| BackgroundIdiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonia. Its pathogenesis is unknown, and its onset is insidious. Progressive dyspnea is observed clinically. The IPF seriously affects patients’ quality of life and prognosis. At present, most studies suggest that alveolar epithelial cell injury, extracellular matrix formation and fibroblast foci excessive deposition are the main pathological features of IPF which eventually damage alveolar structure and fully form alveolar fibrosis and vesiculous cellular lung. This leads to persistently and progressively damage to lung function. So far, no effective drugs have been invested to treat the IPF. Only long-term oxygen therapy is strongly recommended. Over the last decade, we find through clinical observation that IPF’s pathogenesis are mostly due to Zheng Xu Biao Shi. We think that Zong Qi Xu Xian is the initial causing factor for its occurrence and Fei Luo Bi Zu found throughout the disease. Zong Qi Xu Xian block the running of blood and body fluids, forming phlegm cloud and blood stasis. At the early stage of the IPF, the disease blocks the body system. As the disease gets more serious, it combines with the endogenous phlegm, which further blocks pulmonary collaterals, and eventually leads to blockage of the lung network. The clinical use of Tong Fei Luo Bu Zong Qi Fang that dredge pulmonary collaterals, blood circulation, and supplement Zong Qi achieves better results than other treatments. In order to further examine its effect on patient activity endurance, and to explore the molecular mechanism of biological effects, the study conducts a randomized, blank control, prospective clinical trials and animal experiments.Part 1. A clinical study on the effect of Tong Fei Luo Bu Zong Qi Fang on the activity endurance of patients with idiopathic pulmonary interstitial fibrosisPurpose:To investigate the effect of Tong Fei Luo Bu Zong Qi on IPF patients’ activity endurance and evaluate its safety.Methods:Our sample include 60 cases of outpatient who met the inclusion criteria of IPF patients in Xiyuan hospital, Chinese Academy of Traditional Chinese Medicine. We randomly divided the patients into treatment and control groups,30 cases in each group. The control group was treated with large dosage of n-acetyl-1-cysteine, while the treatment group was treated with Tong Fei Luo Bu Zong Qi Fang plus large dosage of n-acetyl-1-cysteine. The treatment period is three months. Follow-up examination is conducted three months after the treatment. We compared between two groups of patients before and after the treatment for the following conditions:a six-minute walk test, life quality using the Saint George life quality questionnaire, pulmonary function, difficulty in breathing, and coughing. We also compare between two groups immediately after the treatment and three months after the treatment for the following conditions:symptoms of TCM syndrome, difficulty in breathing, and coughing. We record any adverse events occurred in two groups.Results:The six-minute walk test:patients of the treatment group walk a longer distance after the treatment than before the treatment, but the difference is statistically insignificant. Patients of the control group walk a shorter distance after the treatment, but the difference is also statistically insignificant. However, if we compare the differences between two groups before and after the treatment, the difference is statistically significant (P< 0.05) and shows that the treatment group achieves a greater improvement over the control group. Saint George life quality survey questionnaire:the overall life quality evaluation shows that the two groups are statistically indifferent from each other. In terms of symptom scores before and after treatment, patients of the treatment group saw a decline after the treatment, but the change is statistically insignificant. Patients of the control group saw an increase after the treatment, but the change is also statistically insignificant. However, if we compare the differences between two groups before and after the treatment, the change of the difference is statistically significant (P< 0.05) and shows that the treatment group achieves a greater improvement over the control group. In terms of activity limitations and psychological conditions, we fail to find statistically significant changes for either single groups or across group comparison. Pulmonary function:we fail to find statistically significant changes for either single groups or across group comparison for the following indexes — the overall effect of lung function and lung volume (Total Lung Capacity, TLC), vital capacity (Vital Capacity, VC), and carbon monoxide diffusing capacity (Diffusion Capacity for Carbon Monoxide, DLCO). Curative effect of TCM syndrome:if we compare the effect of TCM syndrome between two groups before and after the treatment, the change of the difference is statistically significant (P< 0.01) and shows that the treatment group achieves a greater improvement over the control group. Breathing difficulties: Dyspnoea score difference between two groups before and after the treatment is statistically significant (P<0.01) and indicates that the treatment group achieve greater improvement over the control group. Cough:cough score difference between two groups before and after the treatment is statistically significant (P<0.05) and indicates that the treatment group achieve greater improvement over the control group. Compared with the condition immediately after the treatment, patients’ condition after three month is similar in terms of the integration of TCM syndromes, breathing difficulties, coughing, and a six-minute walk test. Safety:no serious adverse events happened to either group.Conclusion:Tong Fei Luo Bu Zong Qi Fang can significantly improve the patient’s activity endurance, improve patients’ quality of life, and slow the decline of patients’lung function. Tong Fei Luo Bu Zong Qi Fang can also relieve symptoms of Dyspnea and cough.Part 2 A study of the mechanism through which Tong Fei Luo Bu Zong Qi Fang treat idiopathic pulmonary interstitial fibrosisClinical trials:Objective:through examining the changes of levels of serum transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α), connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF-AA) among IPF patients before and after the treatment, we reveal the molecular mechanism of Tong Fei Luo Bu Zong Qi Fang and assess its efficacy using those indicators.Method:The first 15 patients who finished the trial were included in this study. We used enzyme Alliance immune adsorption method (ELISA) to measure and compare patients’ levels of serum TGF-beta, TNF-alpha, CTGF, and PDGF-AA content. We conduct statistical analysis on our trial results.Results:the levels of TGF-β among the treatment group declined significantly, and compared with the control group, the difference is also statistically significant (P<0.05). For TNF-alpha and the CTGF, there was no significant changes. The level PDGF-AA is higher after the treatment, but the difference is not statistically significant.Conclusion:The mechanism of Tong Fei Luo Bu Zong Qi Fang treating IPF may be related with lowering the level of serum TGF-β in IPF patients.Animal testing:Objective:through examining the effect of Tong Fei Luo Bu Zong Qi Fang on levels of collagen type Ⅰ and type Ⅲ collagen in lung tissue, TGF-β, Smad3 and Smad7 among experimental rats with the IPF, we study the correlations between various indicators and explore the molecular mechanism of Tong Fei Luo Bu Zong Qi Fang’s treatment of the IPF.Method:We used HE staining to examine the effect of Tong Fei Luo Bu Zong Qi Fang and n-acetyl half cystine on alveolar inflammatory and the degree of pulmonary fibrosis among big rats with the IPF. We used Masson staining to examine the effect of Tong Fei Luo Bu Zong Qi Fang and n-acetyl half cystine on gas road epithelial injury degree score, collagen deposition, and the gas road wall thickness among big rats with the IPF. We used immune imprinted method to examine the effect of Tong Fei Luo Bu Zong Qi Fang and n-acetyl half cystine on lung organization type Ⅰ and Ⅲ collagen, TGF-beta, Smad3, and Smad7. We also examine the correlation between various indicators.Results:Compared with the model group, the group treated with Tong Fei Luo Bu Zong Qi Fang and acetyl half cystine obviously alleviated the degree of alveolar inflammatory and pulmonary fibrosis. Compared with the model group,the groups treated with either Tong Fei Luo Bu Zong Qi Fang or acetyl half cystine had eased epithelial injury (P<0.01), reduced collagen deposition area (P<0.01), and a thinner tracheal wall (P<0.01). However, the differences between the group using with Tong Fei Luo Bu Zong Qi Fang and the one using acetyl half cystine are statistically insignificant. Compared with the model group, the groups treated with either Tong Fei Luo Bu Zong Qi Fang or acetyl half cystine had lower levels of type Ⅰ and Ⅲ collagen in lung organization, TGF-beta, and Smad3 (P<0.01). The differences of all other comparisons are not statistically significant. Compared with the model group, the groups treated with either Tong Fei Luo Bu Zong Qi Fang or acetyl half cystine had a higher level of Smad7 (P<0.01). The differences of all other comparisons are not statistically significant. TGF-β was positively correlated with type Ⅰ, Ⅲ collagen. TGF-β was positively correlated with Smad3 but negatively correlated with Smad7.Conclusion:Through reducing TGF-β, Tong Fei Luo Bu Zong Qi Fang can lower the level of Smad3 and increase the level of Smad7, eventually reduce abnormal deposition of type Ⅰ and Ⅲ collagen of lung tissue. |
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