大鼠煤工尘肺动物模型的研究
摘要
本研究目的旨在建立一种更为合适的安全性高、重复性好、准确、经济、易于制作和评价的煤工尘肺大鼠动物模型。采用气溶胶吸入法和非暴露气管灌注法2种染尘方式建立大鼠煤工尘肺动物模型,分别于染尘后2周、4周、8周、3个月、6个月、9个月、12个月、18个月检测各组实验动物肺功能、血气分析、支气管肺泡灌洗液细胞成分、肺泡灌洗液中TNF-α及TGF-β水平、支气管肺泡灌洗液细胞TNF-α及TGF-β的mRNA表达水平、肺泡巨噬细胞非特异性吞噬功能、肺组织病理、肺组织内羟脯氨酸的含量等指标;并比较各组所制动物模型不同时间、各项指标变化趋势及相关性。通过此项研究,我们首先建立了煤尘气溶胶吸入装置及煤尘气溶胶的制备,并成功采用非暴露气管灌注法和气溶胶吸入法2种染尘方式建立大了鼠煤工尘肺动物模型,两种方法均准确、经济地复制了大鼠煤工尘肺动物模型,以高浓度暴露更为理想;但非气管暴露灌注法对试验者实验技术复杂、动物死亡率较高、短时间内可复制动物模型;气溶胶吸入法动物死亡率低、符合煤工尘肺致病因素和发病环境及煤工尘肺的发生发展过程,简便、易于制作和评价,更为适用于煤工尘肺发病机制、诊断及治疗的临床研究。
Coal worker's pneumoconiosis (CWP) can be defined as the accumulation of coal dust in the lungs and the tissue's reaction to its presence. The disease is divided into 2 categories: simple CWP (SCWP) and complicated CWP (CCWP), or pulmonary massive fibrosis (PMF), depending on the extent of the disease. When this system becomes overwhelmed, the dust-laden macrophages accumulate in the alveoli and may trigger an immune response. Fibroblasts involved in this response secrete reticulin, which entraps the macrophages. If the macrophages lyse, the fibroblastic response is augmented and more reticulin is laid down in the rea.CCWP produces cough, dyspnea, and lung function impairment. If the disease is advanced, cor pulmonale may be found with associated right ventricular heave, large A waves, hepatomegaly, respiratory failure and peripheral edema. Patients with CWP are at a slightly increased risk of developing active TB and non-TB mycobacterial infections. Pathogenesy of CWP is not clear, so Treatment for both SCWP and CCWP is symptomatic and can not prevent development of the disease. Mortality and morbidity of CWP are high, so the study of CWP will be a hard responsibility to benefit the nation and the people.
Pathophysiology of CWP is very complicated and involve in a lot of cells and active materials. Alveolar macrophages engulf the dust, release cytokines that stimulate inflammation, and collect in lung interstitium around bronchioles and alveoli (coal macules). Coal nodules develop as collagen accumulates, and focal emphysema develops as bronchiole walls weaken and dilate. Fibrosis can occur but is usually limited to areas adjacent to coal macules. Distortion of lung architecture, airflow obstruction, and functional impairment are usually mild but can be highly destructive in some patients.
At present, the study and research information of CWP is more less, so the pathogenesy is not extremely clear. Most of the information is from epidemiological investigations, bronchoalveolar lavage fluid and lung biopsy of patients, autopsy, culturing in vitro, and so on. The development process of CWP is ont systematically observed, so the research and application of the treatment is not enough to control the disease. More suitable animal model of CWP is significant wich is not invent now. In recent years, the CWP basic research basically based on dropping coal dust through the trachea the to lung to create mouse coal animal model, the lung pathology of is typical the pathological change process, but the large dose exposition animal model whether accurate reflectiong humanity coal workers’pneumoconiosis or not is another important study direction.To manufacture the appropriate model reflectiong the human chronic disease may be a challenge, specially the CWP . Although the lung fibrosis models induced by Bleomycin are widely used to study the lung fibrosis disease, he different animal only can study the specific lung fibrosis. Because the CWP is different from other pneumoconioses, More suitable animal model of CWP is necessary for the study.
The non-exposed trachea injection method wase used to create CWP animal model is common way wich are more security and less mortality,so it is better. In 2003, we prepared an animal model of CWP by this way, but it wse not consummate. To make the CWP modol by inhalation is less applicated, but it may be a feasible. A big mouse aerosol inspiring installment can be made and the aerosol density can be detected, so to create a similar environment with the pathogenesis factor is not difficult and there is no technical questions. At present, respiratory function examination equipment for the small animals can monitor the big mouse lung function.
Macrophage phagocyting chicken red blood cell,ELISA,RT-PCR,hydroxyproline quantitation and pathology appraisal wich Szapielhad reported are tectonic and received technology, so analyses of the bronchoalveolar lavage fluid, function of cells, cytokine, collogen content and pathology will be well done. In this study, two methods were used to create the CWP model: the non-exposed trachea perfusing coal dust and inspiring coal dust. Assessment based on pathology. All CWP model compared with normal control group, Sodium Chloride control group and SiO2 exposing group. To evaluate and tendency of the bronchoalveolar lavage fluid, function of cells, cytokine, collogen content and pathology, and to analyse dependability among these correlated factors. A more factor, safer, better reproducibility, more precise, cheaper and more easy to be evaluated rat animal model of CWP be created in this study will be applied in the correlated research of CWP in the future, and it will be the foundation of this fild.
All the animals in this study will be executed at 2 weeks, 4 weeks, 8 weeks, 3 moths, 6 moths, 9 moths, 12 moths, 18 moths, and the pulmonary function, blood gas analysis, bronchoalveolar lavage fluid, TNF-αand TGF-βin the bronchoalveolar lavage fluid, TNF-αand TGF-β的mRNA express level, function of alveolar macrophage, lung pathology and hydroxyproline content in the lung were detected. All those factors among the different groups were evaluated. Respirable coal dust and quartz dust and coal dust inspiring system were manufactured. Coal dust inspiring environment with stable aerosol was established.
The coal dust inspiring system can be reproduced, well work and be operated easily, so it can be used by anyone. Pathologically, both diffusing alveolitis and pulmonary interstitial fibrosis were observed in the animals model of CWP : in earlier period(2weeks), alveolitis was observed including alveolar space phlegmasia cells exfiltration , phlegmasia cells infiltrating in the alveolar wall and interval in the whole observing period(18 moths). The longer coal dust exposed, the more severe wse pulmonary interstitial fibrosis. Local emphysema was observed after 3 moths. There were tipical pathological foundings in the models after 3-6 months by non-exposed trachea injection, 6-9 months by inspiring coal dust and 3 months by non-exposed trachea injecting SiO2.
Three targets of the rat pulmonary function of the rat models including breathing rate,FEV1/FVC(%) and blood gas analysis (PO2) were significant difference compared with control group. The longer coal dust exposed, the higher breathing rate and the lower FEV1/FVC(%)and the PO2 were observed in the rat models, especially in the later period. All the three targets of the rat pulmonary function were closely correlated with the lung pathology. It confirmed that chronic bronchitis, emphysema with restrictive ventilatory disorder or/and obstructive ventilatory disorder, venting/ blood ratio disturbance and diffusion function dysfunction because of pulmonary interstitial fibrosis leading to alveoli -capillary membrane thickening.
TNF-αand TGF-βconcentration in the bronchoalveolar lavage fluid and TNF-αand TGF-βmRNA express level in the cells of the bronchoalveolar lavage fluid in the rat models was hager than control group(p<0.05). There was positive correlation between the TNF-αand TNF-αmRNA, TGF-βand TGF-βmRNA, these two cytokines and alveolitis, pulmonary fibrosis. It proveed that these two cytokines were very important in the course of CWP disease. Hydroxyproline content in the lung of pneumoconiosis rat models was higher than the control group(p<0.05). The longer coal dust exposed, the higher hydroxyproline content was. There was positive correlation between the hydroxyproline content and pulmonary fibrosis. It proveed that hydroxyproline conten could reflect the fibrous tissue content of the lung and could be a sensitive target reflecting reflect.
The mortality of the CWP models created by non-exposed trachea perfusing coal dust was higher than the CWP models created by coal dust inspiring and the rat of control group. the safe, exact, cheap coal workers Pneumoconiosis (CWP) rat models were successfully made through the non-exposed trachea perfusing coal dust and inspiring coal dust. the non-exposed trachea perfusing coal dust method need better specification, and there are higher dath rate in the models mdae by this method than inspiring coal dust method. to simulate the etiological factor, the invasion environment and the chronic process of the coal workers Pneumoconiosis, the method of inspiring coal dust will be more suitable to researching in this field.
Coal worker's pneumoconiosis (CWP) can be defined as the accumulation of coal dust in the lungs and the tissue's reaction to its presence. The disease is divided into 2 categories: simple CWP (SCWP) and complicated CWP (CCWP), or pulmonary massive fibrosis (PMF), depending on the extent of the disease. When this system becomes overwhelmed, the dust-laden macrophages accumulate in the alveoli and may trigger an immune response. Fibroblasts involved in this response secrete reticulin, which entraps the macrophages. If the macrophages lyse, the fibroblastic response is augmented and more reticulin is laid down in the rea.CCWP produces cough, dyspnea, and lung function impairment. If the disease is advanced, cor pulmonale may be found with associated right ventricular heave, large A waves, hepatomegaly, respiratory failure and peripheral edema. Patients with CWP are at a slightly increased risk of developing active TB and non-TB mycobacterial infections. Pathogenesy of CWP is not clear, so Treatment for both SCWP and CCWP is symptomatic and can not prevent development of the disease. Mortality and morbidity of CWP are high, so the study of CWP will be a hard responsibility to benefit the nation and the people.
Pathophysiology of CWP is very complicated and involve in a lot of cells and active materials. Alveolar macrophages engulf the dust, release cytokines that stimulate inflammation, and collect in lung interstitium around bronchioles and alveoli (coal macules). Coal nodules develop as collagen accumulates, and focal emphysema develops as bronchiole walls weaken and dilate. Fibrosis can occur but is usually limited to areas adjacent to coal macules. Distortion of lung architecture, airflow obstruction, and functional impairment are usually mild but can be highly destructive in some patients.
At present, the study and research information of CWP is more less, so the pathogenesy is not extremely clear. Most of the information is from epidemiological investigations, bronchoalveolar lavage fluid and lung biopsy of patients, autopsy, culturing in vitro, and so on. The development process of CWP is ont systematically observed, so the research and application of the treatment is not enough to control the disease. More suitable animal model of CWP is significant wich is not invent now. In recent years, the CWP basic research basically based on dropping coal dust through the trachea the to lung to create mouse coal animal model, the lung pathology of is typical the pathological change process, but the large dose exposition animal model whether accurate reflectiong humanity coal workers’pneumoconiosis or not is another important study direction.To manufacture the appropriate model reflectiong the human chronic disease may be a challenge, specially the CWP . Although the lung fibrosis models induced by Bleomycin are widely used to study the lung fibrosis disease, he different animal only can study the specific lung fibrosis. Because the CWP is different from other pneumoconioses, More suitable animal model of CWP is necessary for the study.
The non-exposed trachea injection method wase used to create CWP animal model is common way wich are more security and less mortality,so it is better. In 2003, we prepared an animal model of CWP by this way, but it wse not consummate. To make the CWP modol by inhalation is less applicated, but it may be a feasible. A big mouse aerosol inspiring installment can be made and the aerosol density can be detected, so to create a similar environment with the pathogenesis factor is not difficult and there is no technical questions. At present, respiratory function examination equipment for the small animals can monitor the big mouse lung function.
Macrophage phagocyting chicken red blood cell,ELISA,RT-PCR,hydroxyproline quantitation and pathology appraisal wich Szapielhad reported are tectonic and received technology, so analyses of the bronchoalveolar lavage fluid, function of cells, cytokine, collogen content and pathology will be well done. In this study, two methods were used to create the CWP model: the non-exposed trachea perfusing coal dust and inspiring coal dust. Assessment based on pathology. All CWP model compared with normal control group, Sodium Chloride control group and SiO2 exposing group. To evaluate and tendency of the bronchoalveolar lavage fluid, function of cells, cytokine, collogen content and pathology, and to analyse dependability among these correlated factors. A more factor, safer, better reproducibility, more precise, cheaper and more easy to be evaluated rat animal model of CWP be created in this study will be applied in the correlated research of CWP in the future, and it will be the foundation of this fild.
All the animals in this study will be executed at 2 weeks, 4 weeks, 8 weeks, 3 moths, 6 moths, 9 moths, 12 moths, 18 moths, and the pulmonary function, blood gas analysis, bronchoalveolar lavage fluid, TNF-αand TGF-βin the bronchoalveolar lavage fluid, TNF-αand TGF-β的mRNA express level, function of alveolar macrophage, lung pathology and hydroxyproline content in the lung were detected. All those factors among the different groups were evaluated. Respirable coal dust and quartz dust and coal dust inspiring system were manufactured. Coal dust inspiring environment with stable aerosol was established.
The coal dust inspiring system can be reproduced, well work and be operated easily, so it can be used by anyone. Pathologically, both diffusing alveolitis and pulmonary interstitial fibrosis were observed in the animals model of CWP : in earlier period(2weeks), alveolitis was observed including alveolar space phlegmasia cells exfiltration , phlegmasia cells infiltrating in the alveolar wall and interval in the whole observing period(18 moths). The longer coal dust exposed, the more severe wse pulmonary interstitial fibrosis. Local emphysema was observed after 3 moths. There were tipical pathological foundings in the models after 3-6 months by non-exposed trachea injection, 6-9 months by inspiring coal dust and 3 months by non-exposed trachea injecting SiO2.
Three targets of the rat pulmonary function of the rat models including breathing rate,FEV1/FVC(%) and blood gas analysis (PO2) were significant difference compared with control group. The longer coal dust exposed, the higher breathing rate and the lower FEV1/FVC(%)and the PO2 were observed in the rat models, especially in the later period. All the three targets of the rat pulmonary function were closely correlated with the lung pathology. It confirmed that chronic bronchitis, emphysema with restrictive ventilatory disorder or/and obstructive ventilatory disorder, venting/ blood ratio disturbance and diffusion function dysfunction because of pulmonary interstitial fibrosis leading to alveoli -capillary membrane thickening.
TNF-αand TGF-βconcentration in the bronchoalveolar lavage fluid and TNF-αand TGF-βmRNA express level in the cells of the bronchoalveolar lavage fluid in the rat models was hager than control group(p<0.05). There was positive correlation between the TNF-αand TNF-αmRNA, TGF-βand TGF-βmRNA, these two cytokines and alveolitis, pulmonary fibrosis. It proveed that these two cytokines were very important in the course of CWP disease. Hydroxyproline content in the lung of pneumoconiosis rat models was higher than the control group(p<0.05). The longer coal dust exposed, the higher hydroxyproline content was. There was positive correlation between the hydroxyproline content and pulmonary fibrosis. It proveed that hydroxyproline conten could reflect the fibrous tissue content of the lung and could be a sensitive target reflecting reflect.
The mortality of the CWP models created by non-exposed trachea perfusing coal dust was higher than the CWP models created by coal dust inspiring and the rat of control group. the safe, exact, cheap coal workers Pneumoconiosis (CWP) rat models were successfully made through the non-exposed trachea perfusing coal dust and inspiring coal dust. the non-exposed trachea perfusing coal dust method need better specification, and there are higher dath rate in the models mdae by this method than inspiring coal dust method. to simulate the etiological factor, the invasion environment and the chronic process of the coal workers Pneumoconiosis, the method of inspiring coal dust will be more suitable to researching in this field.
引文
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