Exposures to environmental allergens are the main triggers of asthma, while cigarette smoking is the predominant cause of COPD . Both asthma and COPD are characterized by chronic airway inflammation. The key inflammatory cells involved in COPD (CD8+ T cells, macrophages and neutrophils) are different from those involved in asthma (eosinophils and CD4+ Th2 cells), suggesting that different treatments may be required [9, 22]. However, the treatments for both of these diseases may often overlap. The current standard medications for treating inflammatory lung diseases has evolved to cocktail therapies, which are combinations of several medicines possessing different therapeutic targets and include inhaled glucocorticosteroids, β2-adrenoceptor agonists, leukotriene receptor antagonists, methylxanthines, theophylline, and others [23–26]. However, these therapies produce potential side effects, such as growth retardation, the induction of insulin resistance, the loss of bone mass, immune system suppression, cardiac comorbidity, nausea, emesis, gastrointestinal disturbances, and arrhythmias, but they do not consistently ameliorate airway inflammation in some COPD patients [27–33]. Therefore, there is a need for the development of safe and efficacious treatments [34, 35]. In the present study, we show that exposure to PPE and LPS induces structural and functional changes that are typical of COPD, including airway remodeling, diffuse lung inflammation, goblet cell hyperplasia, alveolar enlargement, and increased numbers of neutrophils, lymphocytes, and macrophages in the airways and alveoli. In addition, in the airways the mucins Muc5AC and Muc5B are found at increased levels in both asthmatic and COPD subjects [36, 37]. Mucin hypersecretion is associated with abnormal epithelial cell growth and differentiation, both inflammatory mediators and growth factors may be involved in the stimulation of mucin production from goblet cells . However, GJHT treatment ameliorated the lung structural and functional changes in the PPE and LPS exposure model. These results may suggest that GJHT is a useful therapeutic agent that prevents the structural and functional changes associated with COPD.
The components of GJHT have been shown to have various biological effects. Rehmannia glutinosa, a major component of GJHT, possesses thrombolytic, hyperglycemic, and anti-inflammatory activities and improves renal functions in diabetic nephropathy [39–43]. In addition, this herb has been reported to suppress the production of TNF-α and IL-1 in mouse astrocytes . Atractylodes macrocephala, another component of GJHT, possesses antioxidant, hepatoprotective, anti-inflammatory, anti-allergic, antithrombotic, antiviral and anticarcinogenic activities [45–47]. Angelica sinensis is well known to have strong immune regulatory effects, such as antiviral activities and improving immune function by increasing CD4+ cells and the CD4+/CD8+ ratio . Liriope platyphylla has been used to treat asthma and bronchial and lung inflammation . In addition, this compound possesses various therapeutic effects for conditions such as obesity, diabetes, inflammation and neurodegenerative disease [50–53]. Scutellaria baicalensis has been used to treat inflammation, cancer, bacterial and viral infections of the respiratory and gastrointestinal tracts [54–56]. Some of the components of GJHT are reported to possess anti-cancer effects for various types of malignancy via distinct molecular mechanisms and include Raphanus sativus[57, 58], Astragalus membranaceus[59–61], Poria cocos, Citrus unshiu, Platycodon grandiflorum and Anthriscus sylvestris. The therapeutic potency of GJHT should be attributed to its combined and synergistic effects on multiple targets as a result of the diverse components of GJHT. In addition, according to the formula suggested by US Food and Drug Administration , human equivalent dose (HED) calculated from mice dosage (100 mg/kg and 300 mg/kg) used in this study was 480 mg/60 kg and 1440 mg/60 kg in human, respectively. We believe that these amounts of GJHT would be applicable dosages to human.
The morphological and inflammatory changes were accompanied by increases in lung IL-1β and IL-6, as observed in humans with COPD [67, 68]. A recent genetic analysis study demonstrated that IL6, IL1RN, IL1B, and IFNG genes were risk factors for the accelerated decline of lung function or baseline lung function in COPD patients . Importantly, their study demonstrated a significant association between IL6 and an IL6-smoking interaction in cardiovascular disease . In addition, high levels of serum or sputum IL-6 have been associated with impaired lung function, pulmonary infections, exacerbations, and skeletal muscle weakness in COPD patients [70–74]. Experimental studies have shown that IL-6 overexpression in the murine lung results in emphysema-like airspace enlargement and airway inflammation . In the present study, GJHT treatment significantly reduced the amounts of IL-1β and IL-6 in the airway, suggesting that the anti-inflammatory effect of GJHT can be attributed to the suppression of proinflammatory cytokine production in the lung. Even though the power calculation result demonstrated that the animal number used in this study was enough to tell the statistical importance, the sample size of this study was relatively small (n = 5,6 each group) that might mislead the data interpretation. To overcome such limitations, additional researches investigating the mechanism of Gamijinhae-tang on lung inflammation are necessary.