Research on the therapeutic mechanism of CHM for COPD

Based on results of this literature review of clinical trials and animal experimental research, the therapeutic mechanism of CHM for treating COPD is summarised according to the following aspects:

 Immunoregulation,

 Balance of oxidants and antioxidants,

 Improvement of blood rheology,

 Prevention of pulmonary hypertension,

 Improvement of respiratory muscle function, anti-inflammatory, antibacterial and bronchodilator action as well as mucous clearance.

54 3.5.7.1 Immunoregulation

The ability of CHM to improve immunoregulatory functions of cellular and humoral immunity has been demonstrated by the effects of inflammatory mediators, the level of immunoglobulins (Ig) and regulation of T lymphocyte subsets (269).

Reduced levels of released inflammatory mediators

COPD is characterised by chronic inflammation of the airway, pulmonary parenchyma and pulmonary vasculature, with impairment of pulmonary structure by inflammatory mediators such as leukotrienes, tumour necrosis factor-alpha (TNF-α) and interleukin (IL)-8.

Significantly reduced serum levels of TNF-α and IL-8 have been found in clinical trials (270-272) and experimental research studies (273, 274). Therefore, CHM may have effects on cytokine activities and prevent the inflammatory response in COPD patients.

Enhanced Ig levels

The serum levels of IgA, IgM and IgG were decreased in patients with COPD relative to healthy subjects (275). CHM has been demonstrated to significantly enhance the levels of IgA, IgG and IgM in patients with COPD compared to controls after Sheng Mai Injection (276).

Therefore, CHM may potentially improve immune-related defences in patients suffering from COPD.

Regulation of T lymphocytes

COPD patients have reduced levels of T lymphocytes including CD3+, CD4+ and CD4+/CD8+ subsets, B cells and natural killer cells compared to healthy subjects, thus implying impairment of cellular immunity function in COPD (277). It was reported that CHM regulated the level of CD3+, CD4+, CD4+/CD8+ and CD8+ T cells in a study that used a formula containing Ren shen, Fu ling, Bai zhu and Ci wu jia and Shan zhu yu etc. and a separate study that used a formula containing Ren shen, Huang qi, Shan yao, Fang feng, Mai dong, Wei jin, Dan shen, Tao ren, Guo lou and Bei mu (275, 278). Therefore, CHM may improve the immunodeficiency of patients with COPD.

3.5.7.2 Regulation of oxidant-antioxidant balance

Because of excessive secretion of TNF-α and IL-8 in patients with COPD leading to neutrophil aggregation in the small airway and accumulation of oxygen radicals, these oxygen

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radicals may attack the endothelial cell membrane and mitochondrial membrane in the airway;

this process causes lipid peroxidation leading to impairment and apoptosis of cells. Dang shen (Salvia miltiorrhiza) injection was found to increase the plasma level of human glutathione peroxidase (GSH-Px) and catalase and decrease lipid peroxidation, which indicated that Salvia miltiorrhiza could markedly attenuate lipid peroxide (LPO) reactions and adjust the antioxidant imbalance in patients with chronic cor pulmonale (279).

3.5.7.3 Improvement of blood rheology

In patients with COPD or cor pulmonale, recurrent infection, hypoxemia and carbon dioxide retention lead to increased haematocrit (Hct) blood and plasma viscosity and fibrinogen, thereby resulting in hyperviscosity syndrome and forming micro-thrombi in the lung. In COPD patients treated with CHM formulae by either oral or inhaled administration, including Zao jiao and Da zao in one study and Ma huang (Zhi), Xing ren, Gan cao, Huang qi and Chi shao in another (280, 281), CHM treatment decreased Hct, fibrinogen, blood viscosity and shear rate.

3.5.7.4 Prevention of pulmonary hypertension

As a result of long-term hypoxemia leading to increased aggregative index of red blood cell and blood viscosity that further cause blood stasis and dysfunction of lung tissue microcirculation, complications of pulmonary hypertension and cor pulmonale are common.

Although the prevalence of pulmonary hypertension in patients with mild and moderate COPD is not known, studies have reported a high prevalence of pulmonary hypertension, which ranges from 30−70% in patients with advanced COPD and hypoxemia. Patients with COPD and hypoxemia had severely elevated pulmonary pressure and pulmonary vascular resistance (PVR) that lead to right heart ventricle dysfunction.

Vasodilator therapy may be effective in decreasing both pulmonary hypertension and systemic blood pressure, although this may also worsen hypoxemia. Studies have demonstrated that CHM may be potentially effective in selectively reducing pulmonary hypertension while not affecting the systemic blood pressure or worsening hypoxemia. In addition, pulmonary hypertension by hypoxemia is recognised to correlate with disturbances of blood coagulation and humoral factors. Therefore, maintaining balance of the ratio of tissue-type plasminogen activator (tPA)/PA inhibitor (PAI) and prostaglandin I2

(PGI2)/thromboxane A (TXA2) as well as that of endothelin and Nitric oxide (NO) is critical for relief of pulmonary hypertension. CHM formulae or single extracts have been

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demonstrated to have possible effects on pulmonary hypertension through different mechanisms described in the following sections.

Decreased mean pulmonary arterial pressure and pulmonary vascular resistance

Decreased mean pulmonary arterial pressure and PVR were found in studies using injection of extracts of single herbs such as Dang gui, Dan shen and Huang qi in the treatment of patients with stable COPD and pulmonary hypertension (PH) (282, 283). In addition, decreased mPAP was also found in studies using oral administration of CHM formulae by comparing pre- and post-treatment data. For example, Zhang (2001) used CHM formulae that included Ren shen, Huang qi, Lu jiao jiao, Ge jie powder, Fa ban xia, Mu li, Ting li zi, Fu ling, Gu zhi, Chuan xiong and Shui zhi for the treatment of patients with stable COPD and pulmonary hypertension (284), while Sun Zikai (2001) used CHM formulae that included Xie bai, Ting li zi, Huang qin, Gua lou pi, Sang bai pi, Zhi ma huang, Fang feng, Dan shen, She gan, Xing ren and Gan cao in the treatment of patients with COPD exacerbations and PH (285).

Enhancement of type plasminogen activator (tPA) / PA inhibitor (PAI) ratio

The tPA protein is involved in the breakdown of blood clots and is found in endothelial cells.

PAI is the inhibitor of activators of plasminogen and fibrinolysis. PAI1 is a serine protease inhibitor protein and is a main inhibitor of the PA. It was reported that a CHM formula Qing Ning Oral Liquid including Huang qi, Bai zhu, Fang feng, Dan shen and Chuan xiong may increase tPA activity and decrease PAI activity in senile COPD patients treated for PH.

Meanwhile, it has been implied that PH is potentially correlated with tPA activity and PAI activity (286).

Prostaglandin I2/Thromboxane A2 balance

Humoral factors play an important role in pulmonary vasoconstriction. Pulmonary vasoconstriction or vasodilatation depends on the ratio of vasoconstrictors/vasodilators. PGI2

is a vasodilator, and causes increases in cAMP in blood platelet cells and suppresses their aggregation, whereas TXA2 is a vasoconstrictor that stimulates activation of new platelets and increases platelet aggregation. Imbalances in the ratio of PGI2/TXA2 lead to hypertension.

Extracts of Mao dong qing leaf administered as a Dihydroxyacetophenone injection were found to reduce the level of plasma atrial natriuretic peptide (ANP), cGMP and blood viscosity, enhance the level of cAMP/cGMP and regulate the balance of the PGI2/TXA2 ratio in patients with stable COPD (287). A Xie Bai capsule consisting of Xie bai, Gua lou, Ban xia

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and Huang lian etc. was found to have similar functions in the treatment of patients with COPD and PH (288).

Nitric oxide (NO) and Endothelin balance

Endothelin (ET) is a protein that constricts blood vessels and raises blood pressure. NO is recognised as an important endothelium-derived vasodilator that plays a major role in maintaining vascular tone in normal pulmonary vasculature (289). Increased ET and decreased NO lead to strongly constricted pulmonary vasculature and PH. Wu found that a CHM formula containing Di huang (Shu), Dang shen, Huang qi, Fu ling, Bai zhu, Ling zhi, Tu si zi, Du zhong, Xing ren (Bei), Su zi, Dan shen and Dang gui decreased the level of serum ET and increased serum NO levels in patients with stable COPD (290), while ET1 was decreased in a study using Dang gui injection in patients with COPD and PH (283).

3.5.7.5 Improvement of respiratory muscle function

In COPD patients, because of increased lung volume, malnutrition, increased airway resistance, hypoxaemia, hypercapnia and respiratory acidosis that cause structural changes of the respiratory muscle and reduction of respiratory function, there is increased energy demand of the respiratory muscle. Conversely, respiratory muscle fatigue is one of causes of leading worsening hypercapnia and respiratory failure that finally form a vicious cycle, thereby accelerating the reduction of exercise tolerance and quality of life. Studies on the effect of Shen Mai Injection have indicated that it may improve diaphragmatic function in COPD patients with respiratory failure and diaphragm fatigue (291); it may also improve respiratory muscle strength and respiratory muscle endurance in COPD patients (292). Shen Mai Injection has been demonstrated to improve adaptability of the diaphragm muscles and further improve the relaxation and contractility function of fatigued diaphragm muscles in a rat experimental model (293).

The results found in randomised clinical trials for the effects of CHMs in stable COPD will be analysed and discussed in chapters six and seven and the results of experimental studies of specific CHM will be discussed in Chapter 8.

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4 Chapter Four: Methods for analysing the classical literature