Elevated levels of circulating histones indicate disease activity in patients with hand, foot, and mouth disease (HFMD)

Li, Xiuhui; Qin, Li; Li, Junhong; Liu, Ying; Chen, Yuping; Ai-ping, LV; Zhang, Jian; Ding, Jianbo; Maltzan, Kristine von; Wen, Tao

doi:10.3109/00365548.2014.943285

Cited by 9 publications

(18 citation statements)

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“…However, HFMD can potentially be life threatening when it progresses critical conditions that have severe complications such as brainstem encephalitis, pulmonary edema, and acute respiratory failure (Tian et al, ). Recently, large HFMD outbreaks have become more frequent in the Asia Pacific region, especially in China, and severe cases were accordingly more commonly observed (Li et al ., , , ; Wu et al ., ; Zhu et al ., ).…”

Section: Introductionmentioning

confidence: 99%

“…Hand, foot, and mouth disease (HFMD) is a common infectious disease that usually affects infants and young children who are 5 years old or younger (Li et al ., , , ; Li et al ., ; Tian et al ., ; Zhou et al ., ). The causative pathogens of HFMD have been identified as enterovirus 71 (EV71) or coxsackievirus type A 16 (CVA16) (Fan et al ., ; Zhang et al ., ).…”

Section: Introductionmentioning

confidence: 99%

“…However, medications, such as antivirals, have not shown convincing clinical efficacy. Traditional Chinese medicines (TCM), including Chinese herbal formulas and injections, were proven to be effective as HFMD treatments (Cao et al ., ; Li et al ., , , ). As recommended by the Ministry of Health of China in 2010, the herb‐derived compound, andrographolide sulfonate (Trade name: Xiyanping injection), has been used in clinical practices to reduce fever and inflammation associated with HFMD (Li et al ., ).…”

Section: Introductionmentioning

confidence: 99%

“…We previously found that neutrophil activation is strongly implicated in the initiation and progression of HFMD, which was characterized by elevated plasma myeloperoxidase (MPO) levels and the concomitant release of inflammatory mediators, including circulating histones and cytokines (Li et al ., , , ). Notably, andrographolide sulfonate is believed to modulate neutrophil adhesion and transmigration (Shen et al ., ).…”

Section: Introductionmentioning

confidence: 99%

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Clinical Efficacy of Andrographolide Sulfonate in the Treatment of Severe Hand, Foot, and Mouth Disease (HFMD) is Dependent upon Inhibition of Neutrophil Activation

Wen

Liang

et al. 2015

Phytotherapy Research

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Andrographolide sulfonate treatment has been shown to improve clinical severe hand, foot, and mouth disease (HFMD) efficacies when combined with conventional therapy. However, the mechanisms for its therapeutic effects remain elusive. In this study, we aimed to investigate whether andrographolide sulfonate exerts its efficacy by acting on neutrophil activation. We obtained serial plasma samples at two time points (before and after 5 days of therapy) from 28 HFMD patients who received conventional therapy and 18 patients who received combination therapy (andrographolide sulfonate plus conventional therapy). Then, we measured plasma myeloperoxidase (MPO), S100A8/A9, histone, and inflammatory cytokine levels. Furthermore, we examined if andrographolide sulfonate had direct effects on neutrophil activation in vitro. We observed that MPO and S100A8/A9 levels were markedly elevated in the HFMD patients before clinical treatment. At 5 days post-medication, the MPO, S100A8/A9, histone, and interleukin-6 levels were markedly lower in the combination therapy group compared with the conventional therapy group. In vitro studies showed that andrographolide sulfonate inhibited lipopolysaccharide-stimulated neutrophil activation, demonstrated by the decreased production of reactive oxygen species and cytokines. These data indicate that neutrophil activation modulation by andrographolide sulfonate may be a critical determinant for its clinical HFMD treatment efficacy. Copyright © 2015 John Wiley & Sons, Ltd.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Clinical Efficacy of Andrographolide Sulfonate in the Treatment of Severe Hand, Foot, and Mouth Disease (HFMD) is Dependent upon Inhibition of Neutrophil Activation

Wen

Liang

et al. 2015

Phytotherapy Research

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“…Extracellular histones are derived from dying tissues [23] or dying neutrophils within neutrophil extracellular traps [24] during host defense to bacterial infections. Histones induce the release of TNF-α, IL-1β, IL-6, and IL-10, while pre-incubation with a histone H4 neutralization antibody protects against these pro-inflammatory responses [25, 26]. Mitogen-activated protein kinase (MAPK) signaling pathways, including extracellular signal-regulated kinase (ERK) and p38 pathways, are key mediators in inflammatory transduction and amplification [27].…”

Section: Introductionmentioning

confidence: 99%

Alpha-Lipoic Acid Suppresses Extracellular Histone-Induced Release of the Infammatory Mediator Tumor Necrosis Factor-α by Macrophages

Chang

Liu

et al. 2017

Cell Physiol Biochem

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Background/Aims: This study investigated signaling pathways via which extracellular histones induce the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) release from the macrophage cell line RAW 264.7 and the anti-inflammatory efficacy of the antioxidant alpha-lipoic acid (ALA). Methods: ELISA and western blotting analyses were conducted to detect the release of TNF-α from histone-stimulated RAW 264.7 macrophages and the associated phospho-activation of MAPKs (ERK and p38) and NF-κB p65. The effects of ALA on the release of TNF-α and phospho-activation of the MAPKs and NF-κB p65 were studied. P < 0.05 was considered statistically significant. Results: Extracellular histones dose-dependently induced TNF-α release from RAW 264.7 cells and increased the phosphorylation of p38, ERK, and NF-κB p65. TNF-α release was markedly suppressed by p38, ERK, and NF-kB inhibitors. ALA reduced histone-induced TNF-α release, ERK/p38 MAPK activation, and NF-kB activation without affecting macrophage viability. Conclusion: Histones induce TNF-α release from macrophages by activating the MAPK and NF-kB signaling pathways, while ALA suppresses this response by inhibiting ERK, p38 and NF-kB. These findings identify potentially critical inflammatory signaling pathways in sepsis and molecular targets for sepsis treatment.

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Local immune dysregulation and subsequent inflammatory response contribute to pulmonary edema caused by Enterovirus infection in mice

Sun

Liu

Dai

et al. 2023

Journal of Medical Virology

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Pulmonary edema that comes on suddenly is the leading cause of mortality in handfoot-and-mouth disease (HFMD) patients; however, its pathogenesis is still largely unclear. A range of research suggest immunopathogenesis during the occurrence of pulmonary edema in severe HFMD patients. Herein, to investigate the potential mechanism of immune dysregulation in the development of pulmonary edema upon Enterovirus (EV) infection, we established mouse infection models for Enteroviruses (EVs) including Coxsackievirus (CV) A6, Enterovirus A71 (EVA71), and CVA2 exhibiting a high incidence of pulmonary edema. We found that EVs infection induced an immune system disorder by reducing the numbers of pulmonary and circulatory T cells, B cells, macrophages, and monocytes and increasing the numbers of lung neutrophils, myeloid-derived suppressor cells (MDSCs), and activated T cells. In addition, the concentrations of C−X−C motif chemokine ligand 1 (CXCL-1), tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and interleukin 6 were increased in EV-infected lungs. Moreover, we found that EVs replication in mice lungs lead to apoptosis of lung cells and degradation of tight junction proteins. In conclusion, EVs infection likely triggered a complexed immune defense mechanism and caused dysregulation of innate immune cells (MDSCs, neutrophils, monocytes, and macrophages) and adaptive cellular immunity (B cells, T cells). This dysregulation increased the release of cytokines and other inflammatory factors from activated immune-related cells and caused lung barrier damage and pulmonary edema.

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Elevated levels of circulating histones indicate disease activity in patients with hand, foot, and mouth disease (HFMD)

Cited by 9 publications

References 18 publications

Clinical Efficacy of Andrographolide Sulfonate in the Treatment of Severe Hand, Foot, and Mouth Disease (HFMD) is Dependent upon Inhibition of Neutrophil Activation

Clinical Efficacy of Andrographolide Sulfonate in the Treatment of Severe Hand, Foot, and Mouth Disease (HFMD) is Dependent upon Inhibition of Neutrophil Activation

Alpha-Lipoic Acid Suppresses Extracellular Histone-Induced Release of the Infammatory Mediator Tumor Necrosis Factor-α by Macrophages

Local immune dysregulation and subsequent inflammatory response contribute to pulmonary edema caused by Enterovirus infection in mice

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