Efficacy of the Chinese herbal formula CUF2 in the treatment of childhood asthma: Animal experiment, in vitro study and randomized, double-blinded, placebo-controlled clinical trial.

摘要

Asthma has long been considered as one of the most common health problems in the world. In Hong Kong, the prevalence of childhood asthma has increased from 4.8% in 1989, to 10.2% in 2002. In spite of the popularity of using Chinese herbs to treat asthma in Hong Kong, evidence on the effectiveness of herbal treatments is lacking. The Chinese herbal formula CUF2 is an innovative formula developed in the Institute of Chinese Medicine, The Chinese University of Hong Kong and it is composed of 5 commonly used Chinese herbs: Radix astragali, Cordyceps sinesis, Radix Scutellaria, Bulbus fritillariae cirrhosae and Radix stemonae. These herbs are chosen because of their well-known effects on either reducing coughing and sputum production, or anti-inflammatory and immunomodulatory activities. Based on the theoretical benefits of CUF2, we conducted a series of animal, in vitro and clinical studies to explore the efficacy, safety and mechanism of action of CUF2.; In the animal study, firstly we attempted to establish a novel murine model of asthma. We adopted a modified sensitization procedure using 10-point subcutaneous and intraperitoneal injections of Ovalbumin (OA) with freshly prepared Al(OH)3 and successfully induced severe airway allergic reactions in young Sprague Dawley (SD) rats. In this SD rat model, allergen exposure triggered accumulation of inflammation cells and eosinophils in the airway submucosa and goblet cells hyperplasia in mucosa, lung function test revealed obstructive lung function changes that included increase of lung resistance (RL) and decrease of dynamic lung compliance (Cdyn). Cytokine and chemokine assays showed that there was a change of the TH1/Th2 balance as illustrated by the high Th2 (interleukin-4)/Th1 (interferon-gamma) ratio. These results demonstrated the feasibility and validity of the SD rat model for studying allergic asthma. This SD model is much cheaper and readily available than the Brown Norway rat model and may facilitate further drug trial in asthma.; Following the establishment of the animal model, we have investigated the effect of CUF2 using this model of asthma. We found that 28 days pretreatment with CUF2 could reduce total cell number and eosinophilia in bronchoalveolar lavage fluid (BALF), prevent the eosinophil infiltration of airways, decrease pulmonary inflammatory cells, and reduce mucus and goblet cell hyperplasia. Especially in the reduction of goblet cell hyperplasia, we demonstrated that there was no significant difference between the effects of high dose CUF2 and dexamethasone (DEX). The eosinophilic immune-inflammatory responses in the airways in OA-sensitized/challenged rats were completely blocked by DEX returning to almost the same as those in normal rats, but the loss of thymus index and body weight were also observed. In contrast to the overall immunosuppressive effects of DEX, decreased production of inflammatory cytokines and chemokines [interleukin (IL)-4, tumor necrosis factor (TNF)-alpha, macrophage inflammatory protein (MIP)-2 and monocyte chemotactic protein-1 (MCP-1)], increased production of IL-10 and interferon-gamma (IFN-gamma) in BALF and no suppression of body weight and thymus index were demonstrated in the CUF2-treated groups. There was a dose-response relationship with more prominent effects seen with higher doses of CUF2. These findings indicate that the CUF2 has anti-airway inflammatory activity and exhibits immunomodulatory effect on Th1/Th2 responses in ovalbumin sensitized rats after allergen challenge, and this may imply its potential application to patients with allergic asthma.; In the in vitro study, we investigated the effect of CUF2 on the release of cytokines and/or gene expression using human mast cell line HMC-1, human bronchial epithelial cell line BEAS-2B, peripheral blood mononuclear cells (PBMCs) from healthy subjects and airway cells present in induced sputum from asthmatic patients. We have shown (1) the CUF2 had no cytotoxic effects