Researchs In Interstitial Lung Disease And Its Mechanism Of Autoimmune Inflammatory Myopathies In Lewis Rats

Objectives:1. To improve the autoimmune inflammatory myopathy model in rats; 2. To study the autoimmune inflammatory myopathy with interstitial lung disease in Lewis rats and build a stable rat model; 3. To explore the pathogenesis of interstitial lung disease in Lewis rats with autoimmune inflammatory myopathy; 4. To reveal the expression and function of TRAIL and its receptors in interstitial lung disease of autoimmune inflammatory myopathies in Lewis rats; 5. To explore the effect and its mechanism.of glucocorticoids on interstitial lung disease of autoimmune inflammatory myopathies in Lewis rats.Methods:1. Group the SD rats, Westar rats and Lewis rats under the strain, sex, immune factors and injected with the mixture of rabbit skeletal muscle homogenate and Freund's complete adjuvant several times. Compared the mortality, muscle pathology scores and other indicators of the differences observed between the various groups; 2. Builde up the autoimmune inflammatory myopathies in Lewis rats by injected with the mixture of rabbit skeletal muscle homogenate and Freund's complete adjuvant several times. Observed lung lesions by the methods of the histopathological examination and immunohistochemistry; 3. Detect the expression levels of TGF-β,CTGF, ICAM, VCAM, and CD 163 in lung tissue taken from Lewis rats of autoimmune inflammatory myopathy with interstitial lung disease by immunohistochemical staining and computer image analysis and compared the difference between the control group; 4. Detect the expression levels of TRAIL and its receptors in lung tissue taken from Lewis rats of autoimmune inflammatory myopathy with interstitial lung disease by immunohistochemical staining and computer image analysis and compared the difference between the control group; 5. Comparing the effect of different doses, different starting pointt of glucocorticoid on pulmonary fibrosis score and the expression levels of TGF-β, CTGF, ICAM, VCAM, TRAIL and its receptors in lung tissue of Lewis rat with autoimmune inflammatory myopathy and interstitial lung disease.Results:1.In three lines of rats, Lewis rat model have the highest ratio of success and the lowest ratio of mortality. Female group has higher success rate than the male group at the same dose of muscle homogenates. And the moderate dose of muscle homogenates is the most appropriate choice. Muscle lesions in 4-5 weeks are the most typical; 2. Part of the rats of autoimmune inflammatory myopathies emerged varying degrees of interstitial lung disease and the rate was 68.8%.The typical interstitial lung lesions was alveolar inflammation and interstitial pulmonary interstitial fibrosis. The most common pathological type was non-specific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP). The results of immunohistochemistry staining seen in a large number of CD8+ T in thickened alveolar septa and a large number of CD20+B lymphocytes around bronchial and blood vessels; 3. Immunohistochemistry combined with computer image analysis showed that the expression levels of TGF-β, CTGF, ICAM and VCAM was significantly increased in lung tissues of in the Lewis rats with autoimmune inflammatory myopathy and interstitial lung disease. The number of CD 163 positive cells also increased significantly; 4. Immunohistochemistry combined with computer image analysis showed that the expression levels of TRAIL and DCR1 was significantly increased in lung tissues of in the Lewis rats with autoimmune inflammatory myopathy and interstitial lung disease. The infiltrating lymphocytes in lung tissues have a higher expression of DCR1. Correlation analysis showed that relationship between the degree of lung alveolar inflammation and CD8+T lymphocyte infiltration and that between the degree of lung fibrosis and the expression of TRAIL; 5. High-dose corticosteroids can be effective in reducing pulmonary interstitial fibrosis the Lewis rats with autoimmune inflammatory myopathy and interstitial lung disease. Low-dose corticosteroid was better in early stage. The mechanism may be associated with reduction of the expression of TGF-β, CTGF, ICAM, TRAIL and DR4.Conclusions:1.Female Lewis rats were injected by moderate dose of muscle homogenates for 4-5 weeks can develop a polymyositis rat model that is similar to the human PM, and with the high ratio of success and the low ratio of mortality this model is ideal for research; 2. For the first time, the autoimmune inflammatory myopathies of Lewis rats showed IIM with ILD pathological features, which may be a good experimental tool for relative reserchs.3. Variety of cytokines such as inflammation and fibrosis cytokines may be involved in the occurrence and development of autoimmune inflammatory myopathies with interstitial lung disease in Lewis rat model which may be the new derection of further study and the new targets of therapeutic reserchs.4. The study firstly demonstrates that the features of ILD shown in EAMs were related with the local immune inflammatory response. The changes in the expression of TRAIL and its receptors between EAMs and controls suggest TRAIL-system probably play a role in the pathogenesis and the pathology of IIM with ILD.5. This study demonstrated that corticosteroids can be effective in reducing the pulmonary fibrosis and the expression levels of variety of cytokines in lung tissues, especially low doses used in early stage can achieve the desired therapeutic effect.