Anti-Inflammatory Effects of Shenfu Injection against Acute Lung Injury through Inhibiting HMGB1-NF-κB Pathway in a Rat Model of Endotoxin Shock.

Xia Liu,Liyan Mei,Fei Ai,Jifei Miao,Qin Xu,Chunwei Chu,Quan Wen,Junfeng Guo,Saixia Zhang,Chaoying Zhang,Jianhong Zhou,Xiangyun Chen,Hui Li

doi:10.1155/2019/9857683

Abstract

Shenfu injection (SFI), a Chinese herbal medicine with substances extracted from Ginseng Radix et Rhizoma Rubra and Aconiti Lateralis Radix Praeparata, is widely used as an anti-inflammatory reagent to treat endotoxin shock in China. However, the mechanism of SFI in endotoxin shock remains to be illuminated. High mobility group box 1 (HMGB1), a vital inflammatory factor in the late stage of endotoxin shock, may stimulate multiple signalling cascades, including κB (NF-κB), a nuclear transcription factor, as well as tumour necrosis factor (TNF)-α and interleukin (IL)-1β, among others in the overexpression of downstream proinflammatory cytokines. An investigation into the effects of SFI on the inhibition of the HMGB1-NF-κB pathway revealed the contribution of SFI to acute lung injury (ALI) in a rat model of endotoxin shock. To assess the anti-inflammatory activity of SFI, 5 ml/kg, 10 ml/kg, or 15 ml/kg of SFI was administered to different groups of rats following an injection of LPS, and the mean arterial pressure (MAP) at 5 h and the survival rate at 72 h were measured. 24 h after LPS injection, we observed pathological changes in the lung tissue and measured the mRNA expression, production, translocation, and secretion of HMGB1, as well as the expression of the NF-κB signal pathway-related proteins inhibitor of NF-κB (IκB)-α, P50, and P65. We also evaluated the regulation of SFI on the secretion of inflammatory factors including interleukin-1 beta (IL-1β) and TNF-α. SFI effectively prevented the drop in MAP, relieved lung tissue damage, and increased the survival rate in the endotoxin shock model in dose-dependent manner. SFI inhibited the transcription, expression, translocation, and secretion of HMGB1, increased the expression of toll-like receptor (TLR4), increased the production of IκB-α, and decreased the levels of P65, P50, and TNF-α in the lung tissue of endotoxin shock rats in a dose-dependent manner. Furthermore, SFI decreased the secretion of proinflammatory cytokines TNF-α and IL-1β. In summary, SFI improves the survival rate of endotoxin shock, perhaps through inhibiting the HMGB1-NF-κB pathway and thus preventing cytokine storm.

Highlights

Acute lung injury (ALI), described by increased capillary permeability and acute inflammatory disorder, is mainly caused by endotoxemia and is common worldwide [1]
Extracellular High mobility group box 1 (HMGB1) has been confirmed as a damage-associated molecular pattern (DAMP), which plays a part in the development of many clinical diseases, such as ALI/ Acute respiratory distress syndrome (ARDS), sepsis, asthma, and cancer [5,6,7,8,9,10,11]. rough binding to receptor for advanced glycation end products (RAGE) and toll-like receptor 2/4 (TLR-2/4), extracellular HMGB1 may activate inflammation-related signalling pathways, including NF-κB and mitogen-activated protein kinase (MAPK) pathways, succeeded by the overproduction of the downstream proinflammatory mediators, tumour necrosis factor (TNF)-α, IL-1β, and IL-8 as well [10]
To estimate the effectiveness of Shenfu injection (SFI) on mean arterial pressure (MAP) of the experimental rats, MAP changes were recorded every 0.5 h for 5 h (Figure 1(b)). e decline in MAP in LPS group was more than 30%, suggesting that the rats were in a state of persistent shock

Summary

Introduction

Acute lung injury (ALI), described by increased capillary permeability and acute inflammatory disorder, is mainly caused by endotoxemia and is common worldwide [1]. Acute respiratory distress syndrome (ARDS), a more severe form of ALI, is a leading cause of mortality with endotoxin shock [2]. Overactivation of the immune system in ALI/ARDS leads to a cascade of proinflammatory mediators, which is likely responsible for the high mortality; anti-inflammatory therapy is important [3]. Rough binding to receptor for advanced glycation end products (RAGE) and toll-like receptor 2/4 (TLR-2/4), extracellular HMGB1 may activate inflammation-related signalling pathways, including NF-κB and mitogen-activated protein kinase (MAPK) pathways, succeeded by the overproduction of the downstream proinflammatory mediators, TNF-α, IL-1β, and IL-8 as well [10]. Recent research findings indicated that inhibiting the HMGB1-mediated TLR4/NF-κB signalling pathway facilitated the treatment of LPS-induced ALI/ARDS [12]

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Results

Conclusion