Therapeutic potential of Panax ginseng and ginsenosides in the treatment of chronic obstructive pulmonary disease

https://doi.org/10.1016/j.ctim.2014.08.006Get rights and content

Highlights

  • The authors reviewed Panax ginseng and ginsenosides for their potential to treat COPD.

  • Experimental cell and animal studies were evaluated.

  • Panax ginseng and ginsenosides have anti-inflammatory and anti-oxidative effects.

  • Panax ginseng and ginsenosides may be suitable therapeutic targets for the treatment of COPD.

Summary

Background

Chronic obstructive pulmonary disease (COPD) is a major global health burden and will become the third largest cause of death in the world by 2030. It is currently believed that an exaggerated inflammatory response to inhaled irritants, in particular cigarette smoke, cause progressive airflow limitation. This inflammation, where macrophages, neutrophils and lymphocytes are prominent, leads to oxidative stress, emphysema, airways fibrosis and mucus hypersecretion. COPD responds poorly to current anti-inflammatory treatments including corticosteroids, which produce little or no benefit. Panax ginseng has a long history of use in Chinese medicine for respiratory conditions, including asthma and COPD.

Objectives

In this perspective we consider the therapeutic potential of Panax ginseng for the treatment of COPD.

Results

Panax ginseng and its compounds, ginsenosides, have reported effects through multiple mechanisms but primarily have anti-inflammatory and anti-oxidative effects. Ginsenosides are functional ligands of glucocorticoid receptors and appear to inhibit kinase phosphorylation including MAPK and ERK1/2, NF-κB transcription factor induction/translocation, and DNA binding. They also inhibit pro-inflammatory mediators, TNF-α, IL-6, IL-8, ROS, and proteases such as MMP-9. Panax ginseng protects against oxidative stress by increasing anti-oxidative enzymes and reducing the production of oxidants.

Conclusion

Given that Panax ginseng and ginsenosides appear to inhibit processes related to COPD pathogenesis, they represent an attractive therapeutic target for the treatment of COPD.

Introduction

Chronic obstructive pulmonary disease (COPD) is a significant public health burden and predicted to be the third leading cause of death by 2030.1 Most cases of COPD are triggered by chronic exposure to cigarette smoke, with symptoms often only appearing after decades of smoking.1 Other risk factors, such as chronic exposure to indoor and outdoor airborne pollutants (wood burning, biomass fuels) and pollutants from car and industrial fumes also contribute to the development of COPD.

People with COPD commonly experience symptoms such as dyspnea, coughing and reduced quality of life, and are susceptible to acute infections and exacerbations that may dramatically worsen symptoms and accelerate lung function decline.2 The underlying pathology is characterized by persistent and progressive airflow limitation associated with an increased chronic inflammatory response, mucus hypersecretion, and structural changes to the airways and lungs.2 These structural changes typically include increased smooth muscle mass in small airways, alveolar wall destruction with airspace enlargement (emphysema), and fibrosis caused by impaired wound healing in response to tissue damage.

Although COPD is a heterogeneous disease, for the purposes of clinical diagnosis and treatment it has been broadly classified into four levels according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD), which includes four stages of increasing airflow limitation, based on lung spirometry tests.2 People diagnosed at all levels of COPD have a forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) of less than 70%. The four levels of COPD are: GOLD 1 mild, FEV1  80%; GOLD 2 moderate, FEV1 between 50% and 80%, GOLD 3 severe, FEV1 between 30% and 50%; and GOLD 4 very severe, FEV1 < 30%. Exacerbation risk and death also increases between levels.

Unfortunately, recommended therapies for diagnosed COPD do not usually treat the underlying cause – chronic inflammation. Therefore, they have little effect on disease progression or mortality. Such treatments include those that mainly rely on dilating the airways and preventing hyperinflation, such as long-acting β2 adrenoceptor agonists (LABA) or long-acting muscarinic receptor antagonists (LAMA), either given alone or in combination. In the later stages of COPD, inhaled corticosteroids (ICS) are also given in combination with LABAs/LAMAs, especially if the person has frequent exacerbations. Although corticosteroids have well-established anti-inflammatory effects (as shown in asthma treatment) they are relatively ineffective in most people with COPD.3

Drugs that target inflammatory pathways and reverse corticosteroid resistance are needed.4 New drugs such as the anti-inflammatory phosphodiesterase (PDE)-4 inhibitor roflumilast, reduce exacerbations in people with severe COPD. However, the search continues for more efficacious and safe anti-inflammatory drugs to treat COPD.4

Although the development of new biologics and small molecules to target inflammatory processes may lead to new therapies, this perspective introduces a novel approach to identify traditional plant-derived medicines with anti-inflammatory properties that could be optimized to treat COPD. A promising candidate is the Chinese herbal medicine, Panax ginseng (PG), which has anti-inflammatory properties. This review will assess pre-clinical studies that have examined the effects of PG extracts and active constituents (ginsenosides) on the known biochemical pathways that control chronic inflammation in COPD.

Cigarette smoke contains thousands of noxious substances in the gas and particulate phase. These substances damage lung epithelial tissue by generating reactive free radicals, which leads to a highly inflammatory environment.5 The mucus-lined epithelial layer of the lung is part of the body's first-line defence system, being a physical barrier to try to stop airborne pathogens and noxious substances – including those in cigarette smoke – entering the lung. As such, this barrier is often sufficient to prevent infection and/or tissue damage. However, when this first-line barrier is breached, immune cells, like resident dendritic cells and macrophages, are activated via receptors which recognize pathogen-associated molecular pattern molecules (PAMPs) on or released by invading pathogens and danger-associated molecular pattern molecules (DAMPs) released from damage cells. These cells are found at higher densities associated with B/T lymphocytes in areas of secondary lymphoid tissue in the epithelial layer (mucosa-associated lymphoid tissue, MALT) and thus are strategically located to respond rapidly and effectively to invading pathogens and tissue damage. The immune response is typified by the release of an array of mediators, cytokines and chemokines, such as tumor necrosis factor alpha (TNF-α); interleukins 6 and 8 (IL-6 and IL-8, CXCL-8); monocyte chemotactic protein-1 (MCP-1, CCL-2), macrophage inflammatory protein 1 α and β (MIP 1α, CCL-3 and MIP 1β, CCL-4); reactive oxygen species (ROS); and proteases (MMP-9)6, 7 from these cells. The chemokines MCP-1, MIP 1α/β and IL-8 attract more immune cells to the site of tissue damage in order to further enhance the inflammatory response and killing of pathogens. At the cellular level cytokines and growth factors released from the inflammatory cells initiate a cascade of events, including phosphorylation of kinases and nuclear factor kappa-B (NF-κB) inducers. Interleukin-1 receptor-associated kinase 1 (IRAK-1) activates NF-κB kinase (IKK) inhibition. Inhibitory protein IκBα then phosphorylates and detaches from NF-κB, leading to NF-κB translocating to the nucleus and binding to DNA, where it transcribes TNF-α.8 IRAK-1 also phosphorylates p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases (ERK1/2), and up-regulates NF-κB's transcriptional activity.9, 10

In COPD, extracellular matrix accumulation, stimulated by growth factors and proteases such as neutrophil elastase (NE), cathepsin G, and proteinase-3, and matrix metalloproteinase (MMP)-8 and MMP-9, produced from neutrophils and cytotoxic T cells, destroy lung parenchyma and stimulate mucus production and tissue fibrosis.11, 12 Growth factors, particularly TGF-β, induce fibroblast proliferation, collagen production and macrophage infiltration, and contribute to fibrosis. Matrix metalloproteinase-9 (MMP-9) is a key protease activated in COPD. It is induced by TGF-β and activates other growth factors.

Oxidative stress also plays a significant role in COPD. Environmental and inflammatory oxidants from cigarette smoke lead to ROS generation, such as superoxides, and augment inflammatory mediator release.5 Physiologically, generation of ROS plays an important role in cell signaling. However, excessive generation under conditions of oxidative stress can, for example, amplify/prolong the inflammatory response (via NF-κB) preventing resolution and increasing tissue damage.10 A further consequence of NF-κB activation is the generation of reactive nitrogen species (RNS) such as nitric oxide (NO) and subsequently peroxynitrite (ONOO) via inducible nitric oxide synthase (iNOS), Endogenous anti-oxidants, such as glutathione, and enzymes, such as superoxide dismutase, catalase and glutathione peroxidase-1, normally protect lungs from oxidative damage. However, in COPD, oxidants and anti-oxidant regulation is imbalanced and free radicals are left unchecked, leading to uncontrolled inflammation.13, 14, 15

Despite our increased understanding of COPD's pathogenesis, there is still an unmet need for effective treatments. Panax ginseng (PG) C.A. Meyer (from the Araliaceae family) and ginsenosides may offer an alternative approach, with recent research showing they have effects that could be used to treat COPD.16 This paper reviews the literature reports that investigate the potential mechanisms of action of PG and ginsenosides. It focuses on actions that are relevant to COPD's inflammatory pathogenesis.

In Chinese medicine PG is commonly used to treat respiratory, gastrointestinal and cardiovascular diseases. Its main bioactive constituents, the ginsenosides are triterpene glycosides with a four-ring steroidal skeleton and attached sugar moieties. There are two main ginsenoside groups: protopanaxadiols (Rb1, Rb2, Rc and Rd) with sugar attached to the C-3 and/or C-20, and protopanaxatriols (Rg1, Rg2, Re and Rf) with sugar attached to C-6 and/or C-20 (Fig. 1). Other constituents include oleanane, with a different C-20 side chain.

Ginsenosides make up 2–4% of the PG root, with Rb1, Rb2, Rc, Rd, Re and Rg1 the most abundant.17 Several ginsenosides are hydrolysed by gut microflora after ingestion, where some of the sugar residues are cleaved off to form metabolites. For example, Rb1 is metabolized to compound K, which has fewer sugar residues. Some evidence suggests ginsenosides may be pro-drugs that require hydrolyses and bio-transformation in the intestines to form new compounds.18

Section snippets

Methods

We conducted a literature search using four English databases (PubMed, EMBASE, CINAHL and AMED) to find relevant experimental research. Studies were screened for relevance. In the first step two independent researchers (JLS and YMD) identified studies that used PG or ginsenosides or ginsenoside metabolites, and investigated inflammation and oxidative stress using cell lines and animal models. Studies were further reviewed by three researchers (ALZ, RH, and JMY) to identify their relevance to

Results of the literature search

The literature showed that PG and ginsenosides have been extensively researched, with more than 1500 original research articles retrieved. Twenty-four of these articles were relevant and are discussed below and shown in Table 1, Table 2. Most of the research was done in Asia (83%), with the remaining done in Europe (10%) and the United States of America (7%).

Discussion

This review reveals that PG and its active components, ginsenosides and their metabolites, exert a wide range of anti-inflammatory and anti-oxidative actions. The mechanisms of action include inhibition of kinase phosphorylation (including MAPK and ERK1/2), NF-κB induction, NF-κB translocation, DNA binding and pro-inflammatory mediator production, specifically TNF-α, IL-6, IL-8, IL-1β and ROS, and proteases (MMP-9) (Fig. 2). The primary PG and ginsenoside mechanisms of action are yet to be

Conclusions

PG and ginsenosides appear to interact with multiple processes and inhibit inflammation and oxidative stress. The reported main mechanisms of action are kinase phosphorylation inhibition including MAPK and ERK1/2; NF-κB induction and translocation; DNA binding; pro-inflammatory mediator reduction (specifically TNF-α, IL-6, IL-8, IL-1β and ROS); and protease (MMP-9) reduction. PG also protects against oxidative stress by increasing anti-oxidative enzymes and reducing the production of oxidants.

Authors’ contributions

The manuscript was written through contributions of all authors. JS, YD and AZ developed the search strategy, eligibility criteria and prepared the draft of the paper. JMY, RH, RV and CX provided critical input into the interpretation of the findings and prepared of the final draft.

Conflict of interest

The authors have no conflicts of interest.

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      Additionally, ginsenoside Rg3 and Rb3 could reduce the migration of neutrophils by negatively regulating PI3K activation, epithelial-mesenchymal transition (EMT), NF-κB activity, and pro-inflammatory cytokines in the CSE-induced BALV/c murine model, basal cells, and a co-culture model of bronchial epithelial cells and neutrophils [85,86]. Importantly, a previous review has discussed that ginsenosides mainly inhibit multiple processes related to the pathogenesis of COPD, such as inflammatory responses (TNF-α, IL-6, IL-1β, NF-κB induction and translocation), oxidative stress (ROS), and kinase phosphorylation (MAPK and ERK1/2) [87]. Collectively, ginsenosides exert anti-inflammatory and immunomodulatory effects by regulating the TGF-β1/Smad3 and NF-κB pathways (Table 2).

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    This work is supported by a National Health and Medical Research Council (NHMRC) Project Grant (Grant No: 616609), and Guangdong Provincial Academy of Chinese Medical Sciences and Guangdong Provincial Hospital of Chinese Medicine, China International Research Grant.

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