, we established LPS-induced cardiac dysfunction mouse model to investigate whether He has the protective effect on the impaired cardiac function, and demonstrate the regulatory mechanism may be involved.


  Materials and Methods Top


Drugs

He (99.999%; Dalian Special Gases Co., Ltd., Dalian, Liaoning, China) was stored in a seamless steel gas cylinder. He was injected into a vacuumed aseptic soft plastic infusion bag (100 mL; Hebei Tiancheng Pharmaceutical Co., Ltd., Cangzhou, Hebei, China) under sterile conditions immediately prior to intraperitoneal injection for animal study. LPS from  Escherichia More Details coli O55:B5 (cat no. L2880, Sigma-Aldrich; MerekKGaA, Darmstadt, Germany) was freshly prepared by dissolving in normal saline (1 mg/mL) immediately prior to intraperitoneal injection.

Animal model of lipopolysaccharide-induced cardiac dysfunction and treatment protocol

Male C57BL/6J mice were purchased from the Animal Center of Guangzhou University of Chinese Medicine (Guangzhou, China). Mice aged about 11 weeks (weight range: 24.3–26.8 g) were used in this study. All experimental procedures and protocols were approved by the Institutional Animal Care and Use Committee in Zhongshan School of Medicine, Sun Yat-sen University (IACUC ethic code no. 2018-057). All mice were provided with humane care according to the National Society of Medical Research and the Guide for the Care and Use of Laboratory Animals published by the NIH (8th Edition, Revised 2011).

Transthoracic echocardiography was performed with the Vevo-2100 high-frequency ultrasound system (VisualSonics Inc., Toronto, Canada) at the baseline. Then, mice with normal cardiac function were randomly assigned to the following four groups: control group (n = 7), LPS group (n = 7), LPS plus low dose of He group (n = 7), and LPS plus high dose of He group (n = 7). In LPS plus low dose of He group and LPS plus high dose of He group, He was daily given at the dose of 0.5 mL/100 g, and 1 mL/100 g by intraperitoneal injection, respectively. On the 4th day, LPS was given by intraperitoneal injection (5 mg/1 kg) to LPS group, LPS plus low dose of He group, and LPS plus high dose of He group, and the control group was treated with saline.[13],[17],[18] Moreover, He was given 0.5 h before LPS injection in LPS plus low dose of He group and LPS plus high dose of He group. Transthoracic echocardiography was performed 4 h post-LPS administration as previously described.[13],[19]

Antibodies and Western blotting

The antibodies against nuclear factor-κB (NF-κB) p65 (cat no. 8242S) and phospho-NF-κB p65 (cat no. 3033) were purchased from Cell Signaling Technology (Danvers, MA, USA). The antibody against TLR4 (cat no. sc203072) was purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA). The antibody against glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (cat no. MB001) was purchased from Bioworld Technology (Nanjing, Jiangsu, China). The antibody against tumor necrosis factor-alpha (TNF-α) (cat no. AF7014) was purchased from Affinity Biosciences Ltd., Cell Signal Transduction (Changzhou, China). The antibody against interleukin-18 (IL-18) (cat no. D046-3) was purchased from MBL BEIJING BIOTECH CO., LTD (Beijing, China). The anti-rabbit IgG HRP-linked antibody (cat no. 7074S) and anti-mouse IgG HRP-linked antibody (cat no. 7076S) were purchased from Cell Signaling Technology (Danvers, MA, USA).

Total proteins were extracted from left ventricular tissue with lysis buffer containing 10% Tris-HCl (1M, pH 6.8), 40% SDS (10%), 20% glycerol, 16% water, 10% phosphatase inhibitor cocktail (Roche, cat no. 4906837001, 10×), and 4% protease inhibitor cocktail (Roche, cat no, 4693132001, 25×). The protein concentration was determined by ultraviolet method using BioDrop μLite ultra-micro protein nucleic acid analyzer (BioDrop, Cambridge, UK). Western blotting was performed as we have previously described.[20] The proteins were transferred to polyvinylidene fluoride membranes (Merck Millipore Ltd., Tullagreen, Carrigtwohill, County Cork), which were incubated with primary and secondary antibodies by standard techniques. The enhanced chemiluminescence (ChemiDoc XRS+ System, Bio-Rad, Hercules, CA, USA) was used to accomplish immunodetection. The Western blot bands were quantified by estimating the “IntDen” value through Image J software (National Institutes of Health, Bethesda, MD, USA).

Statistical analysis

Data were expressed as mean ± standard deviation. GraphPad Prism 5 (GraphPad Software Inc., San Diego, CA, USA) was used for statistical analyses. Statistical analysis was performed by one-way analysis of variance followed by Bonferroni's post hoc test. A value of P < 0.05 was considered significantly different.


  Results Top


He alleviates lipopolysaccharide-induced cardiac dysfunction in a dose-dependent manner

A total of 28 mice with normal levels of left ventricular end-systolic diameter (LVESD), left ventricular end-diastolic diameter (LVEDD), left ventricular percent ejection fraction (EF%), and percent fractional shortening (FS%) were used; these mice were randomly divided into four groups. There was no statistical difference in these parameters among groups [Figure 1]. Four hours after LPS injection, mice in the LPS group exhibited cardiac dysfunction compared with control group, as indicated by decreasing EF% (38.13 ± 8.07 vs. 72.72 ± 4.36, P < 0.001) and FS% (18.01 ± 4.28 vs. 40.92 ± 3.71, P < 0.001), increasing LVESD (2.82 ± 0.39 vs. 1.98 ± 0.23, P < 0.01), while LVEDD (3.43 ± 0.32 vs. 3.34 ± 0.22) was not affected [Figure 2]. Compared with LPS group, the impaired cardiac function was alleviated by high dose of He injection (EF%: 38.13 ± 8.07 vs. 57.29 ± 14.84, P < 0.05; FS%: 18.01 ± 4.28 vs. 30.15 ± 11.25, P < 0.05; LVESD: 2.82 ± 0.39 vs. 2.19 ± 0.43, P < 0.05), while low dose of He injection slightly improved LPS-induced cardiac dysfunction with no statistical difference, and these mice still displayed cardiac dysfunction compared with control group (EF%: 41.21 ± 11.82 vs. 72.72 ± 4.36, P < 0.001; FS%: 19.80 ± 6.62 vs. 40.92 ± 3.71, P < 0.001; LVESD: 2.60 ± 0.43 vs. 1.98 ± 0.23, P < 0.05) [Figure 2]. Therefore, intraperitoneal injection of He can improve LPS-induced cardiac dysfunction in mice.
Figure 1: The echocardiographic parameters of cardiac function in each group at the baseline. (a) Representative M-mode echocardiographic images before treatment; (b-e) quantification of left ventricular end-diastolic diameter, left ventricular end-systolic diameter, percent ejection fraction and percent fractional shortening by echocardiography before treatment. n = 7 in each group, n. s. means that there are no significance among groups.

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Figure 2: The effects of helium on lipopolysaccharide-induced cardiac dysfunction. (a) Representative M-mode echocardiographic images at 4 h after lipopolysaccharide injection; (b-e) quantification of left ventricular end-diastolic diameter, left ventricular end-systolic diameter, percent ejection fraction, and percent fractional shortening by echocardiography at 4 h after lipopolysaccharide injection. n = 7 in each group, ***P < 0.001 versus Control, **P < 0.01 versus Control, *P < 0.05 versus Control, #P < 0.05 versus lipopolysaccharide, n. s. means that there are no significance among groups.

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The effect of He on left ventricular hypertrophic response in the challenge of lipopolysaccharide

LPS has been shown to induce cardiomyocytes hypertrophy in vitro.[21],[22],[23],[24] Therefore, we examined left ventricular hypertrophic response in vivo. At baseline, there was no statistical difference in left ventricular mass average weight (LV mass AW), LV mass AW (corrected = 0.8 × LV mass AW), left ventricular anterior wall thickness in diastole (LVAWd), left ventricular anterior wall thickness in systole (LVAWs), left ventricular posterior wall thickness in diastole (LVPWd), left ventricular posterior wall thickness in systole (LVPWs), left ventricular end-diastolic volume (LVEDV), and left ventricular end-systolic volume (LVESV) among groups [Figure 3]. After 4 h of LPS challenge, LV mass AW and LV mass AW (corrected) had slightly increased compared with that of the control group, and these further increased when receiving low dose of He, whereas high dose of He almost normalized these parameters, although there was no statistical difference among these four groups [Figure 4]a and [Figure 4]b. Moreover, there were no significant differences among groups in LVEDV, LVAWd, and LVPWd, LPS significantly increased LVESV followed by decreased LVAWs and LVPWs compared with control group (LVESV: 31.04 ± 10.91 vs. 12.71 ± 3.80, P < 0.01; LVAWs: 1.00 ± 0.12 vs. 1.28 ± 0.10, P < 0.05; LVPWs: 0.83 ± 0.09 vs. 1.20 ± 0.10, P < 0.001), these parameters had improved by high dose of He injection (LVESV: 17.06 ± 7.16 vs. 31.04 ± 10.91, P < 0.05; LVAWs: 1.22 ± 0.17 vs. 1.00 ± 0.12, no significance; LVPWs: 1.02 ± 0.11 vs. 0.83 ± 0.09, P < 0.05), while low dose of He injection slightly improved these parameters with no statistical difference compared with LPS group (LVESV: 25.57 ± 10.35 vs. 31.04 ± 10.91; LVAWs: 1.07 ± 0.18 vs. 1.00 ± 0.12; LVPWs: 0.96 ± 0.17 vs. 0.83 ± 0.09) [Figure 4]c, [Figure 4]d, [Figure 4]e, [Figure 4]f, [Figure 4]g [Figure 4]h. Therefore, these data indicated that LPS induced left ventricular cavity enlargement, which can be improved by He.
Figure 3: The echocardiographic parameters of cardiac hypertrophy in each group at the baseline. (a) Left ventricular mass average weight, (b) left ventricular mass average weight (corrected), (c) left ventricular anterior wall thickness in diastole, (d) left ventricular anterior wall thickness in systole, (e) left ventricular posterior wall thickness in diastole, (f) left ventricular posterior wall thickness in systole, (g) left ventricular end-diastolic volume and (h) left ventricular end-systolic volume. n = 7 in each group, n. s. means that there is no significance among groups.

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Figure 4: The effects of helium and lipopolysaccharide on cardiac hypertrophic responses. (a) Left ventricular mass average weight, (b) left ventricular mass average weight (corrected), (c) left ventricular anterior wall thickness in diastole, (d) left ventricular anterior wall thickness in systole, (e) left ventricular posterior wall thickness in diastole, (f) left ventricular posterior wall thickness in systole, (g) left ventricular end-diastolic volume and (h) left ventricular end-systolic volume. n = 7 in each group, ***P < 0.001 versus Control, **P < 0.01 versus Control, *P < 0.05 versus Control, #P < 0.05 versus lipopolysaccharide, n. s. means that there is no significance among groups.

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He suppresses toll-like receptor 4-nuclear factor-κB-tumor necrosis factor-alpha/interleukin-18 signaling in heart

Through interacting with its receptor TLR4, LPS promotes the phosphorylation and the nuclear translocation of NF-κB, and then induces the expression of inflammatory cytokines, such as TNF-α, and subsequently TNF-α increases myocardial IL-18 levels.[25],[26],[27] These cytokines may directly disturb cardiac function.[25],[26],[27] We and other researchers have revealed that LPS can induce the expression of TLR4 in heart.[13],[28] Targeting TLR4 by gene knockout or pharmacological inhibitor can alleviate cardiac dysfunction following sepsis.[28],[29] Here, LPS increased cardiac TLR4 expression, NF-κB phosphorylation, and TNF-α and IL-18 expression, which were suppressed by high dose of He treatment [Figure 5], [Figure 6], [Figure 7], [Figure 8]. Moreover, low dose of He treatment also decreased NF-κB phosphorylation and TNF-α expression when compared with LPS group [Figure 6] and [Figure 7]. Although the average levels of TLR4 expression and IL-18 expression in low dose of He treatment group were lower than that of LPS group, there was no statistical significance [Figure 5], [Figure 6], [Figure 7], [Figure 8]. Therefore, the high dose of He inhibits TLR4-NF-κB-TNF-α/IL-18 signaling in response to LPS, indicating the anti-inflammatory effects of He in the heart.
Figure 5: The effects of helium on lipopolysaccharide-induced TLR4 expression in vivo. (a) Western blot bands of TLR4 and GAPDH in heart; (b) quantification of transient TLR4 to GAPDH, the average of TLR4/GAPDH ratio in control group was set as “1.” n = 3 in each group, *P < 0.05 versus Control, #P < 0.05 versus lipopolysaccharide. TLR4: toll-like receptor 4, GAPDH: glyceraldehyde-3-phosphate dehydrogenase.

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Figure 6: The effects of helium on LPS-induced nuclear factor-κB expression and phosphorylation in vivo. (a) Western blot bands of p-p65, p65, and GAPDH in heart; (b) quantification of p-p65 to p65, the average of p-p65/p65 ratio in the control group was set as “1.” n = 3 in each group, *P < 0.05 versus Control, #P < 0.05 versus LPS, ##P < 0.01 versus LPS. LPS: lipopolysaccharide, GAPDH: glyceraldehyde-3-phosphate dehydrogenase.

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Figure 7: The effects of helium on LPS-induced TNF-α expression in vivo. (a) Western blot bands of TNF-α and GAPDH in heart; (b) quantification of TNF-α to GAPDH, the average of TNF-α/GAPDH ratio in the control group was set as “1.” n = 3 in each group, *P < 0.05 versus Control, #P < 0.05 versus LPS, ###P < 0.001 versus LPS. LPS: lipopolysaccharide, TNF-α: tumor necrosis factor-alpha, GAPDH: glyceraldehyde-3-phosphate dehydrogenase.

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Figure 8: The effects of helium on LPS-induced IL-18 expression in vivo. (a) Western blot bands of IL-18 and GAPDH in the heart; (b) quantification of IL-18 to GAPDH, the average of IL-18/GAPDH ratio in the control group was set as “1.” n = 3 in each group, *P < 0.05 versus Control, ##P < 0.01 versus LPS. LPS: lipopolysaccharide, IL-18: interleukin-18, GAPDH: glyceraldehyde-3-phosphate dehydrogenase.

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  Discussion Top


With the lower density and viscosity, which can reduce work of breathing, the nonanesthetic noble gas He is clinically used in treating airway obstruction and ventilation disorders in children and adults.[1] Studies from recent years confirmed the cellular protective effects of He. He preconditioning consisting gas mixture of 70 vol% He and 30 vol% oxygen inhalation for three 5-min periods interspersed with three 5-min washout periods using room air protects mouse liver against ischemia and reperfusion (I/R) injury via increasing Akt phosphorylation in hepatocytes.[30] The plasma from volunteers breathing 79% He reduces hypoxia-induced cell damage in human endothelial cells.[8] Similarly, He preconditioning before a subsequent coronary artery occlusion (30 min) and 3 h of reperfusion significantly reduces the infarct size in rabbit hearts.[31] He can also reduce infarct size in young rats; however, He has no effect on infarct size in aged Wistar rats.[32] He concentrations of 70%, 50%, and 30% but not 10% reduced infarct size,[33] and a short episode of He postconditioning (15 min) reduced infarct size, whereas prolonged He postconditioning (30 and 60 min) during early reperfusion did not induce cardioprotection in the rat heart.[34] Moreover, He-induced early preconditioning and postconditioning are abolished in obese Zucker rats in vivo.[35] These indicate that the protective effect of He on I/R in heart is age-, strain-, dose-, and time-dependent.[6],[32],[33],[34],[35] In this study, we found that high dose (1 mL/100 g), rather than low dose (0.5 mL/100 g) of He can improve LPS-induced left ventricular dysfunction and cavity enlargement in male C57BL/6J mice.

The cardiomyocyte TLR4 is involved in cardiac dysfunction during sepsis. TLR4 expression in the heart is increased after LPS challenge.[28],[36] TLR4 knockout mice and chimeras deficiency in myocardial TLR4 by bone marrow transplantation, are resistant to LPS-mediated cardiac dysfunction.[28],[36] The pharmacological TLR4 antagonism eritoran tetrasodium (E5564) partially prevents LPS-induced blood pressure reduction and preserves cardiac function.[29] We have previously revealed that H2 protected against LPS-induced cardiac dysfunction via suppressing TLR4 expression.[13] In the current study, we find that the protective effects of high dose of He on LPS-induced cardiac dysfunction are related to its inhibition on TLR4 expression in heart.

TLR4 activation leads to the expression and secretion of pro-inflammatory cytokines via activating transcription factor NF-κB.[27] Mechanistically, NF-κB binds to its inhibitor IκB and is sequestered in the cytoplasm of most unstimulated cells.[37],[38] Stimulation of cells with a variety of agents, such as LPS, leads to the phosphorylation of IκB by IκB kinase (IKK) complex, and then IκB dissociates from NF-κB, which then enters the nucleus to turn on a battery of genes important for immune and inflammatory responses.[37],[38] Cleavage of IκBα by calpain induces myocardial NF-κB activation, and cardiac dysfunction in septic mice.[39] Overexpression of cardiac I-κBα prevents endotoxin-induced myocardial dysfunction,[40] and IKK inhibitor reduces the multiple organ dysfunction caused by sepsis in mice.[41] In this study, LPS-induced NF-κB phosphorylation was suppressed by He in a dose-dependent manner, and the high dose of He treatment was more efficient.

LPS induces TNF-α expression in cardiomyocytes via TLR4-NF-κB signaling, thus contributing to myocardial dysfunction during sepsis.[25],[42],[43] Eliminating both TNF receptor (TNFR)-1 and TNFR-2 was required to restore cardiomyocytes shortening during LPS treatment.[44] In addition to TNF-α, myocardial IL-18 content was also increased in response to LPS.[26] In TNF−/− mice, myocardial IL-18 levels were not significantly different between the saline control and LPS-treated groups, however compared with LPS-treated wild-type mice, myocardial IL-18 expression had decreased after LPS challenge in TNF−/− mice.[26] This suggests that TNF-α was required for the LPS-induced increase in myocardial IL-18 levels and the cardiodepressive role of TNF-α during endotoxemia may be mediated via induction of IL-18.[26] IL-18 may, in turn, be a direct cardiodepressant or may mediate endotoxemic myocardial dysfunction via induction of and/or synergy with IL-1β, ICAM-1, and VCAM-1.[26] Therefore, IL-18 gene deletion or neutralization of IL-18 attenuates LPS-induced myocardial dysfunction.[26],[45] It has been reported that inhaled 70 vol% He modulates the inflammatory response by increasing hepatic IL-10 mRNA levels, which indicates the possible anti-inflammatory effects of He in tissue parenchymal cells.[46] Thus, we investigated the influence of He on LPS-induced TNF-α and IL-18 expression in heart. LPS promoted TNF-α and IL-18 expression in heart, which can also be suppressed by He in a dose-dependent manner.


  Conclusion Top


He protects against LPS-induced cardiac dysfunction in mice in a dose-dependent manner. The He-mediated cardioprotection is partially related to its inhibition on TLR4-NF-κB-TNF-α/IL-18 signaling in heart.

Financial support and sponsorship

This work was supported by the project funded by China Postdoctoral Science Foundation (no. 2019M653238), the National Natural Science Foundation of China (no. 81900376 and no. 81901447), the Natural Science Foundation of Guangdong Province (no. 2018A030313657 and no. 2018A030313733), and Guangdong famous Traditional Chinese Medicine inheritance studio construction project (no. 20180137).

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]



 

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