The Study On The Mechanism Of Prevention And Treatment Of Pulmonary Fibrosis Through Intervention Of Notch Signaling Pathway Using Methods In Nourishing Lung And Dredging Collaterals

Pulmonary fibrosis is the final pathological outcome of many respiratory diseases; main clinical symptoms include aggravated and progressive dyspnea, restrictive ventilatory defects with reduced diffusion capacity, lung hypoxemia and diffuse radiographic lesions. Given that there is a lack of effective therapy for the disease, coupled with increased incidence in recent years, prevention and treatment for pulmonary fibrosis has become one of the major challenge for medicine. According to the onset of clinical symptoms and characteristics of this disease, this study suggests that pulmonary fibrosis belongs to the collateral disease category from the TCM perspective, deficiency of the lung and stagnation in collateral are the main pathogenesis, and Nourishing Lung and removing obstruction in collaterals is the treatment approaches. Thus, the study conducted a systematic and in-depth literature reviews and theoretical discussion into the adoption of nourishing lung and dredging collaterals as a treatment method, with the focus in studying of the Notch signaling pathway related to the development of Pulmonary Fibrosis, using a well-tested clinical prescription "Yangfei Huoxue Prescription", and carried out experimental research on its pharmacological mechanism.The study is divided into three parts:the first part is literature review which looks into the studies of Chinese and Western medicine on pulmonary fibrosis, as well as related content on Notch signaling pathway. Pulmonary fibrosis is a Western medicine disease name, caused by a variety of pathogenic factors such as occupational pollution, infected with pathogenic microorganisms, drug side effects, its development can be summarized in into three stages, the formation of alveolar immune inflammation, lung parenchymal injury and pulmonary fibrosis, and there is still no effective treatment, the traditional medicine treatment, such as corticosteroids, immunosuppressant which will cause apparent side effects through long-term use. The Chinese medicine appears to have more advantage in disease prevention and treatment, as the treatment method is safe, effective, and with fewer side effects. Chinese medicine does not have a disease correspond with the name of pulmonary fibrosis, but its related symptoms can be found in the symptoms manifestation among the various diseases in Chinese Medicine, in, "cough"、 "dyspnea"、"lung distension"、"consumptive lung disease"、"Bi syndrome of lung". Exposure to external pathogen, internal injuries and chronic illness are reasons which can lead to pulmonary fibrosis, but most of the time the onset of the disease was triggered by deficiency in the lung, involving spleen and kidney, stagnation of phlegm, which resulted deficiency complicated with excess symptoms. Modern medicine approaches to the treatment of this disease based on characteristics of the pathogenesis and pathological development, its mechanism of treatments involves inhibition of the restraining inflammation, regulating the extracellular matrix metabolism, the intervention of apoptosis, the regulation of angiogenesis. The development of pulmonary fibrosis involves multiple signaling pathways, while the newly discovered, Notch is closely related to it. Its widely present in the organism, and the factors such as inflammation, metabolism of extracellular matrix, angiogenesis, immune response, oxidative stress, affect the development of pulmonary fibrosis, thus, this study was to conduct a research in the prevention of pulmonary fibrosis from the perspective of the Notch signaling pathway using methods in nourishing lung and dredging collaterals.The second part is the theoretical research on pulmonary fibrosis. The study indicated that the pathogenesis of this disease located in the lung-collateral, deficiency of qi and yin are the basis for the onset of pathology, stasis in the lung-collateral are the basic lesion, thus the deficiency of the lung and stagnation in collateral are the main pathogenesis, the pathological nature of the disease typified as deficiency complicated with excess symptoms, and the method of nourishing lung and dredging collaterals is an important treatment method. For the pathogenesis of this disease, treatment using the principle of nourishing lung (supplementing qi and nourishing yin) and dredging collaterals, besides meeting the pathological features of the disease, the use of nourishing yin and supplementing qi can help to remove blood stasis couple with the use of promoting blood circulation and dredging of collateral will help to improve the efficacy. Clinically, while using the nourishing lung and dredging collaterals method in the Treatment of pulmonary fibrosis, we should first identify the major symptoms. Given that the pathological nature of the disease typified as deficiency complicated with excess symptoms, and deficiency in both qi and blood, the application of the method should look into the consideration of balancing between nourishing and dredging as the fundamental approach. Depending on the development and the nature of the disease, flexibility should be observe in applying integrative method such as cleansing heatiness in phlegm, nourishing the kidney yin and so on, so as to prevent fibrotic lesions, to promote the body’s speedy recovery.The third part is the experimental study. To further understand the use of the nourishing lung and dredging collaterals method in the prevention and treatment of pulmonary fibrosis, this study adopted "Yangfei Huoxue Prescription" as prescription to be used in the experiment, and from the perspective of the Notch signaling pathway, observed how the prescription affect the pathological, Notch receptors and ligands, activating enzymes and their associated molecules influence in rats with pulmonary fibrosis. The results show significant improvements of alveolitis and the development of pulmonary fibrosis in rats with pulmonary fibrosis using the prescription, indicating that the use of "Yangfei Huoxue Prescription" is an effective prescription in the prevention and treatment of pulmonary fibrosis. Its pharmacological mechanism, correlate with the reduction of Notchl, NICD1, Notch4, Jaggedl, Dll 4, suggesting that prevention and treatment of pulmonary fibrosis can be achieved through intervention of Notch signal transduction. Further studies showed that the prescription can inhibit the classical pathway activation of Notch signalling pathway, which may be one of the ways it affects Notch signal transduction. It was also observed that the prescription in relation to inflammation-related factors such as Adhesion Molecules and Aquaporin, can significantly reduce adhesion molecule ICAM-1, VCAM-1, the expression of the diversion channel protein AQP1, AQP5, suggesting the association with that the prescription’s pharmacological mechanism in prevention and treatment of pulmonary fibrosis.In conclusion, through systematic study conducted through literature review, theoretical analysis, and experimental research on the use of the nourishing lung and dredging collaterals method in the prevention and treatment of pulmonary fibrosis, through the Notch signaling pathway level intervention, gave a preliminary affirmation on the use of the method in the prevention and treatment of the disease. Its findings, besides providing an important theoretical guidance for the prevention and treatment of pulmonary fibrosis using Chinese Medicine, also serve as a good foundation for future in-depth theoretical research, clinical and experimental research to be conducted on similar topics.