Modified Haoqin Qingdan Decoction Exerts Antioxidant Effect via Activating PI3K/Akt/Nrf2 Pathway on Allergic Asthma Mice

Abstract

Objective

The aim of this study was to investigate the antioxidant effect and potential mechanism of Modified Haoqin Qingdan Decoction on ovalbumin (OVA)-induced allergic asthma (AA) mice.

Methods

The AA model of mice was induced by OVA combined with aluminum hydroxide. Resistance Index (RI) in airway was analyzed by AniRes2005 animal pulmonary function analyzer. H&E staining was used to evaluate the pathological changes of lung tissue. The apoptosis in lung tissue was detected by TUNEL staining. The percentage of EOS cells in bronchoalveolar lavage fluid was determined by flow cytometry. The levels of IL-1β, IL-6, IL-4, GM-CSF, TNF-α, and IFN-γ in serum were determined by ELISA. Biochemical kits were used to detect levels of SOD, MDA, and GSH-Px in lung tissue. The protein expression of PI3K, p-PI3K, Akt, p-Akt, and nucleoprotein Nrf-2 in lung tissue was detected by western blotting.

Result

Modified Haoqin Qingdan Decoction reduced RI, alleviated the degree of histopathological damage, inhibited apoptosis rate, reduced the proportion of EOS cells, downregulated IL-1β, IL-6, IL-4, GM-CSF, TNF-α, IFN-γ, and MDA, upregulated SOD, GSH-Px, p-PI3K, p-Akt, and nucleoprotein Nrf-2.

Conclusion

Modified Haoqin Qingdan Decoction activated nucleoprotein Nrf2 by regulating the PI3K/Akt signaling pathway to exert its protective effect against inflammatory and oxidative stress in AA mice.

Keywords

allergic asthma modified Haoqin Qingdan Decoction PI3K/Akt/Nrf2 oxidative stress inflammation

Introduction

Allergic asthma (AA) is a complex chronic inflammatory disease of the airways.¹ It is mainly characterized by eosinophilic inflammation, mucus hypersecretion, and airway hyperresponsiveness, manifested by chronic airway inflammation, decreased airway function, and airway tissue remodeling. Children are susceptible to AA due to the imperfection of the body's immune system and poor resistance. Currently, glucocorticoids, β2 agonists and leukotriene modulators are mostly used in the treatment of AA to provide rapid relief of asthma exacerbations, reduce bronchoconstriction, and decrease airway inflammation.^2,3 However, there are still some patients with unsatisfactory treatment results and long-term use of such drugs can produce significant toxic side effects. Traditional Chinese medicine has been studied extensively in the treatment of allergic diseases such as asthma, and has definite clinical efficacy, especially in reducing the side effects of western drugs, and long-term use does not reduce immunity.⁴

Haoqin Qingdan decoction, originated from the Qing Dynasty's “Common Febrile Disease,” is a herbal formulation that has the effect of clearing gallbladder, inducing dampness, harmonizing the stomach and resolving phlegm.^5,6 It has a remarkable effect in the clinical treatment of bronchial asthma. This prescription can effectively relieve fever and cough symptoms in patients with pneumonia, and its mechanism may be to enhance immune function, reduce the secretion of pro-inflammatory cytokines, and then achieve antiviral effect. The high dose Haoqinqingdan decoction can improve the ratio of T lymphocyte subgroup and Th1/Th2 cell balance more effectively.⁷ On the basis of the classic Haoqin Qingdan Decoction, several anti-accumulation drugs were added, namely Modified Haoqin Qingdan Decoction. It is made from 11 medicinal materials including Herba Artemisiae annuae, Scutellaria baicalensis Georgi, Fructus Aurantii Immaturus, Caulis Bambusae in Taeniam, Pericarpium Citri Reticulatae, Rhizoma Pinelliae, Poria, Biyu powder [consisting of Indigo Naturalis, Talcum and Radix Glycyrrhizae], Massa Medicata Fermentata, Crataegi Fructus and Fructus Hordei Germinatus. However, the mechanism of its treatment of AA is not clear.

The PI3K/Akt/Nrf2 pathway plays an important regulatory role in the oxidative stress and inflammatory response of the body.⁸ Blocking PI3K/Akt signaling pathway may attenuate ovalbumin (OVA)-induced early airway remodeling by regulating the abnormal process of epithelial-mesenchymal transition.⁹ Nrf2 is one of the most important transcription factors in the cellular response to oxidative stress.¹⁰ Several studies have confirmed that Nrf2 is one of the target proteins of AKT, and either AKT or its upstream PI3K inhibitors can inhibit Nrf2 activity. The aim of this experiment was to investigate the effect of PI3K/Akt activation of Nrf2 on oxidative stress and airway inflammation in AA.

The treatment of asthma must be based on a full understanding of the pathogenesis and blocking the key pathways of its development. Based on the above understanding, the present study used OVA-induced AA mice model to investigate the antioxidant effect of Modified Haoqin Qingdan Decoction and its related molecular mechanism, which provides the experimental basis for the clinical application of Chinese medicine to prevent and treat asthma.

Materials and Methods

Reagent

Modified Haoqin Qingdan Decoction consists of Qing Hao 4.5g, Huang Qin 9g, Zhi Ke 4.5g, Zhu Ru 4.5g, Chen Pi 4.5g, Ban Xia 4.5g, Fu Ling 9g, Bi Yusan [consisting of Qing Dai, Hua Shi and Gan Cao] 9g, Shen Qu 4.5g, Shan Zha 4.5g, Mai Ya 4.5g with the Latin names Herba Artemisiae annuae, Scutellaria baicalensis Georgi, Fructus Aurantii Immaturus, Caulis Bambusae in Taeniam, Pericarpium Citri Reticulatae, Rhizoma Pinelliae, Poria, Biyu powder [consisting of Indigo Naturalis, Talcum and Radix Glycyrrhizae], Massa Medicata Fermentata, Crataegi Fructus and Fructus Hordei Germinatus, respectively. The drug was prepared according to the pharmacological experimental methodology of Chinese medicine^11,12: firstly, the drug was soaked for 30 min, the first decoction was boiled with 10 times the amount of water, boiled and filtered after 40 min of low heat. The second decoction was filtered by adding 8 times the amount of water, boiled and filtered after 40 min of low heat; the 2 filtrates were combined and then the filtrate was concentrated to 1g/1mL of the raw drug solution. The clinical dose of 63 g raw herbs/60 kg body weight is 1.05 g/kg. Based on the conversion factor (×6.3), the medium dose of Modified Haoqin Qingdan Decoction is 6.62 g/kg.

Animals

Thirty-six female BALB/c mice of SPF grade, body weight 18 to 22 g, were purchased from Chengdu Dashuo Biological Co. The mice were housed in a clean animal laboratory at 18 °C to 22 °C with air circulation, free diet, and drinking water. The animal experiments were performed in strict accordance with the standards of the Animal Ethics Committee of Chengdu University of Traditional Chinese Medicine.

AA Model

After 1 week of adaptive feeding, the mice were randomly divided into 6 groups: control, AA model group (OVA), budesonide group (BUDE), Modified Haoqin Qingdan Decoction low dose group (M-HQQD-L), Modified Haoqin Qingdan Decoction medium dose group (M-HQQD-M), and Modified Haoqin Qingdan Decoction high dose group (M-HQQD-H). Each group had 6 mice. The AA model was established in the sensitization and excitation periods. Mice were injected intraperitoneally with 200 μL sensitizing solution (100 μg OVA + 200 μg aluminum hydroxide dry powder + 200 μL PBS) on the 1st day and the 14th day, respectively. On the 21st to 27th day, 5 mL 1% OVA solution was nebulized continuously for 30 min each time, once a day for 7 d. The drug was administered by gavage 30 min before each nebulization. The M-HQQD-L, M-HQQD-M, and M-HQQD-H groups were given Modified Haoqin Qingdan Decoction 3.31, 6.62, and 13.24 g/kg by gavage; BUDE group was atomized with 5 mL budesonide suspension for 30 min. The control group and model (OVA) group were given saline 10 ml/kg by gavage. After the last intervention, mice were fasted for 24 h, and bronchoalveolar lavage fluid (BALF) was collected.

Lung Function

Resistance Index (RI) in airway was analyzed using the AniRes 2005 animal lung function analyzer. Mice were anesthetized by 10% sodium pentobarbital, immobilized, and the skin of the neck was cut and the trachea exposed. Mice were extubated and connected to a ventilator. The respirator frequency was set at 120 r/min, the baseline was adjusted with PBS for the first time, and the basal value of airway resistance was recorded for 1 min; subsequently, the atomization of acetylcholine (ACh) was applied with the mass concentrations of 0, 0.25, 0.5, and 1 μg/kg, respectively. Each time was performed for 1 min and recorded RI (cm H₂O·s·mL) on 3 min.

H&E Staining

Lung tissues were routinely dehydrated, embedded in paraffin, sectioned at 5 μm, and stained with HE. Finally, the sections were placed under a microscope to observe the histopathological changes of lung tissue.

TUNEL Staining

Lung tissue sections were dewaxed, dehydrated and incubated with TUNEL solution at room temperature for 1 h. The sections were then sealed with anti-fluorescent bursting agent and the apoptotic cells were observed under confocal microscope. The apoptosis rate was quantified by using Image-pro plus software system.

Flow Cytometry

The percentage of eosinophil (EOS) cells in BALF was determined by flow cytometry.

BALF (0.7 mL) was collected, centrifuged at 3000 r/min for 10 min, discard the supernatant, add 100 μL mixed antibody (0.5 μL CCR3 antibody, 0.5 μL CD170 antibody, and 0.5 μL CD11c antibody) and incubate at 4 °C for 30 min. Added 1 mL PBS-2% FBS to terminate the reaction, centrifuged, discard the supernatant and added 500 μL PBS-2% FBS to resuspend the cells. The EOS percentage was determined on a flow cytometer.

ELISA Analysis

Added each sample with different concentrations of standards to the reaction wells and incubated for 1 h at room temperature, and added the enzyme labeled antibody and incubated for 0.5 h. The chromogenic solution was incubated for 25 min and the color development was terminated after avoiding light. The absorbance value (OD) was measured at 450 nm by enzyme marker. The levels of IL-1β, IL-6, IL-4, GM-CSF, TNF-α, and IFN-γ in serum were calculated according to the standard curves drawn from the OD values of different concentrations of the standards.

Biochemical index

The lung tissue was homogenized by adding precooled lysis solution at 4 °C, and then rested on ice for 30 min, centrifuged at 3000 r/min for 20 min, and the supernatant was aspirated. Biochemical methods were used to detect the levels of SOD, MDA, and GSH-Px in lung tissue, and the operation steps were performed strictly according to the kit instructions.

Western Blotting

The total protein was extracted from lung tissues by adding pre-cooled lysate at 4 °C and homogenized on ice for 30 min. 12,000 rpm centrifugation was performed for 20 min, and the supernatant was extracted. Bicinchonininc acid assay was used to detect the total protein concentration. After protein denaturation, SDS-PAGE gel electrophoresis, PVDF transfer, 5% skimmed milk powder closure for 1 h, TBST wash, then add diluted PI3K, Akt, p-PI3K, p-Akt and nucleoprotein Nrf-2 primary antibody and incubate at 4 °C overnight. The next day, HRP-labeled secondary antibody was added and incubated at room temperature for 1 h. ECL luminescence kit was used to detect the protein, and the gel system was imaged, and the results were analyzed in grayscale using Image J software.

Statistical Analysis

The experimental data were expressed as mean ± standard deviation (SD), and SPSS 20.0 software was used for statistical analysis of all data. One-way ANOVA was used for comparison between multiple groups, and when *P < .05, **P < .01, ***P < .001, indicated a significant difference.

Results

Effect of Modified Haoqin Qingdan Decoction on the Pathological Changes of Lung Tissues in AA Mice

H&E staining (Figure 1A) was used to evaluate the pathological changes of lung tissues in mice. No obvious pathological changes were seen in the lung tissues of control group. In OVA group, there were inflammatory infiltrations around the lung tissue, bronchi, and blood vessels. Modified Haoqin Qingdan Decoction and budesonide significantly reduced the degree of inflammation. Inflammatory infiltration caused apoptosis of lung tissue cells leading to their structural and functional damage. TUNEL staining (Figure 1B) was used to detect the effect of Modified Haoqin Qingdan Decoction on apoptosis rate in the lung tissue of mice with AA. The results showed that apoptosis rate was significantly increased in OVA group compared with control group, and was decreased by Modified Haoqin Qingdan Decoction and budesonide. It showed that Modified Haoqin Qingdan Decoction had a protective effect on the lung tissues of AA mice.

Figure 1.

Effect of modified Haoqin Qingdan decoction on the pathological changes of lung tissues in AA mice. (A) H&E staining for histopathological changes of lung tissue. (B) TUNEL staining for apoptosis rate.

Figure 2.

Effect of Modified Haoqin Qingdan Decoction on the percentage of EOS in BALF of AA mice.

Effect of Modified Haoqin Qingdan Decoction on the Percentage of EOS in BALF of AA Mice

EOS is labeled with CCR3 antibody, CD170 antibody, and CD11c antibody. The study showed that CCR3 + CD170+ % and CD11c− % were significantly increased in OVA group compared with control group. The CCR3 + CD170+ % and CD11c− % were significantly decreased after Modified Haoqin Qingdan Decoction and budesonide treatment (Figure 2).

Figure 3.

Effect of modified Haoqin Qingdan decoction on the lung function of AA mice.

Effect of Modified Haoqin Qingdan Decoction on the Lung Function of AA Mice

The changes in airway responsiveness of each group of mice were detected by AniRes 2005 animal lung function analyzer. The results (Figure 3) showed that the RI in OVA group increased significantly with the increase of ACh concentration. Compared with control group, the RI in OVA group was significantly upregulated when the concentration of ACh was 1.0 µg/kg. The RI in M-HQQD-H and BUDE groups all decreased to some extent.

Effects of Modified Haoqin Qingdan Decoction on Inflammation-Related Indexes in AA Mice

Compared with control group, the levels of IL-1β, IL-6, IL-4, GM-CSF, TNF-α, and IFN-γ were significantly increased in OVA group. These changes in inflammatory factors were reversed by Modified Haoqin Qingdan Decoction and budesonide treatment (Figure 4).

Figure 4.

Effects of modified Haoqin Qingdan Decoction on inflammation-related indexes in AA mice.

Effects of Modified Haoqin Qingdan Decoction on Oxidative Stress-Related Factors in Lung Tissue of AA Mice

The results showed that the levels of SOD and GSH-Px were significantly decreased, and MDA level was significantly increased in OVA group compared with control group. Modified Haoqin Qingdan Decoction and budesonide upregulated SOD and GSH-Px, and downregulated MDA level (Figure 5). This indicated that Modified Haoqin Qingdan Decoction was able to inhibit the oxidative stress response and reduced the oxidative stress damage in the lung tissue of AA mice.

Figure 5.

Effects of Modified Haoqin Qingdan Decoction on oxidative stress-related factors in lung tissue of AA mice.

Effect of Modified Haoqin Qingdan Decoction on PI3K/Akt/Nrf-2 Pathway in Lung Tissue of AA Mice

There were no significant changes in PI3K and Akt protein expression in each group. The results showed that the protein expression of p-PI3K and p-Akt was significantly decreased and the nuclear protein Nrf-2 was significantly increased in OVA group compared with control group. The expression of p-PI3K, p-Akt, and nuclear protein Nrf-2 increased significantly after treatment with Modified Haoqin Qingdan Decoction and budesonide (Figure 6).

Figure 6.

Effect of Modified Haoqin Qingdan Decoction on PI3K/Akt/Nrf-2 pathway in lung tissue of AA mice.

Discussion

The main features of asthma are variable bronchoconstriction and airway hyperresponsiveness, which leads to a constrictive response of the airways due to various stimuli.^13,14 The airway inflammation associated with asthma is thought to involve multiple cells and cytokines mediating cell recruitment. The present study confirmed that OVA-induced AA showed pathological changes including inflammatory cell infiltration, exhibiting typical AA pathology. EOS are the predominant cells accumulating in asthma and allergic inflammation and correlate with the severity of asthma disease.¹⁵ In this study, Modified Haoqin Qingdan Decoction significantly reduced the percentage of EOS in BALF, suggesting that Modified Haoqin Qingdan Decoction has an inhibitory effect on EOS production in AA thereby relieving asthma.

Inflammation and related pathological changes in lung tissue can affect the physiological function of the lungs, causing increased airway resistance and altered respiratory function. Children with AA have bronchospasm at the onset of the disease, which can lead to airflow restriction, permanent changes in airway diameter and abnormal lung function over time. Pulmonary function tests are useful in confirming the diagnosis of bronchial asthma and in assessing the degree of asthma control. In this study, Modified Haoqin Qingdan Decoction significantly reduced the RI and improved the lung function in AA mice.

Airway inflammation is the pathologic basis of AA.¹⁶ It is now widely accepted that an imbalance in Th1/Th2 and Th17/Treg immune response, which induces recruitment and activation of inflammatory cells in lung tissue, is an important factor contributing to the development of airway inflammation in asthma.^17–19 It has been shown that lipopolysaccharide exposure alleviates asthma in mice by regulating Th1/Th2 and Treg/Th17 balance.²⁰ Ephedrae Herba polysaccharides inhibit the inflammation of OVA induced asthma by regulating Th1/Th2 and Th17/Treg cell immune imbalance.²¹ Platycodin D attenuates airway inflammation via suppression Th2 transcription factor in a murine model of acute asthma.²² In this study, we found that Modified Haoqin Qingdan Decoction significantly reduced the serum levels of IL-1β, IL-6, IL-4, GM-CSF, TNF-α, and IFN-γ in AA mice. This suggested that Modified Haoqin Qingdan Decoction can inhibit the type 2 inflammatory response in AA.

Oxidative stress plays an important role in the pathological process of asthma.^23,24 Kleniewska et al.²⁵ found that the products of oxidative stress in the body, such as the accumulation of reactive oxygen species, can produce tissue damage, and proved that oxidative stress overreaction is a key link in the pathogenesis of asthma. Hydrogen gas inhalation improves lung function and protects established airway inflammation in the allergic asthmatic mice model which may be associated with the inhibition of oxidative stress process.²⁶ Betaine improved airway inflammation of lung tissue which may be associated with the antioxidant properties of betaine.²⁷ SOD is an only antioxidant that scavenges superoxide, while GSH-Px is one of the main components of the non-enzymatic antioxidant system. SOD and GSH-Px provide cell protection against damage from oxygen free radicals.²⁸ In the present study, Modified Haoqin Qingdan Decoction increased MDA levels and decreased SOD activity and GSH-Px level in lung tissue of AA mice, indicating that, Modified Haoqin Qingdan Decoction attenuated the oxidative stress response in AA mice.

The PI3K/Akt/Nrf2 pathway is an important intracellular signaling pathway that plays an important regulatory role in the cellular oxidative stress and inflammatory response. The Akt is a downstream signaling molecule and target kinase of PI3K and is activated by inducing its phosphorylation by PI3K. The p-Akt induces the dissociation of Nrf2 from Keap1 (Kelch-like ECH-associated protein) and promotes ARE (antioxidant response element) to induce antioxidant enzymes, thereby inhibiting oxidative stress and mitochondrial damage.^29,30 Azithromycin influences airway remodeling in asthma via the PI3K/Akt/MTOR/HIF-1α/VEGF pathway.³¹ Alpinetin prevents inflammatory responses in OVA-induced AA through modulating PI3K/AKT/NF-κB and HO-1 signaling pathways in mice.³² In the present study, Modified Haoqin Qingdan Decoction treatment significantly upregulated the expression of p-PI3K, p-Akt, and nuclear protein Nrf2 in lung tissue of AA mice. This suggested that the therapeutic effect of Modified Haoqin Qingdan Decoction on AA mice may be related to the activation of PI3K/Akt/Nrf2 pathway. However, the regulatory mechanism of Nrf2 target molecules is complex, and pathway inhibitors were not set up for experiments in this study, which needs to be followed up with in-depth studies. In addition, this study did not explore whether PI3K/Akt signaling pathway inhibitor could inhibit the level of Nrf2 nuclear translocation induced by Modified Haoqin Qingdan Decoction, which needs further investigation.

Conclusion

In conclusion, Modified Haoqin Qingdan Decoction had some therapeutic effects on AA mice, and its mechanism may be related to the activation of PI3K/Akt/Nrf2 pathway and thus the inhibition of inflammatory response and oxidative stress.

Supplemental Material

sj-doc-1-npx-10.1177_1934578X241242933 - Supplemental material for Modified Haoqin Qingdan Decoction Exerts Antioxidant Effect via Activating PI3K/Akt/Nrf2 Pathway on Allergic Asthma Mice

Supplemental material, sj-doc-1-npx-10.1177_1934578X241242933 for Modified Haoqin Qingdan Decoction Exerts Antioxidant Effect via Activating PI3K/Akt/Nrf2 Pathway on Allergic Asthma Mice by Xiaojun Dong, Qi Zhang, Juan Gu, Mingxing Cai, Yuan Gan and Yanni Ye, Xun Yang, Dou Ding, Xiuwen Xia in Natural Product Communications

Footnotes

Acknowledgments

The technical assistance and equipment support of Chengdu Lilai Biotechnology Co., LTD, Sichuan, China, are appreciated for this study.

Author Contributions

Xiaojun Dong, Qi Zhang, and Juan Gu conceived and designed the experiments. Mingxing Cai and Yuan Gan performed the experiments. Yanni Ye and Xun Yang analyzed the data. Dou Ding contributed to the reagents and materials. Xiaojun Dong wrote the manuscript.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical Approval

This study was approved by the Administration Committee of Experimental Animals, Guizhou Province, China.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Zunyi Science and Technology Bureau (No. [2022]143) and Guizhou Provincial Science and Technology Department Project (No. ZK[2023]587).

ORCID iD

Dou Ding

Statement of Human and Animal Rights

All procedures in this study were conducted in accordance with the “Ethics Committee of Zunyi Medical And Pharmaceutical College (ID: ZMPC-2301-001)” approved protocols.

Statement of Informed Consent

There are no human subjects in this article and informed consent is not applicable.

Supplemental Material

Supplemental material for this article is available .

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Supplementary Material

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