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. 2024 Apr 30:15:1362404.
doi: 10.3389/fimmu.2024.1362404. eCollection 2024.

Green tea extract suppresses airway inflammation via oxidative stress-driven MAPKs/MMP-9 signaling in asthmatic mice and human airway epithelial cells

Jeong-Won Kim  1 , Jin-Hwa Kim  1 , Ji-Soo Jeong  1 , Chang-Yeop Kim  1 , Eun-Hye Chung  1 , Sung-Hwan Kim  2 , Eui-Ju Hong  1 , Hyo-Jung Kwon  1 , Je-Won Ko  1 , Tae-Won Kim  1
Affiliations

Green tea extract suppresses airway inflammation via oxidative stress-driven MAPKs/MMP-9 signaling in asthmatic mice and human airway epithelial cells

Jeong-Won Kim et al. Front Immunol. .

Abstract

Introduction: The anti-inflammatory effect of green tea extract (GTE) has been confirmed in asthmatic mice, however, the pharmacological mechanism is not fully elucidated.

Methods: To investigate the therapeutic efficacy of GTE in asthma and identify specific pathways, murine model of allergic asthma was established by ovalbumin (OVA) sensitization and the challenge for 4 weeks, with oral treatment using GTE and dexamethasone (DEX). Inflammatory cell counts, cytokines, OVA-specific IgE, airway hyperreactivity, and antioxidant markers in the lung were evaluated. Also, pulmonary histopathological analysis and western blotting were performed. In vitro, we established the model by stimulating the human airway epithelial cell line NCI-H292 using lipopolysaccharide, and treating with GTE and mitogen-activated protein kinases (MAPKs) inhibitors.

Results: The GTE100 and GTE400 groups showed a decrease in airway hyperresponsiveness and the number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) compared to the OVA group. GTE treatment also reduced interleukin (IL)-13, IL-5, and IL-4 levels in the BALF, and OVA-specific immunoglobulin E levels in the serum compared to those in the OVA group. GTE treatment decreased OVA-induced mucus secretion and airway inflammation. In addition, GTE suppressed the oxidative stress, and phosphorylation of MAPKs, which generally occurs after exposure to OVA. GTE administration also reduced matrix metalloproteinase-9 activity and protein levels.

Conclusion: GTE effectively inhibited asthmatic respiratory inflammation and mucus hyperproduction induced by OVA inhalation. These results suggest that GTE has the potential to be used for the treatment of asthma.

Keywords: asthma; green tea extract; inflammation; matrix metalloproteinase-9; mitogen-activated protein kinase signaling; oxidative stress.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Green tea extract (GTE) decreases airway hyperresponsiveness (A), inflammatory cells in bronchoalveolar lavage fluid (B), and ROS production (C). Values are shown as means ± SD (n = 8). Significant differences: ## p < 0.01 vs. NC; *, ** p < 0.05 and p < 0.01 vs. OVA, respectively. Scale bar = 100 µm.
Figure 2
Figure 2
Green tea extract (GTE) inhibits the inflammation (A) and mucus overproduction (B) in lungs after ovalbumin (OVA) administration. Values are shown as means ± SD (n = 8). Significant differences: ## p < 0.01 vs. NC; *, ** p < 0.05 and p < 0.01 vs. OVA, respectively. Scale bar = 100 µm.
Figure 3
Figure 3
Green tea extract (GTE) inhibits the increased levels of interleukin (IL)-4 (A), IL-5 (B), IL-13 (C) in the bronchoalveolar lavage fluid (BALF), and total immunoglobulin (Ig) E (D) and ovalbumin (OVA)-specific IgE (E) in serum. Values are shown as means ± SD (n = 8). Significant differences: ## p < 0.01 vs. NC; *, ** p < 0.05 and p < 0.01 vs. OVA, respectively.
Figure 4
Figure 4
Green tea extract (GTE) reduces matrix metalloproteinase (MMP)-9 levels in lung tissue as confirmed by immunohistochemistry (A) and western blotting (B). GTE alleviated MMP-9 activity as confirmed by zymography (C). Values are shown as means ± SD (n = 8). Significant differences: ## p < 0.01 vs. NC; *, ** p < 0.05 and p < 0.01 vs. OVA, respectively. Scale bar = 100 µm.
Figure 5
Figure 5
Green tea extract (GTE) suppresses ERK, JNK, and p38 phosphorylation (A). Densitometric values were calculated using ChemiDoc (B). Values are shown as means ± SD (n = 8). Significant differences: ## p < 0.01 vs. NC; *, ** p < 0.05 and p < 0.01 vs. OVA, respectively.
Figure 6
Figure 6
Green tea extract (GTE) reduces oxidative stress in lung tissue. (A) Malondialdehyde (MDA), (B) glutathione (GSH), (C) catalase (CAT), (D) glutathione reductase (GR), (E) superoxide dismutase (SOD) levels. Values are shown as means ± SD (n = 8). Significant differences: ## p < 0.01 vs. NC; *, ** p < 0.05 and p < 0.01 vs. OVA, respectively.
Figure 7
Figure 7
The concentration of (A) green tea extract (GTE) and (B) epigallocatechin gallate (EGCG) used in the experiment was determined based on the cytotoxicity results in NCI-H292 cells. GTE and EGCG reduced the increased levels of (C, F) interleukin (IL)-1β, (D, G) IL-6, (E, H) tumor necrosis factor (TNF)-α in the lipopolysaccharide (LPS)-stimulated cells. Cells were pretreated with 10, 20, and 40 µg/mL of GTE or 20 µg/mL of EGCG before LPS (0.5 µg/mL) treatment. Values are shown as means ± SD (n = 3). Significant differences: ## p < 0.01 vs. NC; *, ** p < 0.05 and p < 0.01 vs. LPS, respectively.
Figure 8
Figure 8
Green tea extract (GTE) inhibits dose-dependently increased ERK, JNK, and p38 phosphorylation and matrix metalloproteinase (MMP)-9 expression (A). GTE (40 µg/mL) and epigallocatechin gallate (EGCG, 20 μg/mL) suppress increased ERK, JNK, and p38 phosphorylation and matrix metalloproteinase (MMP)-9 expression (C). Densitometric values were calculated using ChemiDoc (B, D). Cells were pretreated with 10, 20, and 40 µg/mL of GTE before LPS (0.5 µg/mL) treatment. Values are shown as means ± SD (n = 3). Significant differences: ## p < 0.01 vs. NC; *, ** p < 0.05 and p < 0.01 vs. LPS, respectively.
Figure 9
Figure 9
Effects of green tea extract (GTE) on the mitogen-activated protein kinase (MAPK) pathway in terms of matrix metalloproteinase (MMP)-9 production in lipopolysaccharide (LPS)-stimulated NCI-H292 cells. Cells were pretreated with 40 µg/mL of GTE, and 10 µM of PD098059, SP600125, and SB203680 before LPS (0.5 µg/mL) treatment (A). Densitometric values were calculated using ChemiDoc (B). Values are shown as means ± SD (n = 3). Significant differences: ## p < 0.01 vs. NC; *, ** p < 0.05 and p < 0.01 vs. LPS, respectively.
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Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the research fund of Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2021R1I1A3050864). This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (2021R1A4A1033078).
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