Ginsenoside Rh2 Ameliorates Lipopolysaccharide-Induced Acute Lung Injury by Regulating the TLR4/PI3K/Akt/mTOR, Raf-1/MEK/ERK, and Keap1/Nrf2/HO-1 Signaling Pathways in Mice

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Abstract

The anti-inflammatory effect of ginsenoside Rh2 (GRh2) has labeled it as one of the most important ginsenosides. The purpose of this study was to identify the anti-inflammatory and antioxidant effects of GRh2 using a lipopolysaccharide (LPS) challenge lung-injury animal model. GRh2 reduced LPS-induced proinflammatory mediator nitric oxide (NO), tumor necrosis factor-alpha, interleukin (IL)-1β, and anti-inflammatory cytokines (IL-4, IL-6, and IL-10) production in lung tissues. GRh2 treatment decreased the histological alterations in the lung tissues and bronchoalveolar lavage fluid (BALF) protein content; total cell number also reduced in LPS-induced lung injury in mice. Moreover, GRh2 blocked iNOS, COX-2, the phosphorylation of IκB-α, ERK, JNK, p38, Raf-1, and MEK protein expression, which corresponds with the growth of HO-1, Nrf-2, catalase, SOD, and GPx expression in LPS-induced lung injury. An in vivo experimental study suggested that GRh2 has anti-inflammatory effects, and has potential therapeutic efficacy in major anterior segment lung diseases.

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Baicalein, an active component of Scutellaria baicalensis, protects against lipopolysaccharide-induced acute lung injury in rats.

Chen-Liang Tsai, Yu-Chieh Lin, Hui-Min Wang … (2014)

Baicalein (BE), a phenolic flavonoid extracted mainly from the root of Scutellaria baicalensis Georgi, a Chinese herb, is traditionally used in oriental medicine. Several studies have demonstrated that BE exerts many beneficial effects including anti-inflammatory and antioxidant activities. However, its effect on acute lung injury (ALI) and the molecular mechanisms involved remain unclear and warrant further investigation. The aim of the study is to investigate whether BE improves lipopolysaccharide (LPS, intratracheally, i.t.)-induced ALI in rats, and further study the underlying mechanisms of its activity. Rats were administrated with LPS (5mg/kg/body weight, i.t.) through a 24-gauge catheter to establish the ALI model. The effects of BE on the levels of pro-inflammatory cytokines, nitrite/nitrate in bronchoalveolar lavage fluid, and the expression of nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and nuclear factor-kappa B (NF-κB) activation as well as the histopathological changes were evaluated. Results showed that BE (20mg/kg, i.p.) treatment markedly attenuated LPS-induced lung edema, elevation of the levels of IL-1β, TNF-α, IL-6, CINC-3, and nitrite/nitrate in bronchoalveolar lavage fluid accompanied by a remarkable improvement of lung histopathological symptoms. The LPS-enhanced inflammatory cell infiltration and myeloperoxidase activity, O2(-) formation and the expression of inducible nitric oxide synthase and nitrotyrosin in lungs were all attenuated by BE. Notably, BE could augment Nrf2/HO-1 cascade, but inhibited NF-κB activation in LPS-instilled lungs that was strongly reversed by blocking HO-1 activity. This study is the first to demonstrate that BE protects against LPS-induced ALI in rats. The underlying mechanisms may include inhibition of NF-κB-mediated inflammatory responses and upregulation of Nrf2/HO-1 pathway, which ultimately alleviates the pathological symptoms of ALI. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

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Protective effects of luteolin against lipopolysaccharide-induced acute lung injury involves inhibition of MEK/ERK and PI3K/Akt pathways in neutrophils

Jen-pei Lee, Yi-Ching Li, Hung-Yi Chen … (2010)

Aim: To investigate whether luteolin, the major polyphenolic components of Lonicera japonica, has beneficial effects against lipopolysaccharide (LPS)-induced acute lung injury (ALI) and to determine whether the protective mechanism involves anti-inflammatory effects on neutrophils. Methods: ALI was induced with intratracheal instillation of LPS in mice. The level of ALI was determined by measuring the cell count and protein content in bronchoalveolar lavage (BAL) fluid. Neutrophils were stimulated with formyl-Met-Leu-Phe (fMLP) or LPS in vitro. Chemotaxis and superoxide anion generation were measured to evaluate neutrophil activation. The potential involvement of intracellular signaling molecules in regulating neutrophil activation was analyzed by using Western blot. Results: LPS induced ALI in mice, as evidenced with leukocyte infiltration and protein leakage into the lungs. Luteolin attenuated LPS-induced leukocyte infiltration and protein extravasation. In cell studies, luteolin attenuated the fMLP-induced neutrophil chemotaxis and respiratory burst (IC50 0.2±0.1 μmol/L and 2.2±0.8 μmol/L, respectively), but had a negligible effect on superoxide anion generation during phorbol myristate acetate stimulation. Furthermore luteolin effectively blocked MAPK/ERK kinase 1/2 (MEK), extracellular signal-regulated kinase (ERK), and Akt phosphorylation in fMLP- and LPS-stimulated neutrophils. Conclusion: These results indicate that luteolin has beneficial effects against LPS-induced ALI in mice, and the attenuation of neutrophil chemotaxis and respiratory burst by luteolin involves the blockade of MEK-, ERK-, and Akt-related signaling cascades.

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Emodin Ameliorates LPS-Induced Acute Lung Injury, Involving the Inactivation of NF-κB in Mice

Min Xiao, Zhi Tao Zhu, Wei Zhang … (2014)

Acute lung injury (ALI) and its severe manifestation of acute respiratory distress syndrome (ARDS) are well-known illnesses. Uncontrolled and self-amplified pulmonary inflammation lies at the center of the pathology of this disease. Emodin, the bio-active coxund of herb Radix rhizoma Rhei, shows potent anti-inflammatory properties through inactivation of nuclear factor-κB (NF-κB). The aim of this study was to evaluate the effect of emodin on lipopolysaccharide (LPS)-induced ALI in mice, and its potential bio-mechanism. In our study, BALB/c mice were stimulated with LPS to induce ALI. After 72 h of LPS stimulation, pulmonary pathological changes, lung injury scores, pulmonary edema, myeloperoxidase (MPO) activity, total cells, neutrophils, macrophages, TNF-α, IL-6 and IL-1β in bronchoalveolar lavage fluid (BALF), and MCP-1 and E-selectin expression were notably attenuated by emodin in mice. Meanwhile, our data also revealed that emodin significantly inhibited the LPS-enhanced the phosphorylation of NF-κB p65 and NF-κB p65 DNA binding activity in lung. Our data indicates that emodin potently inhibits LPS-induced pulmonary inflammation, pulmonary edema and MCP-1 and E-selectin expression, and that these effects were very likely mediated by inactivation of NF-κB in mice. These results suggest a therapeutic potential of emodin as an anti-inflammatory agent for ALI/ARDS treatment.

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Author and article information

Journal

Journal ID (nlm-ta): Nutrients

Journal ID (iso-abbrev): Nutrients

Journal ID (publisher-id): nutrients

Title: Nutrients

Publisher: MDPI

ISSN (Electronic): 2072-6643

Publication date (Electronic): 01 September 2018

Publication date Collection: September 2018

Volume: 10

Issue: 9

Electronic Location Identifier: 1208

Affiliations

[1 ]Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung 413, Taiwan; hyh3033@ 123456gmail.com (Y.-H.H.); yschang@ 123456mail.cmu.edu.tw (Y.-S.C.)

[2 ]Department of Pharmacy, Kuang Tien General Hospital, Taichung 433, Taiwan

[3 ]Taichung City New Pharmacist Association, Taichung 420, Taiwan

[4 ]Department of Food Nutrition and Health Biotechnology, Asia University, Taichung 413, Taiwan; dengjs@ 123456asia.edu.tw

Author notes

[* ]Correspondence: gjhuang@ 123456mail.cmu.edu.tw ; Tel.: +886-4-2205-3366 (ext. 5508)

Article

Publisher ID: nutrients-10-01208

DOI: 10.3390/nu10091208

PMC ID: 6163254

PubMed ID: 30200495

SO-VID: 4a40fdf3-4c5a-470f-bd1b-73c920e786c8

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Ginsenoside Rh2 Ameliorates Lipopolysaccharide-Induced Acute Lung Injury by Regulating the TLR4/PI3K/Akt/mTOR, Raf-1/MEK/ERK, and Keap1/Nrf2/HO-1 Signaling Pathways in Mice

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Inflamed lung in vitro co-culture models

Most cited references 37

Baicalein, an active component of Scutellaria baicalensis, protects against lipopolysaccharide-induced acute lung injury in rats.

Protective effects of luteolin against lipopolysaccharide-induced acute lung injury involves inhibition of MEK/ERK and PI3K/Akt pathways in neutrophils

Emodin Ameliorates LPS-Induced Acute Lung Injury, Involving the Inactivation of NF-κB in Mice

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