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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 7  |  Issue : 3  |  Page : 383-390

Protective effect of ginsenoside rd on lipopolysaccharide-induced acute lung injury through its anti-inflammatory and anti-oxidative activity


1 Department of Pharmacy, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
2 Guangzhou Darui Biotechnology Co., Ltd., Guangzhou, China
3 Obstetrics and Gynecology, Shenzhen Longhua District Central Hospital, Shenzhen, China
4 Medical Laboratory, Shenzhen Longhua District Central Hospital, Shenzhen, China
5 Department of Clinical Laboratory Medicine, Guangdong Second Provincial General Hospital, Guangzhou, China
6 College of pharmacy, Jinan University, Guangzhou, China

Date of Submission09-Aug-2021
Date of Acceptance02-Sep-2020
Date of Web Publication9-Aug-2021

Correspondence Address:
Prof. Yong-Li Situ
601 Huangpu Avenue West, Guangzhou City, Postal Code: 510632, Guangdong Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/wjtcm.wjtcm_12_21

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  Abstract 


Background: Inflammation and oxidation stress are key factors in the mechanism of acute lung injury (ALI). Therefore, suppression of the inflammatory response and oxidative stress could be a potential strategy to treat lipopolysaccharide (LPS)-induced ALI. Ginsenoside Rd (Rd), a natural Ginseng extract, alleviates inflammation and oxidative stress in several diseases such as Alzheimer's disease and cerebral ischemia, but its effect on ALI is still unclear. Aims and Objectives: To explore the protective effect of Rd on LPS-induced ALI and explored associated mechanisms. Materials and Methods: Mice were divided into five groups: A sham-operated group, a LPS-induced ALI group, and three LPS groups pretreated with Rd doses of 20, 40, and 80 mg/kg, respectively. The pathological changes of lung, collagen deposition, pulmonary edema, inflammatory cytokine, oxidative stress and the expression levels of TLR4 and NF-κB were detected. Results: The oral administration of Rd dose dependently attenuated histopathologic changes in the lung, lung edema, pulmonary collagen deposition, protein concentration in bronchoalveolar lavage fluid (BALF), myeloperoxidase (MPO) activity, and inflammatory cell infiltration. In addition, Rd suppressed the LPS-induced inflammatory cytokines tumor necrosis factor-α, interleukin (IL)-6, and IL-1 β in BALF. The productions of oxidative stress-related enzymes (catalase, superoxide dismutase, and glutathione peroxidase) in lung tissue were significantly upregulated by Rd administration. However, malondialdehyde and pulmonary MPO activity was reduced in the Rd-pretreated groups when compared with LPS-induced ALI group. Rd treatment also dose dependently suppressed LPS-induced NF-κB activation and TLR4 expression. Conclusion: Overall, these findings provide evidence that Rd pretreatment inhibits LPS-induced ALI through anti-inflammatory and antioxidative actions, suggesting that it could be a promising protective drug for LPS-induced ALI.

Keywords: Acute lung injury, ginsenoside Rd, inflammatory, oxidative stress


How to cite this article:
Chen J, Fang WX, Li SJ, Xiao SX, Li HJ, Situ YL. Protective effect of ginsenoside rd on lipopolysaccharide-induced acute lung injury through its anti-inflammatory and anti-oxidative activity. World J Tradit Chin Med 2021;7:383-90

How to cite this URL:
Chen J, Fang WX, Li SJ, Xiao SX, Li HJ, Situ YL. Protective effect of ginsenoside rd on lipopolysaccharide-induced acute lung injury through its anti-inflammatory and anti-oxidative activity. World J Tradit Chin Med [serial online] 2021 [cited 2022 Aug 8];7:383-90. Available from: https://www.wjtcm.net/text.asp?2021/7/3/383/323499




  Introduction Top


Acute lung injury (ALI) is common and devastating in several clinical disorders with high rates of morbidity and mortality worldwide.[1],[2] ALI is a severe respiratory syndrome characterized by complicated mechanisms that involve increased vascular permeability, inflammation, and oxidation stress.[3] Inflammatory and oxidative stresses are key factors involved in the onset and progression of ALI.[4],[5] Research indicates that ALI is caused by lipopolysaccharide (LPS), burns, trauma, and shock.[6] LPS also has been confirmed as a primary factor in the etiology of ALI.[7] Epidemiology indicates that ALI/ARDS can occur in patients of all ages.[8],[9],[10] The common therapeutic interventions are glucocorticoids and elastase inhibitors (severus sodium), but these involve several adverse effects. Therefore, there is an urgent need for a novel therapeutic drug to treat ALI and targeting the regulatory mechanisms of inflammation and oxidative stress may have substantial therapeutic potential for ALI.

Panax ginseng, a perennial herb and member of the Araliaceae family, is a well-known traditional herbal medicine which has been widely used in Korea and China. Ginsenosides are the main active ingredient of Ginseng and have numerous pharmacological effects.[11] Ginsenosides are divided into three main categories, ginsenoside (Rb1, Rb2, Rd, Rg3, and Rh2), oleanolic acid derivatives (ginsenoside Ro), and protopanaxatriols (ginsenoside Rg1, Re, Rg2, Rh1, and Rf), and protopanaxadiol.[12] Rd is one of the main active ingredients of ginsenosides in Ginseng[13] and has remarkable antioxidative, anti-inflammatory, and antiapoptotic effects in several diseases such as cerebral ischemia, Alzheimer's disease, and spinal cord ischemia/reperfusion injury.[14],[15],[16] However, to our knowledge, there are no reports on the effects of Rd in LPS-induced ALI. Therefore, in this study, animals subjected to LPS-induced ALI were used to examine the protective potential of Rd. In addition, we assessed whether these protective effects were associated with its anti-inflammatory and anti-oxidative effects.


  Materials and Methods Top


Reagents

Enzyme-linked immunosorbent assay (ELISA) kits of tumor necrosis factor-α (TNF-α), interleukin (IL)-1 β, and IL-6 were purchased from Boster Biological Technology co. Ltd (Wuhan, Hubei, China). BCA protein assay kits were purchased from Beyotime (Shanghai, Jiangsu, China). Wright-Giemsa staining kit and myeloperoxidase (MPO) kits were purchased from Jiancheng Bioengineering Institute of Nanjing (Nanjing, Jiangsu, China). Ginsenoside Rd (purity >98%) was purchased from Nanjing Jingzhu Bio-technology Co. Ltd (Nanjing, Jiangsu, China). Antibodies of TLR4, NF-κB p65, and β-actin were obtained from Santa Cruz Biotechnology (Autogen, Bioclear, UK). LPS (Escherichia coli 055:B5) was obtained from Sigma Chemical Co. (St. Louis, MO, USA).

Animals

Specific pathogen-free male C57BL/6 mice, which weighed 18–22 g were obtained from Guangdong Medical Laboratory Animal Center (Guangdong, China). Mice were bred in a room at 24°C ± 1°C, in a 12 h light-dark cycle, and a relative humidity of 60% ± 10% for 1 week before use. Animals had access to food and water ad libitum. Research protocols were approved by the Ethical Committee of Guangdong laboratory animals monitoring institute (IACUC2017029). All methods were performed in accordance with the relevant guidelines and regulations.

Lipopolysaccharide -induced acute lung injury model

The mice were randomly assigned to five groups as follows: (1) Sham-operated mice (Sham group, 24 mice); (2) LPS-induced ALI group (ALI group, 24 mice); (3, 4, and 5) LPS-induced ALI mice pre-treated with Rd separately at doses of 20, 40, and 80 mg/kg (20 mg/kg, 40 mg/kg, and 80 mg/kg Rd groups, 24 mice); in the pretreatment groups, mice were treated orally with Rd or saline 7 days before LPS-induced ALI. 30 min following the last administration, the ALI model was established by the administration of 10 mg/kg LPS by intravenous tail injection followed by a 24 h observation.[17] Following surgery, mice returned to their cages and fed and watered freely.

Pathological observation of the lung tissue

The lower lobes of right lungs were dipped in 4% paraformaldehyde for 60 h, then dehydrated using graded ethanol, embedded in paraffin, cut into 4 μm sections, and dyed with hematoxylin and eosin (HE) and Masson. Blinded morphologic observations of the lower lobes of the right lungs were conducted with light microcopy.

Measurement of lung wet-to-dry weight ratio

The upper and middle lobes of the right lung were collected to determine the wet-to-dry weight ratio to assess pulmonary edema. Lung tissue was obtained after the mice were euthanized with an intraperitoneal injection of pentobarbital sodium (40 mg/kg), dislocated the neck of the mice, and lung samples were weight after acquisition. The samples were then dehydrated at 80°C for 48 h until weights were constant. The wet-to-dry weight ratio = wet weight/the dry weight.[18]

Broncho-alveolar lavage fluid collection, cell counting, and protein concentration detection in bronchoalveolar lavage fluid

Bronchoalveolar lavage fluid (BALF) was collected as previously described.[19] Briefly, the lungs were flushed three times with sterile saline with a tracheal cannula. After centrifugation (1000 rpm, 10 min, 4°C), the supernatant was extracted and stored at −20°C for the assessment of protein concentrations. The protein concentration of the BALF was determined using a BCA protein assay kit. The sedimented cells were resuspended in 50 μl saline, and the number of neutrophils was determined using the Wright-Giemsa staining.

Measurement of myeloperoxidase activity in lung tissue

After induction of LPS for 24 h, mice were anesthetized, and the left lung tissues were obtained and weighed. A 10% homogenate of lung tissue was produced by homogenization in normal saline. After centrifugation (10,000 ×g, 2 min, 4°C), the MPO activity was assayed with a test kit. The samples were then evaluated at 460 nm with a microplate reader.

Measurement of inflammatory cytokine in bronchoalveolar lavage fluid

After 24 h of LPS treatment, the levels of TNF-a, IL-1 β, and IL-6 were assessed by ELISA according to the manufacturer's instructions.

Measurements of oxidative stress in lung tissue

We estimated the activities of antioxidant enzymes including catalase (CAT, expressed as U/g protein), superoxide dismutase (SOD, expressed as U/g protein), glutathione peroxidase (GPX, expressed as U/g protein), and the content of malondialdehyde (MDA, expressed as nmol/mg protein) level in lung homogenates[20] using commercial kits.

Western blot analysis

A 10% homogenate of lung tissue was obtained as described above. Total protein levels were obtained with tissue protein extraction solution. Equivalent proteins were separated by 12% SDS-PAGE and transferred to nitrocellulose membranes. They were then blocked with 10% nonfat milk for 1 h, and the nitrocellulose membranes were incubated with the primary antibodies TLR4 (1:300) and NF-κB p65 (1:300) overnight at 40C. Membranes were washed five times and incubated with horseradish peroxidase-labeled secondary antibodies for 1 h at room temperature. Finally, the signal was visualized using the enhanced chemiluminescence detection system, and the densities of the immunobands were quantitated. All data were corrected and normalized with β-actin.

Statistical analysis

Statistical analyses were performed with SPSS 16.0 Statistical software (IBM company,New York, USA) and statistical significance was set at P < 0.05 or P < 0.01. Results are presented as means ± standard error of mean and were analyzed with one-way factorial analysis ANOVA with Bonferroni's correction.


  Results Top


Rd attenuates lipopolysaccharide-induced lung histopathologic changes

To investigate the effects of Rd on LPS-induced ALI in mice, pathological changes of lung tissue in ALI mice were observed by HE staining. Compared to the sham group [Figure 1]a, LPS caused severe ALI, which was characterized by alveolar wall thickening, edema, and infiltration of inflammatory cells [Figure 1]b. Treatment of Rd markedly ameliorated LPS-induced pulmonary injury in a dose-dependent manner [Figure 1]c, [Figure 1]d, [Figure 1]e.
Figure 1: Rd protects against lipopolysaccharide-induced acute lung injury in mice. Mice were given Rd (20, 40, and 80 mg/kg) by lavage 30 min after administration of LPS. Lung tissues from each group were processed for histological evaluation at 24 h after LPS challenge. The lung tissue sections were stained with HE, ×200. (a) Sham group, (b) acute lung injury group, (c) 20 mg/kg Rd group, (d) 40 mg/kg Rd group, (e) 80 mg/kg Rd group

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Rd attenuates lipopolysaccharide-induced collagen deposition in trachea

Collagen deposition in ALI mice was observed with Masson staining to assess the effects of Rd on LPS-induced ALI. Compared to the sham group [Figure 2]a, LPS caused severe collagen deposition [Figure 2]b. Treatment of Rd markedly ameliorated LPS-induced collagen deposition in a dose-dependent manner [Figure 2]c, [Figure 2]d, [Figure 2]e.
Figure 2: Rd protects against lipopolysaccharide-induced pulmonary fibrosis in mice. Mice were given Rd (20, 40, and 80 mg/kg) by lavage 30 min after administration of lipopolysaccharide. Lung tissues from each group were processed for histological evaluation at 24 h after lipopolysaccharide challenge. Representative histological changes of lungs obtained from mice of different groups. Lung tissue sections were stained with Masson staining, ×200. (a) sham group, (b) acute lung injury group, (c) 20 mg/kg Rd group, (d) 40 mg/kg Rd group, and (e) 80 mg/kg Rd group

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Rd attenuates lipopolysaccharide-induced lung edema and protein leakage

To further assess the protective effect of Rd on LPS-induced ALI, lung edema [Figure 3]a, an indicator of LPS-induced ALI, and the protein concentration in BALF [Figure 3]b, an indicator of pulmonary permeability, were evaluated. The lung wet-to-dry ratio and protein concentrations in BALF were significantly increased in the ALI group when compared to the sham group (P < 0.01). Compared to the ALI group, pretreatment with Rd significantly decreased lung edema and protein permeability in a dose-dependent manner (P < 0.05 or 0.01).
Figure 3: Effects of Rd on wet-to-dry weight ratio of lung tissue and protein concentration in the bronchoalveolar lavage fluid of lipopolysaccharide -induced acute lung injury mice. Mice received Rd (20, 40, and 80 mg/kg) 7 days before lipopolysaccharide challenge. The lung wet-to-dry weight ratio (a) and the protein concentrations in bronchoalveolar lavage fluid (b) were determined at 24 h after lipopolysaccharide challenge. Values are mean ± standard error of mean (n = 6 for each group). *P < 0.05 and **P < 0.01 versus sham group; #P < 0.05 and ##P < 0.01 versus ALI group; ^P < 0.05 and ^^P < 0.01 versus 20 mg/kg Rd group

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Rd attenuates pulmonary myeloperoxidase activity and inflammatory cell infiltration

Neutrophil infiltration in lung tissue is a major histological marker of LPS-induced immunological response and inflammation. MPO activity is another important marker of neutrophil infiltration. The ALI group exhibited significant increases in pulmonary MPO activity and neutrophil infiltration when compared to the sham group (P < 0.01). Furthermore, pulmonary MPO activity and the number of infiltrated neutrophils were decreased more by pretreatment in Rd mice compared to ALI mice (P < 0.05 or 0.01) [Figure 4].
Figure 4: Effects of Rd on lipopolysaccharide-induced pulmonary myeloperoxidase activity and the number of infiltrated neutrophils. (a) MPO activity in the lung homogenates. (b) The number of infiltrated neutrophils in the bronchoalveolar lavage fluid. Values are mean ± standard error of mean (n = 6 for each group). *P < 0.05 and **P < 0.01 versus sham group; #P < 0.05 and ##P < 0.01 versus acute lung injury group; ^P < 0.05 and ^^P < 0.01 versus 20 mg/kg Rd group

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Rd attenuates lipopolysaccharide-induced inflammatory cytokine production

TNF-α, IL-1 β, and IL-6 are inflammatory cytokines which play a crucial role in the pathogenesis and progression of LPS-induced ALI. In the current study, the effects of Rd on TNF-α, IL-1 β, and IL-6 were evaluated by ELISA assay. Compared to the sham group, the content of TNF-α, IL-1 β, and IL-6 significantly increased in ALI group (P < 0.01). However, pretreatment with Rd decreased TNF-α, IL-1 β, and IL-6 in a dose-dependent manner (P < 0.05 or 0.01) [Figure 5].
Figure 5: Effects of Rd on the concentration of inflammatory cytokines in bronchoalveolar lavage fluid. 24 h after lipopolysaccharide-induced acute lung injury, the lungs of each group were flushed with sterile saline and bronchoalveolar lavage fluid was collected. The concentrations of the inflammatory cytokines tumor necrosis factor-α (a), interleukin-1 β (b), and interleukin-6 (c) were detected using an enzyme-linked immunosorbent assay assay. Values are mean ± standard error of mean (n = 6 for each group). *P < 0.05 and **P < 0.01 versus Sham group; #P < 0.05 and ##P < 0.01 versus ALI group; ^P < 0.05 and ^^P < 0.01 versus 20 mg/kg Rd group

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Rd attenuates lipopolysaccharide-induced acute lung injury oxidative stress

Oxidative stress plays an important role in the process of ALI-induced LPS, and oxidative stress induces lipid peroxidation of cell membranes, inhibits antioxidative enzyme activity (SOD, CAT, and GPx), and induces MDA generation. As shown in [Figure 6], the ALI group exhibited decreases in CAT, GPX, and SOD activity (P < 0.01) and increased MDA content (P < 0.01). Pretreatment with Rd significantly increased the activities of CAT, GPX, and SOD (P < 0.05 or 0.01) and decreased the content of MDA (P < 0.05 or 0.01) in a dose-dependent manner. Compared with the 20 mg/kg Rd group, the 80 mg/kg dose significantly increased the activities of CAT, GPX, and SOD (P < 0.05) and decreased MDA content (P < 0.05).
Figure 6: Effects of Rd on catalase, glutathione peroxidase, superoxide dismutase, and malondialdehyde in lipopolysaccharide induced acute lung injury mice. After pretreatment with Rd (20, 40, and 80 mg/kg) for 7 days, mice were exposed to lipopolysaccharide-induced acute lung injury and sacrificed 24 h after lipopolysaccharide challenge. The activities of catalase (a), glutathione peroxidase (b), superoxide dismutase (c), and malondialdehyde (d) in lung tissue were evaluated. Values are mean ± standard error of mean (n = 6 for each group). *P < 0.05 and **P < 0.01 versus Sham group; #P < 0.05 and ##P < 0.01 versus acute lung injury group; ^P < 0.05 and ^^P < 0.01 versus 20 mg/kg Rd group

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Rd inhibits lipopolysaccharide-induced TLR4 expression and NF-κB activation

TLR4 is the upstream regulatory factor for NF-κB. The effect of Rd on TLR4 expression was assessed by Western blotting. Compared to sham group, TLR4 expression was significantly increased in the ALI group. Pretreatment of Rd decreased TLR4 expression in a dose-dependent manner (P < 0.05 or 0.01) [Figure 7]. The production of inflammatory cytokines is regulated by NF-κB. In the current study, the effects of Rd on NF-κB activation were detected with Western blotting. Compared to sham group, the NF-κB activity was significantly increased in the ALI group (P < 0.01). Pretreatment of Rd decreased NF-κB activity in a dose-dependent manner (P < 0.05 or 0.01) [Figure 7].
Figure 7: Rd inhibits lipopolysaccharide-induced TLR4 expression and NF-κB activation. Relative optical densities of TLR4 (a) and NF-κB (b) Values are mean ± standard error of mean (n = 6 for each group). *P < 0.05 and **P < 0.01 versus Sham group; #P < 0.05 and ##P < 0.01 versus acute lung injury group

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  Discussion Top


Our results demonstrated that pretreatment with Rd attenuates lung histopathologic changes including edema, collagen deposition, inflammation, protein concentration in the BALF, MPO activity, inflammatory cell infiltration, and inhibition of TLR4 signaling pathways. These results indicate that Rd has potential protective effects against LPS-induced ALI.

Male mice were selected in this experiment to avoid the influence of estrogen fluctuation. LPS, the major component of the cell walls of Gram-negative bacteria, is a reliable inducer of ALI.[21] LPS exposure results in lung edema by inducing the production of liquids in the lung.[22] The current study found that pretreatment of Rd dose dependently decreased lung wet-to-dry ratio. LPS can also promote the production of inflammatory cells in the lung.[23] MPO activity is evaluated to quantify neutrophil infiltration to lung.[24] We found that Rd dose dependently inhibited the activity of MPO, implying that Rd could inhibit neutrophil infiltration in lung tissue. In addition, lung histopathologic examination revealed that Rd dose dependently attenuates inflammatory cell infiltration and lung damage. These results indicate that pretreatment of Rd has substantial protective effects on LPS-induced ALI in mice.

Previous studies have reported that LPS can induce the production of inflammatory cytokines in lung tissue.[25],[26] The production of inflammatory cytokines induces inflammatory cell infiltration into the lungs and causes inflammation.[27] In the current study, Rd inhibited LPS-induced inflammatory cytokine production in a dose-dependent manner. TLR4 can specifically recognize LPS,[28],[29] and NF-κB is an important transcription factor which regulates inflammatory cytokine gene transcription.[30],[31] TLR4 is activated by LPS, which induces the activation of NF-κB. Our study found that pretreatment of Rd d inhibited LPS-induced TLR4 expression and NF-κB activation in a dose-dependent manner. These results suggest that it may be possible to improve ALI through the NF-kappa B signaling pathway.

LPS destroys the alveolar-capillary barrier that mediates pulmonary gas exchange. Activated neutrophils increase the permeability of the alveolar-capillary barrier and also promote the production of reactive oxygen species (ROS). Furthermore, LPS can directly promote the production of ROS in lung tissue, and ROS enhances the inflammatory response and results in lung injury.[32] Although it is important to have an appropriate amount of ROS for innate immune system functioning, elevated levels of ROS can lead to tissue injury, apoptosis, and necrosis.[33] Therefore, inhibition of oxidative stress may prevent LPS-induced ALI. The present results suggest that Rd treatment significantly attenuates the activities of CAT, GPX, SOD, and MDA content in a dose-dependent manner. These results suggest that it may be possible to reduce ALI through the antioxidative injury pathway. Whether Rd injection will be more effective? It is to be further studied.


  Conclusion Top


Our findings indicate that the protective effect of Rd on LPS-induced ALI involves its ability to attenuate lung histopathology, edema, collagen deposition, inflammatory, protein concentration in the BALF, MPO activity, and inflammatory cell infiltration by attenuating oxidative stress and inflammation. Rd may be a promising therapeutic agent for the prevention and/or treatment of LPS-induced ALI.

Compliance with ethical standards

All animal experiments and methods were performed in accordance with the Health Guide for the Care and Use of Laboratory Animals published by the National Institute of Health.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Butt Y, Kurdowska A, Allen TC. Acute lung injury: A clinical and molecular review. Arch Pathol Lab Med 2016;140:345-50.  Back to cited text no. 1
    
2.
Standiford TJ, Ward PA. Therapeutic targeting of acute lung injury and acute respiratory distress syndrome. Transl Res 2016;167:183-91.  Back to cited text no. 2
    
3.
Abraham E, Matthay MA, Dinarello CA, Vincent JL, Cohen J, Opal SM, et al. Consensus conference definitions for sepsis, septic shock, acute lung injury, and acute respiratory distress syndrome: Time for a reevaluation. Crit Care Med 2000;28:232-5.  Back to cited text no. 3
    
4.
Qiang L, Yuan J, Shouyin J, Yulin L, Libing J, Jian-An W. Sesamin attenuates lipopolysaccharide-induced acute cung injury by inhibition of TLR4 signaling pathways. Inflammation 2016;39:467-72.  Back to cited text no. 4
    
5.
Sun LC, Zhang HB, Gu CD, Guo SD, Li G, Lian R, et al. Protective effect of acacetin on sepsis-induced acute lung injury via its anti-inflammatory and antioxidative activity. Arch Pharm Res 2017;41:1199-210.  Back to cited text no. 5
    
6.
Enkhbaatar P, Traber D. Pathophysiology of acute lung injury in combined burn and smoke inhalation injury. Clin Sci 2004;107:137-43.  Back to cited text no. 6
    
7.
Mei SH, McCarter SD, Deng Y, Parker CH, Liles WC, Stewart DJ. Prevention of LPS-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1. PLoS Med 2007;4:e269.  Back to cited text no. 7
    
8.
Kneyber MC, Markhorst DG, Adrienne CR. Management of acute lung injury and acute respiratory distress syndrome in children: A different perspective. Crit. Care Med 2009;37:3191-2.  Back to cited text no. 8
    
9.
Mortelliti MP, Manning HL. Acute respiratory distress syndrome. Indian Pediatr 2010;47:861-8.  Back to cited text no. 9
    
10.
Raghavendran K, Pryhuber GS, Chess PR, Davidson BA, Knight PR, Notter RH. Pharmacotherapy of acute lung injury and acute respiratory distress syndrome. Curr Med Chem 2008;15:1911-24.  Back to cited text no. 10
    
11.
Kim HJ, Kim P, Shin CY. A comprehensive review of the therapeutic and pharmacological effects of ginseng and ginsenosides in central nervous system. J Ginseng Res 2013;37:8-29.  Back to cited text no. 11
    
12.
Zhang C, Du F, Shi M, Ye R, Cheng H, Han J, et al. Ginsenoside Rd protects neurons against glutamate-induced excitotoxicity by inhibitingca(2+) influx. Cell Mol Neurobiol 2012;32:121-8.  Back to cited text no. 12
    
13.
Zhang X, Shi M, Bjørås M, Wang W, Zhang G, Han J, et al. Ginsenoside Rd promotes glutamate clearance by up-regulating glial glutamate transporter GLT-1 via PI3K/AKT and ERK1/2 pathways. Front Pharmacol 2013;4:152.  Back to cited text no. 13
    
14.
Li N, Zhou L, Li W, Liu Y, Wang J, He P. Protective effects of ginsenosides Rg1 and Rb1 on an Alzheimer's disease mouse model: A metabolomics study. J Chromatogr B Anal Technol Biomed Life Sci 2015;985:54-61.  Back to cited text no. 14
    
15.
Liu JF, Yan XD, Qi LS, Li L, Hu GY, Li P, et al. Ginsenoside Rd attenuates Aβ25-35-induced oxidative stress and apoptosis in primary cultured hippocampal neurons. Chem Biol Interact 2015;239:12-8.  Back to cited text no. 15
    
16.
Wang B, Zhu Q, Man X, Guo L, Hao L. Ginsenoside Rd inhibits apoptosis following spinal cord ischemia/reperfusion injury. Neural Regen Res 2014;9:1678-87.  Back to cited text no. 16
[PUBMED]  [Full text]  
17.
Zhang Y, Zhang M, Wang CY, Shen A. Ketamine alleviates LPS induced lung injury by inhibiting HMGB1-RAGE level. Eur Rev Med Pharmacol Sci 2018;22:1830-6.  Back to cited text no. 17
    
18.
Tang F, Fan K, Wang K, Bian C. Atractylodin attenuates lipopolysaccharide induced acute lung injury by inhibiting NLRP3 inflammasome and TLR4 pathways. J Pharmacol Sci 2018;136:203-11.  Back to cited text no. 18
    
19.
Ali YM, Abd El-Aziz AM, Mabrook M, Shabaan AA, Sim RB, Hassan R. Recombinant chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS) protects against LPS-induced lung injury in mice. Clin Immunol 2018;18:S1521-6616.  Back to cited text no. 19
    
20.
Wu XL, Feng XX, Li CW, Zhang XJ, Chen ZW, Chen JN, et al. The protective effects of the supercritical-carbon dioxide fluid extract of Chrysanthemum indicum against lipopolysaccharide-induced acute lung injury in mice via modulating Toll-like receptor 4 signaling pathway. Mediators Inflamm 2014;2014:246407.  Back to cited text no. 20
    
21.
Liu S, Feng G, Wang GL, Liu GJ. p38MAPK inhibition attenuates LPS-induced acute lung injury involvement of NF-kappaB pathway. Eur J Pharmacol 2008;584:159-65.  Back to cited text no. 21
    
22.
Aggarwal S, Gross CM, Kumar S, Dimitropoulou C, Sharma S, Gorshkov BA, et al. Dimethylarginine dimethylaminohydrolase II overexpression attenuates LPS-mediated lung leak in acute lung injury. Am J Respir Cell Mol Biol 2014;50:614-25.  Back to cited text no. 22
    
23.
Li D, Ci X, Li Y, Liu C, Wen Z, Jie J, et al. Alleviation of severe inflammatory responses in LPS-exposed mice by schisantherin A. Respir Physiol Neurobiol 2014;202:24-31.  Back to cited text no. 23
    
24.
Xu M, Cao FL, Zhang YF, Shan L, Jiang XL, An XJ, et al. Tanshinone IIA therapeutically reduces LPS-induced acute lung injury by inhibiting inflammation and apoptosis in mice. Acta Pharmacol Sin 2015;36:179-87.  Back to cited text no. 24
    
25.
Ouyang W, Zhou H, Liu C, Wang S, Han Y, Xia J, et al. 25-Hydroxycholesterol protects against acute lung injury viatargeting MD-2. J Cell Mol Med 2018;22:5494-503.  Back to cited text no. 25
    
26.
Pinheiro AJ, Gonçalves JS, Dourado ÁW, de Sousa EM, Brito NM, Silva LK, et al. Punica granatum L. Leaf extract attenuates lung inflammation in mice with acute lung injury. J Immunol Res 2018;2018:6879183.  Back to cited text no. 26
    
27.
Strieter RM, Belperio JA, Keane MP. Cytokines in innate host defense in the lung. J Clin Invest 2002;109:699-705.  Back to cited text no. 27
    
28.
Murdock JL, Núñez G. TLR4: The winding road to the discovery of the LPS receptor. J Immunol 2016;197:2561-2.  Back to cited text no. 28
    
29.
Yin H, Tan Y, Wu X, Yan H, Liu F, Yao Y, et al. Association between TLR4 and PTEN involved in LPS-TLR4 signaling response. Biomed Res Int 2016;2016:6083178.  Back to cited text no. 29
    
30.
Hung LC, Lin CC, Hung SK, Wu BC, Jan MD, Liou SH, et al. A synthetic analog of alpha-galactosylceramide induces macrophage activation via the TLR4-signaling pathways. Biochem Pharmacol 2007;73:1957-70.  Back to cited text no. 30
    
31.
Youn HS, Lee JY, Saitoh S, Miyake K, Kang KW, Choi YJ, et al. Suppression of MyD88- and TRIF-dependent signaling pathways of toll-like receptor by (−)-epigallocatechin-3-gallate, a polyphenol component of green tea. Biochem Pharmacol 2006;72:850-9.  Back to cited text no. 31
    
32.
Geerts L, Jorens PG, Willems J, De Ley M, Slegers H. Natural inhibitors of neutrophil function in acute respiratory distress syndrome. Crit Care Med 2001;29:1920-4.  Back to cited text no. 32
    
33.
Grommes J, Soehnlein O. Contribution of neutrophils to acute lung injury. Mol Med 2011;17:293-307.  Back to cited text no. 33
    


    Figures

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


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  In this article
Abstract
Introduction
Materials and Me...
Results
Discussion
Conclusion
References
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