The Health Effect Of Occupational Dust And The Effect Of Th1/Th2 Immunity Imbalance In The Pneumoconiosis Pathogenesis

The health effects of long-term exposure to occupational dust including pneumoconiosis, chronic obstructive pulmonary disease, acute and chronic respiratory inflammation, and cancer.Pneumoconiosis is an occupational pulmonary fibrosis disease caused by chronic inhalation and deposition of dust in the lungs. Pneumoconiosis is incurable. Because pulmonary fibrosis is irreversible. Therefore, the researches focus on the pathogenesis of pneumoconiosis.Previous studies showed that the dust that staying in the bronchioles and pulmonary alveolus, macrophages engulfed dust particles and produced many inflammatory mediators and chemokines, which can lead to immune effector cells accumulation, cytokine network imbalance, eventually lead to the lungs or systemic immune dysfunction and persistent lung injury and fibrosis.In this study, we put attention on health effect from occupational dust exposure and the role of Th1/Th2 cells in the developing of pneumoconiosis. The study consists of three parts. First, the health effects from occupational dust exposure. Second, the characteristics and influencing factors of pneumoconiosis among dust-exposed workers. Third, the role of Th1/Th2 immunity imbalance in the pneumoconiosis pathogenesis. PartⅠThe health effects of occupational dust exposureSectionⅠMortality of workers exposed to occupational dust in pottery factoriesThis part was designed to investigate cause-specfic mortality among workers in three pottery factories in Jingdezhen.A cohort of 4828 workers registered in the employment record from 1960 to 1974 in 3 pottery factories in Jingdezhen and employed at least one year was identified. SMRs were calculated based on Chinese national mortality. Trend analysis was used to analyze the effects of cumulative dust exposure on SMRs of main causes of death.All subjects were followed up to the end of 2003 with an accumulation of 128475.76 person-years. A total of 1522 workers died, and the mortality was 1185 per 100,000 person-years. The cumulative mortality was 31.52%. The results showed that malignant neoplasm, cardiovascular diseases, respiratory diseases and pulmonary tuberculosis were main illnesses threatening workers' life span. These four diseases accounted for 72.34% of all deaths. The mortality of all-causes was found to be significantly higher than the national average level. Positive dose-response relationship between SMRs and cumulative dust exposure was observed from all-causes, respiratory diseases, pneumoconiosis and pulmonary tuberculosis. Female workers are 26.66% of all workers. The main disease threaten female workers in porcelain factories were pneumoconiosis, tuberculosis, hypertensive heart disease, genitourinary system diseases.The findings indicated that dust was the main occupational hazard of exposure workers in porcelain industry. Positive dose-response relationship between SMRs and cumulative dust exposure was observed in all-causes, respiratory diseases, pneumoconiosis and pulmonary tuberculosis. SecionⅡThe cause-specific prevelance of workers exposed to occupational dustThis section was designed to understand cause-specific prevelance among workers in pottery factories. The cluster sampling method was to select research subjects for health examination among survivors in above cohort members. The health examination included pulmonary function, electrocardiogram, liver function and many other medical contents, and collected blood samples for blood routine examination. Dust exposure data was assessed in terms of cumulative total dust.A total of 885 workers in three pottery factories of Jingdezhen were studied in this research.Among them,288 workers were non-exposed workers,438 workers were healthy dust exposed but health workers, and 159 workers were pneumoconiosis. The results found that the cumulative incidence of vascular diseases, lung function and ECG abnormalities were significantly higher in the exposed group than those in the non-exposed group. Compared with non-exposed group, the exposed workers had higher blood pressure and triglyceride. Compared with exposed group, the prevelance of COPD and pulmonary tuberculosis were increased among pneumoconiosis cases. We also observed lung function decrease were statistically significant higher in pneumoconiosis group than that in dust exposed group. The precent of lung injury was increased when the the stage of pneumoconiosis developed.The health effects of occupational dust exposure included lung function decrease, ECG abnormalities, and higher blood pressure and triglyceride. The health damage of pneumoconiosis cases included pulmonary tuberculosis, lung functions injury, and BMI decrease. Part II The study of the characteristics and influencing factors of pneumoconiosisThis part was conducted to describe the characteristics of ceramic pneumoconiosis and to explore the factors which influence the incidence of pneumoconiosis among workers at the pottery factories in Jingdezhen city. The results will be used to prevent ceramic pneumoconosis in future. A cohort study was conducted in three pottery factories in Jingdezhen city. The research subjects included all workers employed at least one year during 1960 to 1974. The follow-up was traced up to the end of 2003. The silicosis was diagnosed according to national roentgeno diagnostic criteria of pneumoconiosis by local radiologist group.A total of 2992 dust-exposed workers included in the study. Among them, there were 757 cases were classed to stage 0+ and 587 cases were diagnosed as pneumoconiosis.The incidence of silicosis was 0.5% among dust-exposed workers. The incidence of pneumoconiosis was higher for those start dust exposure between 1950 and 1960, and the age of first diagnosis was mainly from 40 to 60 years old. The latency of pneumoconiosis was 31.7±7.7 years. The average duration of upgrade from stage 0+ toⅠ,ⅠtoⅡ,ⅡtoⅢwas 7.5 years,4.4 years, and 6.9 years respectively. A clear dust exposure-response relation was observed between cumulative exposure to silica and cumulative risk of pneumoconiosis. When cumulative total dust exposure for subject exceed 100 mg/rn3·y, the cumulative risk of silicosis was accelerant increased. Excepted for cumulative exposure, tuberculosis (RR=20.9, p<0.01), smoking amount (RR=1.3, p<0.05), year of first exposure (RR=1.5, p<0.01) and gender (RR=2.0, p<0.01) were main factors influenced the incidence of pneumoconiosis. A total of 902 subjects were included to explore the role of tumor necrosis factor-α(TNF-α)-308 and hOGG1 Ser326Cys gene polymorphism in genetic susceptibility-to pneumoconiosis. Among them, there were 598 were dust-exposed workers, and 157 cases were diagnosed as pneumoconiosis. The risk of pneumoconiosis in subjects with G/A+A/A genotype was 1.9-fold of those with G/G genotype (95%CI:0.7-5.1). The risk of pneumoconiosis for male ceramic workers who smoked higher than 20 pack-y and worked with cumulative dust exposure higher than≥180 mg/m3·y of G/A+A/A genotype were 8.8-fold of workers of G/G genotype.A clear exposure-response relation was detected for pneumoconiosis in Jingdezhen pottery factories. The cumulative exposure, tuberculosis, smoking amount, year of first exposure and gender were the main risk factors to increase incidence of pneumoconiosis. TNF-αgene polymorphism did not play an important role in susceptibility to pneumoconiosis. TNF-αgene polymorphism interacted with cumulative exposure, gender, smoking amount during the process of pneumoconiosis. Compared with pneumoconiosis of other industries, the pneumoconiosis in pottery factories were characterized with relatively long latency, larger proportion of stage 0+ pneumoconiosis and normal upgrade years.PartⅢThl/Th2 immune imbalance in the pathogenesis of pneumoconiosisIn this part, we analysised the relationship between the Th1/Th2 balance and pneumoconiosis. This part was designed as an epidemiological case-control study. The cases were pneumoconiosis patients, the control subjects were healthy coal dust-exposed workers and healthy non-dust-exposed workers. A total of 186 workers who were took medical examination in Taiyuan Shanxi during 2008 and 2009 were included in this study. There were 87 penumoconiosis,56 healthy coal dust-exposed workers,43 healthy non-dust-exposed workers.The lymphocytes from peripheral blood of subjects were collected and then subtype them by flow cytometry method. First, the lymphocytes were tagged by surface molecules CD3-antibody and CD4-antibody, and then they were tagged by intra-cellular Cytokines IL-4-antibody and IFN-γ-antibody. According these tags, we subtyped lymphocytes as CD4, CD8, Th1/Th2 and Tc1/Tc2. Bronchoalveolar lavage fluid (BALF) were collected for pneumoconiosis cases and healthy dust-exposed workers, the concentration of Th1/Th2 cytokines, included IFN-y, IL-2, IL-4, IL-10 and pulmonary surfactant protein SPA and SPD in BALF and plasma were tested by using enzyme-linked immunosorbent assay (ELISA). Then we analyzed of the relationship between the expressions levels of cytokines and pulmonary functions. SectionⅠThe association of Thi/Th2 immune imbalance with pneumoconiosisCompared with non-exposed group, the CD3+ T cells and CD8+ T cells in dust-exposed group were significantly increase, the CD4+ T cells and CD4/CD8 ratio in dust-exposed group were significantly decreased, CD8+ T cells increased significantly, the ratio of Th1/Th2 and the ratio of Tcl/Tc2 in exposed group were significantly decreased. The plasma levels of IL-4 were significantly increased and plasma IL-10 levels were significantly decreased in healthy dust-exposed group in compared with healthy workers.Compared with non-exposed group, the CD3+ T cells and CD8+ T cells in pneumoconiosis were significantly increase, the CD4+T cells and CD4/CD8 ratio in pneumoconiosis were significantly decreased, CD8+ T cells increased significantly, the ratio of Th1/Th2 and the ratio of Tc1/Tc2 in pneumoconiosis were significantly decreased.Compared with dust-exposed group, Th2 cells, Th1 and Tc1 cells was significantly increased among pneumoconiosis cases. The ratio of Thl/Th2 and the ratio of Tcl/Tc2 were no significant difference in dust-exposed group and pneumoconiosis group. The levels of IL-10 in plasma and bronchoalveolar lavage fluid were significantly increased in pneumoconiosis compared with dust-exposed group.These results implied that Th1/Th2 imbalance plays an important role in the development of pneumoconiosis and an obvious Th2 advantage was showed in pneumoconiosis patients.SecionⅡThe association of Th1/Th2 immune imbalance with lung functionWe analyzed the associated lung function and the status of Th1/Th2 among all subjects. The positive correlations were found between the ratios of CD4/CD8, Th1/Th2, Tc1/Tc2 and PEF%, DLco%.The negative correlations were shown between Th2,Tc2 and MVV%, PEF%, DLco%.The positive correlation between IFN-y (Thl cytokine) and VC%, FEV1.0%, MVV% and DLco%There were negative correlation between IL-4 (Th2 cytokine) and VC%, FEVi.o%, MVV% and DLco%, and the correlation coefficient were-0.293,-0.327,-0.329, respectively. There were no significant correlation between cytokines in BALF and in plasma.There was positively correlated between Thl cell and Thl cytokine and lung function, negatively correlated between Th2 cell and Th2 cytokine and lung function.In conclusions, the mortality of the cohort subjects was 1185 per 100,000 person-year, the standardized mortality ratio for all causes was 1.07. Positive dose-response relationship between SMRs and cumulative dust exposure was observed in all-causes, respiratory diseases, pneumoconiosis and pulmonary tuberculosis. A clear exposure-response relation was detected for ceramic pneumoconiosis in Jingdezhen pottery factories. The cumulative exposure, tuberculosis, smoking amount, year of first exposure and gender were the main risk factors to increase incidence of ceramic silicosis. Thl/Th2 imbalance plays an important role in the development of pneumoconiosis and an obvious Th2 advantage was showed in pneumoconiosis patients. There was positively correlated between IFN-y (Thl cytokine) and lung function, negatively correlated between and IL-4 (Th2 cytokine) and lung function.There were limitation in this study. We counld not take physical examination for all cohort members at the end of follow because of fund and some subjects didn't stay in Jingdezhen. The study of Thl/Th2 balance pneumoconiosis was a case control study, it is difficult to determine the order of fibrosis and immune imbalance.