Anti-Inflammatory Effects of Chinese Herbal Medicine on COPD: A Systematic Review

Background: Airway inflammation and inflammatory mediators play an imperative role in the pathogenesis of COPD. Currently, understanding of the anti-inflammatory effect of Chinese herbal medicine (CHM) on COPD is limited, and CHM’s mechanism of actions is unclear. This systematic review (SR) evaluates anti-inflammatory effects of CHM on the concentration of various inflammatory mediators, such as Tumor Necrosis Factor-alpha (TNF-α) and interleukin-8 (IL-8), in the sputum and serum of COPD patients. Methods: The studies chosen for this SR were obtained from Chinese and English databases. The study selection criteria were based on randomized, controlled trials of stable COPD patients on adjunct oral CHM; and the changes in concentration of inflammatory mediators post-treatment were analyzed via meta-analysis. Results: 2,268 patients in 29 studies were evaluated. 2 studies were assessed to be of low-risk in all domains. The results showed significant reduction in the serum level of IL-8 (mean: -1.27 and 95% confidence interval (CI) [-1.86, -0.68]) and TNF-α (Mean: -0.72 and 95% CI [-1.01, -0.43]) in patients treated with CHM plus bronchodilators, compared to bronchodilators alone. Conclusion: This SR explains CHM’s mechanism of action, and demonstrates CHM’s anti-inflammatory effects on patients with stable COPD. *Corresponding author: An X, H and J CRO PTY. LTD, Australia, Tel: 0061401777369; E-mail: xuedongan@hotmail.com Received February 25, 2016; Accepted May 10, 2016; Published May 16, 2016 Citation: Miao Q, Cong X, Du Y, Wang B, Qiao CY, et al. (2016) Anti-Inflammatory Effects of Chinese Herbal Medicine on COPD: A Systematic Review. Lung Dis Treat 2: 107. doi:10.4172/2472-1018.1000107 Copyright: © 2016 Miao Q, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Introduction
Chronic obstructive pulmonary disease (COPD) is a complex disease with multiple pathogeneses [1]. Airway inflammation plays an imperative role in the pathogenesis of COPD. A wide range of inflammatory mediators are associated with COPD; interleukin-8 (IL-8), IL-6, Tumor Necrosis Factor-alpha (TNF-α), and matrix metalloproteinase (MMP-9) have been shown to induce neutrophil production, alveolar macrophages release, emphysema formation, and lung remodeling [2]. Compared to healthy subjects, patients with stable COPD had an increased expression of inflammatory mediators, particularly in sputum and serum [3,4]. In addition, these inflammatory mediators correlated with clinical outcomes of lung function, BODE index, frequency of COPD exacerbation, and severity and mortality of COPD [5][6][7].
The use of Chinese herbal medicine (CHM) as an adjunct therapy for COPD has been documented in more than one hundred clinical trials over the past decade. Previous systematic reviews (SR) have shown that oral CHM provided symptom relief, improved Quality of life (QoL) and lung function, and reduced frequency of COPD exacerbation [8,9]. However, understanding of CHM's anti-inflammatory effects is limited and CHM's mechanism of action (MOA) is not clear. This study aims to investigate the effects of CHM on inflammatory mediators in induced sputum and serum in patients with stable COPD, as well as its MOA.

Materials and Method
This SR was conducted by Standard for Systematic Review [10] and guided by Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA) [11].
Search strategy included identifying search databases and search terms. Relevant studies were selected from both English and Chinese databases. English databases included PubMed, CINAHL, and CENTRAL (Cochrane Central Register of Controlled Trials); Chinese databases included CNKI, CQVIP and Wan fang. Appropriate search terms (per guideline of Cochrane Airways Group) were used to identify appropriate studies. Potential studies were chosen from their respective inceptions until August 2014, without language restrictions.
Search terms were identified through PubMed using medical subject headings (MeSH) relevant to COPD and from the Cochrane Airways Group Specialized Register of COPD trials. These terms were separated into those relevant to COPD, such as 'Pulmonary disease,

Outcome measure
The outcomes were mainly focused on the level of IL-8 examined and TNF-α in serum and sputum, and also involved the level of transforming growth factor-β1 (TGF-β1), and IL-6 in serum.

Data extraction and collection
The relevance of title, abstract, and citations were assessed by two reviewers. Full articles were assessed by two reviewers. The Methodological Quality was assessed by two reviewers, audited by a third reviewer. The decision making process to include potential studies is outlined as a flow diagram based on the template provided by PRISMA [11]. Details of each study's treatment regimen were reported as RCTs using Consolidated Standards of Reporting Trials (CONSORT) [14].

Data synthesis and analysis
Datasets were analyzed with RewMan 5.3. The continuous data was expressed as Mean Difference (MD), standardized MD (Std. MD), and 95% Confidential Interval (CI). The model of Random Effects was applied for heterogeneity. All data sets were imported from RewMan and assessed by GRADEpro.

Results
3,886 potential studies were initially identified. 3,143 remained after duplicates were eliminated. Further screening resulted in the exclusion of 2,921 studies for various reasons: 323 were not RCTs (case reports, surveys, retrospective studies, etc.), 333 did not relate to COPD or had additional complications of respiratory failure, heart failure, pulmonary hypertension or cor-pulmonale, 94 had inappropriate treatment regimen, 965 did not include biomarkers in its outcomes, 212 were non-human trials, 807 were review articles, and 187 used non-CHM adjunct therapy. Of the 222 remaining studies, 81 did not administer oral CHM, 66 did not include desired outcomes, and 3 had patients with non-stable COPD (such as COPD exacerbation or unidentified COPD courses) as well as 3 others. 29 studies met all required criteria, and were retrieved and analyzed in this SR ( Figure 1).

Intervention
Medication regimens were based on GOLD guideline for management of patient with stable COPD [45]. Bronchodilators such as inhaled beta-2-agonists (salbutamol and salmeterol), anticholinergics (Tiotropium bromide), or theophylline tablets with salmeterol/ fluticasone propionate were used as mainstay treatments. Experimental groups consisted of CHM formulae or extraction of a single Chinese herb plus one drug of any category of bronchodilators. Control groups consisted of one drug of any category of bronchodilators alone or with placebo.

Studies with serum test
Chen et al. [37] BufeiHuoxue Decoction (dose contains): Banxia 10 g, Chuanxiong 15 g, Danggui 10 g, Dihuang 20 g, Dilong 10 g, Fuling 15 g, Gancao 6 g, Honghua 6 g, Huajuhong 15 g, Huangjing 20 g, Huangqi 30 g, Laifuzi 15 g, Taoren 10 g, Wuweiz 6 g, Xiyangshen 10 g, Yinyanghuo 10 g   were low risk. The Blinding Method in three studies [17,29,42] were low risk; one study [20] had high risk due to its inadequate description of its Blinding Method. The remaining twenty five studies did not clearly describe its methods. Outcome Assessments were low risk in every study. Incomplete Data was either high risk in three studies without using of intention to treat analysis [17,33,36] or unclear in three studies [21,24,26]. Two studies were unclear of their Selective Reporting method [24,26]. Other Bias was assessed as low risk in all studies based on baseline data comparison ( Figure 2).

Assessment of the quality of grading of recommendation
The quality of Grading of Recommendation for the serum concentration of IL-8, TNF-α, TGF-β1, IL-6, and the sputum concentration of IL-8 was assessed as moderate level. The sputum concentration of TNF-α was assessed as low level due to its small sample size (Table 3).

Outcomes
In twenty two studies with 1,755 participants, the serum level of IL-8, TNF-α, TGF-β1, and IL-6 were analyzed. Sputum levels of IL-8 and TNF-α were tested and reported in eight studies with 498 participants. Sputum level of IL-10 and MMP-9 was tested in one study [38]. The original data of IL-8, IL-6, TNF-α, and TGF-β1 were not included in four studies, and therefore not included in the meta-analysis [23,24,26,30].
Due to the usage of both Enzyme-Linked Immunosorbent Assay and Radioimmunoassay, the different units were converted and consolidated based on the Wang study before the meta-analysis [29].
In four studies with 552 participants, the serum level of TGF-β1 was found to be significant reduced [17,19,29,43]. Figure 3 shows six studies with 643 patients. The data was used from Wang [29]

Adverse events
Minor adverse events (AEs), such as abdominal distension, were found in five patients in one study [40]; two studies reported no AEs [16,24]; Wang [29] reported similar percentage ratio of subjects that experienced AEs. The remaining studies did not mention occurrence of AEs.

Discussion
This SR included 29 RCTs, and focused on the change in concentration levels of inflammatory mediators in both serum and sputum in patients with stable COPD. The experimental group received oral CHM (in the form of pill, tablet, granule, capsule, or decoction) plus bronchodilators (per GOLD guideline). The control group received bronchodilators, either alone or with placebo. Six studies were found in English databases and twenty three in Chinese databases. Twenty seven studies were conducted in China and two in Japan.
The methodological quality was of low risk-of-bias for all domains in two studies. The quality of evidence was assessed as low by GRADEpro for the meta-analysis of TNF-α in induced sputum, and moderate for other inflammatory mediators.
The study findings indicated that certain CHM formulae appear to reduce systemic inflammatory response in patients with stable COPD. A significant reduction in the concentration of IL-8, IL-6, and TNF-α, and TGF-β1 in serum, and IL-8 and TNF-α in induced sputum were found in the experimental groups compared to control groups. In addition, a statistically significant higher heterogeneity rate was also found through meta-analysis, which maybe correlated to the duration of intervention, severity of COPD, various differentiation syndromes, usage of various bronchodilators, and subject population in each trial. Further sub-analysis was not conducted in this SR due to limitation of high amount of studies.
Three RCTs reported a change in the concentration level of IL-8, IL-6, MMP-9, and TNF-α in induced sputum for stable COPD patients treated with salmeterol/fluticasone, roflumilast, and nutritional supplementation [46][47][48]; improvement to lung function and quality of life were also observed in the same studies. Therefore, the reduced level of inflammatory mediators in either induced sputum or serum may have caused a decrease in airway inflammation, which presumably explains the MOA.  TNF-α, IL-8 in serum, and lung function were assessed in twelve studies [22][23][24]26,27,29,32,[34][35][36][37]41]. The QoL was assessed by the St. George Respiratory Questionnaire in five studies [19,24,29,30,37]. TNF-α in sputum and lung function was assessed in three studies [25,31,40]. All results demonstrated that usage of adjunctive CHM had similar anti-inflammatory effect as salmeterol/fluticasone, roflumilast and nutritional supplementation, which further indicates CHM's potential MOA.
The theory of Chinese Medicine (CM) defines COPD as lung distension, and its differentiation of syndromes (differential diagnosis) include phlegm retention and deficiency of organs, which mainly correlates to deficiencies in lung, spleen, and kidney function. The goal of CM is to replenish the lung, invigorate the spleen, and tonify the kidney. In the 29 studies, the two most commonly used formulae were Bu Fei Tang (replenish lung) and Bu Zhong Yi Qi Tang (invigorate spleen). The most commonly used herbs consisted of Huang Qi (Astragalus membranaceus), Bai Zhu (Atractylodes macrocephala), Dang Shen (Codonopsis pilosula), and Wu Wei Zi (Schisandra chinensis).
Previous studies (on animal models) have shown that Bu Fei Tang affected the expression of MMP-9 on airway remodeling, and significantly reduced the level of TNF-α and IL-8 in a COPD rat model in Bronchial Alveolar Lavage Fluid with lung Qi deficiency [49,50]. Bu Zhong Yi Qi Tang has been shown to increase the rat T-lymphocytes division and the amount of IL-2 produced in mice with spleen deficiency [51].
Ginseng is consisted of ginsenosides and ginseng polysaccharides. Its pharmacological actions have been investigated worldwide. In mice, the extract was found to decrease airway inflammation [52].
Astragalus was found to modify responses of lipopolysaccharidestimulated macrophages and reduce the production of TNF-α, IL-6 and IL-10 [53]. Dang Shen extract (Codonopsis pilosula) was found to suppress the release of TNF-α, also indicating anti-inflammatory effects [54].
One of the components of Wu Wei Zi (Schisandra chinensis) is Schisandrin B, which down-regulated the production of proinflammatory mediators, such as TNF-α and IL-6. Bai Zhu (Atractylodes macrocephala) extracts were found to have anti-inflammatory effects on TNF-α and nitric oxide production from peritoneal macrophages in mice [55] and in a rat lung cell membrane chromatography model [56].
Based on clinical studies and experiments, the MOA of CHM on COPD includes: 1. Decrease in cytokine levels and suppression of airway inflammation; 2. Improvement of overall immune functions; 3. Maintenance of oxidant-antioxidant balance; and 4. Regulation of proteases and anti-proteases levels [57].
However, due to inconsistent methods used to measure inflammatory mediators, the small number of studies, the small sample size, and poor quality of methodology of certain studies, the effect of CHMs on inflammatory mediators could not be completely confirmed. Moreover, AEs related to liver and kidney function should be investigated in future clinical trials. Further, RCTs on CHM therapy should be reported through CONSORT 2010 [14,58].

Conclusion
This SR explains CHM's mechanism of action, demonstrates CHM's anti-inflammatory effects, and shows that CHM is well tolerated by patients with stable COPD. Furthermore, using CHM adjunctively has shown to be beneficial in treating and slowing the progression of COPD.

Author's Contribution
Dr. Xuedong An and Dr Qing Miao are the guarantor, and will take responsibility for the manuscript, including the data and analysis of data. They contributed to the concept and design of this systematic review. XC, CQ, and BW contributed to data research and extraction. Dr. Yifei Du, Xiaodong Cong and Carole Yujia Qiao had full access to all the data in the study and take responsibility for the integrity of the data, accuracy of data analysis, and interpretation of data. Xuedong An and Carole Yujia Qiao contributed to writing the first draft of this manuscript. Xiaodong Cong, Bing Wang, and Qing Miao contributed by reviewing the manuscript. Xuedong and Yifei Du contributed to the final revision of the manuscript.

Funding
This study was funded by Beijing Municipal Science and Technology Commission of China (NO.Z131107002213053). The sponsors were not involved in this manuscript.