矽肺患者细胞免疫水平及肺功能的相关性研究
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摘要
目的
矽肺是我国目前危害严重、发病率极高的职业病，近年来发病率有明显增加的趋势。这些与以前工业企业对职业病防治意识不够，设备简陋，工作条件差有关。矽肺是由于长期吸入游离二氧化硅粉尘所致的以肺部弥漫性纤维化为主的全身性疾病。最常见的并发症就是肺结核，矽肺的期别愈高，肺结核的合并率愈高。机体对结核的主要免疫保护机制是细胞免疫，体液免疫对控制结核分支杆菌的作用不重要。推测矽肺患者易并发肺结核的原因可能与机体细胞免疫水平变化密切相关。在慢性阻塞性肺病患者中，外周气道中CD_8细胞数量明显增加，与气流受限具有一定相关性。但CD8细胞是否与矽肺患者的肺功能具有相关性，目前国内外尚无报道。本实验通过对矽肺患者及相同条件下健康人群的细胞免疫水平和肺功能进行检测，观察Ⅰ、Ⅱ、Ⅲ期矽肺患者的细胞免疫水平及肺功能状态，并探讨两者间是否存在内在联系。
方法
选取无粉尘及其他毒物接触史，在沈阳市职业病院体检正常的企事业单位退休人员30人作为健康组，年龄在60岁—75岁之间；选取在沈阳市职业病院目前收治的矽肺患者50人作为矽肺组，年龄在60岁—75岁之间，按照国家制定的《尘肺病诊断标准(GBZ70-2002)》由沈阳市职业病诊断组确诊为矽肺，其中Ⅰ期矽肺30人、Ⅱ期矽肺12人、Ⅲ期矽肺8人。通过流式细胞仪检测外周血中T淋巴细胞亚群；通过肺功能检测矽肺患者大小气道通气功能。
结果
1．矽肺患者CD_4、CD_8及CD_4／CD_8与正常组的比较，将Ⅰ期矽肺组(35人)、Ⅱ期矽肺组(12人)和Ⅲ期矽肺组(8人)共计50人与健康组30人共同进行比较。矽肺组的CD4百分数较健康组明显下降，CD8百分数较健康组明显上升，CD4／CD8比值较健康组明显下降，以上三组数据比较均有显著性差异(P＜0.05)。随着矽肺期别的增加，CD4百分数逐渐下降，CD8百分数逐渐升高，CD4／CD8比值也逐渐降低，但以上三个组间变化无显著性差异(P＞0.05)。2．各组间肺功能的比较。用力肺活量(FVC)、第1秒用力呼气量(FEV1)、第1秒用力呼气量占预计值的百分比(FEV1％)及75％肺活量时最大用力呼气流速占预计值的百分比(V75％)均是反映大气道通气功能情况的肺功能指标，FVC＞80％预计值为正常，FEW1＞80％预计值为正常，正常FEV1％＞80％，正常V75％＞70％。Ⅰ期矽肺组中FEV1％和V75％均在正常范围，提示大气道通气功能正常，而Ⅱ期矽肺组和Ⅲ期矽肺组中FEV1％和V75％明显低于正常值范围，并且与Ⅰ期矽肺组比较具有显著性差异(P＜0.05)，Ⅱ期矽肺组和Ⅲ期矽肺组间以上数值差异不明显(P＞0.05)。50％肺活量时最大用力呼气流速占预计值的百分比(V50％)、25％肺活量时最大用力呼气流速占预计值的百分比(V25％)均是反映小气道通气功能情况的肺功能指标，正常V50％＞70％，正常V25％＞70％。三组中V50％和V25％均低于正常范围，提示三组患者均存在小气道通气功能障碍，Ⅱ期矽肺组和Ⅲ期矽肺组以上数值明显低于Ⅰ期矽肺组，该差异具有显著性意义(P＜0.05)，Ⅱ期矽肺组和Ⅲ期矽肺组间以上数值差异不明显(P＞0.05)。3．CD4细胞百分比、CD8细胞百分比及CD4／CD8与肺功能的相关性分析：根据两变量服从二元正态分布，外周血CD4细胞百分比、CD8细胞百分比及CD4／CD8与肺功能大小气道的主要指标第1秒用力呼气量占预计值的百分比、50％肺活量时最大用力呼气流速占预计值的百分比、25％肺活量时最大用力呼气流速占预计值的百分比用公式推算相关系数，直线相关分析结果提示50％肺活量时最大用力呼气流速占预计值的百分比与CD8细胞百分比呈显著负相关(r=-0.456，P＜0.01)，与CD4细胞百分比呈显著正相关(r=0.448，P＜0.01)，与CD4／CD8比值呈显著正相关(r=0.492，P＜0.01)；25％肺活量时最大用力呼气流速占预计值的百分比与CD8细胞百分比呈显著负相关(F=-0.571，P＜0.01)，与CD4细胞百分比呈显著正相关(r=0.527，P＜0.01)，与CD4／CD8比值呈显著正相关(r=0.535，P＜0.01)。
结论
矽肺患者CD4百分数、CD4／CD8比值较健康组明显下降，而CD8百分数明显上升，提示其细胞免疫水平明显下降，推测肺结核的发病率增加可能与此有关；随着矽肺期别的增加，肺功能的各项指标也均有下降趋势，矽肺患者外周血T淋巴细胞亚群可能对其肺功能具有一定影响，CD8+T淋巴细胞对矽肺患者可能具有加重小气道通气功能障碍的作用。
Purpose
In our courtry,silicosis is the most serious occupational disease,it has a highmorbidity nate,with a tendency to rise in recent years.Mary factors such as, lessprecaution against occupational disease, from the factory, simple and crudeequipments, bad working conditions must have something to do with it. Silicosis issystemic disease with obciously extensive fibrosis in the lung after long time in hale offree silicon dioxide dust. Pulmonary tuberculosis is the most commomcomplication, the higher stage of silicosis, the higher morbidity of tuberculosis. Inhuman, bodies, the main immune mechanism against tuberculosis is cellularimmunity, humoral immunity has less impact on mycobacterium tuberculosis. So wecan see the change of cellular immunity in humman bodies may has an intensiverelationship with occurance of tuberculosis for silicosis patients. For COPDpatients'number of CD8 cellsincreases significantly in peripheral airways. it has somerelation with airflow vestriction. There is no reports in an abroad on relation betweenCD8 cells and pulmonary function of silicosis patiens. In this experiment, we testseparately cellular immunity level and pulmonary function of silicosis patiens andhealthy people, observe cellular immunity level and pulmonary function ofⅠ,Ⅱ,Ⅲstage silicosis patients, then oliscuss the relation between them.
Method
Choose 30 retired persons whose health examination are normal in ShenYangoccupational disease hospital, with no dust and other toxicants contact history, and age beween 60 to 75 to be healthy group. Choose 50 silicosis patients in ShenYangoccupational disease hospital to be silicosis group, age between 60 to 75 whose diseasediagnoseal according to country silicosis Diagnostic Standard (GBZ70-2002).Ⅰstage:30 persons,Ⅱstage:12 persons;Ⅲstage :8 persons. Test lymphocytesubgroup with flow cytometry (FCM) instrument; evaluate large and small airwayfunction by testing pulmonary function.
Results
Make comparison about CD4 lymphocyte, CD8 lymphocyte and ratio of CD4 toCD8 of silicosis patients:Ⅰstage:30 persons,Ⅱstage:12 persons;Ⅲstage :8persons, sum to 50 persons and 30 persons in healthy group, CD4 lymphocytepercentage decreases significantly compared with healthy group. CD8 lymphocytepercentage increases significantly compared with healthy group, and ratio of CD4 toCD8 decreases significantly. Difference of each group is significant, p＜0.05.With theincrease of silicosis stages. CD4 lymphocyte percentage increases gradually. There isno significant difference among the 3 stage groups (p＜0.005). Make comparison aboutpulmonary function among the 3 stage groups. FVC, FEV1, FEV1% and V75% all canreflex ventilation function of large airways. FVC＞80% estimuate number isnormal. FEV1＞80% estimuate number is normal. Normal FEV1%＞80%, normalV75%＞70%.Ⅰstage in silicosis group, FEV1% and V75% numbers are in normallimits, it means large airway function is normal, whileⅡ,Ⅲstage in silicosisgroup, FEV1% and V75% numbers are lower significant difference withⅠstage(p＜0.05), but there is no significant difference betweenⅡandⅢstagegroups(p＞0.05). V50%, V25% both can reflex ventilation function of smallairway. Normal V50%＞70%, normal V25%＞70%. In all theⅠ,Ⅱ,Ⅲstage, V50% andV25% numbers are both lower than normal limit numbers, it shows that patients ofthe 3 three groups have vertilation dysfunction in their small airways. Correlationanalysis of CD4 lymphocyte percentage, CD8 lymphocyte percentage, ratio of CD4 toCD8 and pulmonary function according to the two variable quantities comply with bivariate normal distribution, presults of CD4 percentage, CD8 percentage ratio of CD4to CD8, FEV1、V50% and V25% analized by related modulus formula calculation andstraight line correlation analysis show that:V50 has a negative relation with CD8percentage (r=-0.456,p＜0.01), V50 has a positive relation with CD4 percentage(r=0.448,p＜0.01), V50 has a positive relation with CD4/CD8(r=0.492,p＜0.01);V25%has a negative relation with CD8 (r=-0.571,p＜0.01),V25% has a positive relation withCD4(r=0.537,p＜0.01),V25 has a positive relation with CD4/CD8 (r=0.535,p＜0.01).
Results
CD4 percentage ratio of CD4 to CD8 of silicosis patients decrease significantlycompare with healthy group,while CD8 percentage increases significantly, it showsthat patients' cellular immunity level decreases obviously, which we can speculate hassomething to do with the increase of pulmonary tuberculosis morbidity; With theincrease of pulmonary tuberculosis morbidity; With the increase of silicosis stagespulmonary functions indexes show a decrease tendency. Peripheral T lymphocytesubgroups of silicosis patients have certain influence to pulmonary function, CD8 Tlymphocyte has negative effect on ventilation function of small airway.
矽肺是我国目前危害严重、发病率极高的职业病，近年来发病率有明显增加的趋势。这些与以前工业企业对职业病防治意识不够，设备简陋，工作条件差有关。矽肺是由于长期吸入游离二氧化硅粉尘所致的以肺部弥漫性纤维化为主的全身性疾病。最常见的并发症就是肺结核，矽肺的期别愈高，肺结核的合并率愈高。机体对结核的主要免疫保护机制是细胞免疫，体液免疫对控制结核分支杆菌的作用不重要。推测矽肺患者易并发肺结核的原因可能与机体细胞免疫水平变化密切相关。在慢性阻塞性肺病患者中，外周气道中CD_8细胞数量明显增加，与气流受限具有一定相关性。但CD8细胞是否与矽肺患者的肺功能具有相关性，目前国内外尚无报道。本实验通过对矽肺患者及相同条件下健康人群的细胞免疫水平和肺功能进行检测，观察Ⅰ、Ⅱ、Ⅲ期矽肺患者的细胞免疫水平及肺功能状态，并探讨两者间是否存在内在联系。
方法
选取无粉尘及其他毒物接触史，在沈阳市职业病院体检正常的企事业单位退休人员30人作为健康组，年龄在60岁—75岁之间；选取在沈阳市职业病院目前收治的矽肺患者50人作为矽肺组，年龄在60岁—75岁之间，按照国家制定的《尘肺病诊断标准(GBZ70-2002)》由沈阳市职业病诊断组确诊为矽肺，其中Ⅰ期矽肺30人、Ⅱ期矽肺12人、Ⅲ期矽肺8人。通过流式细胞仪检测外周血中T淋巴细胞亚群；通过肺功能检测矽肺患者大小气道通气功能。
结果
1．矽肺患者CD_4、CD_8及CD_4／CD_8与正常组的比较，将Ⅰ期矽肺组(35人)、Ⅱ期矽肺组(12人)和Ⅲ期矽肺组(8人)共计50人与健康组30人共同进行比较。矽肺组的CD4百分数较健康组明显下降，CD8百分数较健康组明显上升，CD4／CD8比值较健康组明显下降，以上三组数据比较均有显著性差异(P＜0.05)。随着矽肺期别的增加，CD4百分数逐渐下降，CD8百分数逐渐升高，CD4／CD8比值也逐渐降低，但以上三个组间变化无显著性差异(P＞0.05)。2．各组间肺功能的比较。用力肺活量(FVC)、第1秒用力呼气量(FEV1)、第1秒用力呼气量占预计值的百分比(FEV1％)及75％肺活量时最大用力呼气流速占预计值的百分比(V75％)均是反映大气道通气功能情况的肺功能指标，FVC＞80％预计值为正常，FEW1＞80％预计值为正常，正常FEV1％＞80％，正常V75％＞70％。Ⅰ期矽肺组中FEV1％和V75％均在正常范围，提示大气道通气功能正常，而Ⅱ期矽肺组和Ⅲ期矽肺组中FEV1％和V75％明显低于正常值范围，并且与Ⅰ期矽肺组比较具有显著性差异(P＜0.05)，Ⅱ期矽肺组和Ⅲ期矽肺组间以上数值差异不明显(P＞0.05)。50％肺活量时最大用力呼气流速占预计值的百分比(V50％)、25％肺活量时最大用力呼气流速占预计值的百分比(V25％)均是反映小气道通气功能情况的肺功能指标，正常V50％＞70％，正常V25％＞70％。三组中V50％和V25％均低于正常范围，提示三组患者均存在小气道通气功能障碍，Ⅱ期矽肺组和Ⅲ期矽肺组以上数值明显低于Ⅰ期矽肺组，该差异具有显著性意义(P＜0.05)，Ⅱ期矽肺组和Ⅲ期矽肺组间以上数值差异不明显(P＞0.05)。3．CD4细胞百分比、CD8细胞百分比及CD4／CD8与肺功能的相关性分析：根据两变量服从二元正态分布，外周血CD4细胞百分比、CD8细胞百分比及CD4／CD8与肺功能大小气道的主要指标第1秒用力呼气量占预计值的百分比、50％肺活量时最大用力呼气流速占预计值的百分比、25％肺活量时最大用力呼气流速占预计值的百分比用公式推算相关系数，直线相关分析结果提示50％肺活量时最大用力呼气流速占预计值的百分比与CD8细胞百分比呈显著负相关(r=-0.456，P＜0.01)，与CD4细胞百分比呈显著正相关(r=0.448，P＜0.01)，与CD4／CD8比值呈显著正相关(r=0.492，P＜0.01)；25％肺活量时最大用力呼气流速占预计值的百分比与CD8细胞百分比呈显著负相关(F=-0.571，P＜0.01)，与CD4细胞百分比呈显著正相关(r=0.527，P＜0.01)，与CD4／CD8比值呈显著正相关(r=0.535，P＜0.01)。
结论
矽肺患者CD4百分数、CD4／CD8比值较健康组明显下降，而CD8百分数明显上升，提示其细胞免疫水平明显下降，推测肺结核的发病率增加可能与此有关；随着矽肺期别的增加，肺功能的各项指标也均有下降趋势，矽肺患者外周血T淋巴细胞亚群可能对其肺功能具有一定影响，CD8+T淋巴细胞对矽肺患者可能具有加重小气道通气功能障碍的作用。
Purpose
In our courtry,silicosis is the most serious occupational disease,it has a highmorbidity nate,with a tendency to rise in recent years.Mary factors such as, lessprecaution against occupational disease, from the factory, simple and crudeequipments, bad working conditions must have something to do with it. Silicosis issystemic disease with obciously extensive fibrosis in the lung after long time in hale offree silicon dioxide dust. Pulmonary tuberculosis is the most commomcomplication, the higher stage of silicosis, the higher morbidity of tuberculosis. Inhuman, bodies, the main immune mechanism against tuberculosis is cellularimmunity, humoral immunity has less impact on mycobacterium tuberculosis. So wecan see the change of cellular immunity in humman bodies may has an intensiverelationship with occurance of tuberculosis for silicosis patients. For COPDpatients'number of CD8 cellsincreases significantly in peripheral airways. it has somerelation with airflow vestriction. There is no reports in an abroad on relation betweenCD8 cells and pulmonary function of silicosis patiens. In this experiment, we testseparately cellular immunity level and pulmonary function of silicosis patiens andhealthy people, observe cellular immunity level and pulmonary function ofⅠ,Ⅱ,Ⅲstage silicosis patients, then oliscuss the relation between them.
Method
Choose 30 retired persons whose health examination are normal in ShenYangoccupational disease hospital, with no dust and other toxicants contact history, and age beween 60 to 75 to be healthy group. Choose 50 silicosis patients in ShenYangoccupational disease hospital to be silicosis group, age between 60 to 75 whose diseasediagnoseal according to country silicosis Diagnostic Standard (GBZ70-2002).Ⅰstage:30 persons,Ⅱstage:12 persons;Ⅲstage :8 persons. Test lymphocytesubgroup with flow cytometry (FCM) instrument; evaluate large and small airwayfunction by testing pulmonary function.
Results
Make comparison about CD4 lymphocyte, CD8 lymphocyte and ratio of CD4 toCD8 of silicosis patients:Ⅰstage:30 persons,Ⅱstage:12 persons;Ⅲstage :8persons, sum to 50 persons and 30 persons in healthy group, CD4 lymphocytepercentage decreases significantly compared with healthy group. CD8 lymphocytepercentage increases significantly compared with healthy group, and ratio of CD4 toCD8 decreases significantly. Difference of each group is significant, p＜0.05.With theincrease of silicosis stages. CD4 lymphocyte percentage increases gradually. There isno significant difference among the 3 stage groups (p＜0.005). Make comparison aboutpulmonary function among the 3 stage groups. FVC, FEV1, FEV1% and V75% all canreflex ventilation function of large airways. FVC＞80% estimuate number isnormal. FEV1＞80% estimuate number is normal. Normal FEV1%＞80%, normalV75%＞70%.Ⅰstage in silicosis group, FEV1% and V75% numbers are in normallimits, it means large airway function is normal, whileⅡ,Ⅲstage in silicosisgroup, FEV1% and V75% numbers are lower significant difference withⅠstage(p＜0.05), but there is no significant difference betweenⅡandⅢstagegroups(p＞0.05). V50%, V25% both can reflex ventilation function of smallairway. Normal V50%＞70%, normal V25%＞70%. In all theⅠ,Ⅱ,Ⅲstage, V50% andV25% numbers are both lower than normal limit numbers, it shows that patients ofthe 3 three groups have vertilation dysfunction in their small airways. Correlationanalysis of CD4 lymphocyte percentage, CD8 lymphocyte percentage, ratio of CD4 toCD8 and pulmonary function according to the two variable quantities comply with bivariate normal distribution, presults of CD4 percentage, CD8 percentage ratio of CD4to CD8, FEV1、V50% and V25% analized by related modulus formula calculation andstraight line correlation analysis show that:V50 has a negative relation with CD8percentage (r=-0.456,p＜0.01), V50 has a positive relation with CD4 percentage(r=0.448,p＜0.01), V50 has a positive relation with CD4/CD8(r=0.492,p＜0.01);V25%has a negative relation with CD8 (r=-0.571,p＜0.01),V25% has a positive relation withCD4(r=0.537,p＜0.01),V25 has a positive relation with CD4/CD8 (r=0.535,p＜0.01).
Results
CD4 percentage ratio of CD4 to CD8 of silicosis patients decrease significantlycompare with healthy group,while CD8 percentage increases significantly, it showsthat patients' cellular immunity level decreases obviously, which we can speculate hassomething to do with the increase of pulmonary tuberculosis morbidity; With theincrease of pulmonary tuberculosis morbidity; With the increase of silicosis stagespulmonary functions indexes show a decrease tendency. Peripheral T lymphocytesubgroups of silicosis patients have certain influence to pulmonary function, CD8 Tlymphocyte has negative effect on ventilation function of small airway.
引文
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2 郑荣梁：自由基生物学[M]．北京：高等教育出版社，1992．23—27．
3 何凤生：中华职业医学[M]．北京：人民卫生出版社，1999．812—813．
4 Poter DW, millecchia L, Robinson VA, et al. Enhanced nitric oxide and reactive oxygen species productions and damage after inhalation of silica [J]. Am J Physiol Lung Cell Mol Physiol, 2002, 283: LA85—493.
5 Fredetzky A, Grau V, Wieckenberg M, et al. Long term iNOS expression in thoracic lymph nodes of silicofic rats[J].Immunobiology, 2002,205:219—230.
6 王穆兰，刚葆琪．现代劳动卫生学[M]．北京：人民卫生出版社，1994．64—65．
7 张琪风，张群卫．尘肺病变对BAL排出物影响的实验研究[J]．工业卫生与职业病，1995，21(5)：266—268．
8 Caotranova V, Porter D, millecchia L, et al. Effect of inhaled crystalline silica in a rat modle: time course of pulmonary reactions [J]. Mol Cell Belchem, 2002, 234—235, 177—184.
9 杨青：大鼠矽肺BALF中DPPC与Ⅱ型细胞改变关系的研究[J]．中国工业医学杂志，1995，8(6)：324—325．
10．谢尔凡，杨宗诚．吸入尘粒对肺表面活性物质系统的作用[J]．中华预防医学杂志，1995，29(2)：108—110．
11 张尚明．羟自由基对人胚成纤维细胞的体外作用[J]．卫生研究，1994，23(4)：24—26．
12 George A. Modulation of fibroblast proliferation by oxygen free radical [J]. Biochem J. 1990, 265: 659—660.
13 陈元秀，等．[J]．生物化学杂志，1991，7：447—450．
14 陈亚萍，等．[J]．生物化学杂志，1993，9：65—69．
15 Kovacs E J, et al. [J]. Obstet Gynecol,1993,83:29—36.
16 Sunderkotter C, et al. [J].J Leukocyto Biol, 1994, 55: 410—422.
17 Battegay EJ, et al. [J]. Cell, 1990, 63: 515—524.
18 Piguet PF, et al. [J]. Cytokines,1993, 5: 57—61.
19 PiguetPF, et al. [J] .Nature, 1990,344(15):245- 247.
20 Varga J, et al. [J] .Ear J Clin Invest, 1990,20: 487-493.
21 KhaliltN.et al. [J] J Clin Invest,1993,92:1812-1818.
22 Denis M . [J] .Immunol, 1994,82(4):584-590.
23 Erin M C,Douglas PL,Berran Y, et al .Significance of genetic information in risk assessment and individual classification using silicosis as a case (J) .Ann OccupHyg,2002,46(4):375-381.
24 Koskinen H,Tiilikainen A,Nordman H. Increased prevalence of HLA-Aw19 and of the phenogroup Aw19,B18 in advanced silicosis (J) .Chest, 1983,83(6):848-852.
25 Rihs HP, Lipps P,May-Taube K, et al. Immunogenetic studies on HLA-DR in German coal miners with and without coal worker's pneumoconisis (J) .Lung,1994,172(6):347-354.
26 Yucesoy B,Vallyathan V,Landsittel DP,et al.Association of tumor necrosis factor -alpha and interleukin-1 gene polymorphisms with silicosis ( J ) .Toxicol Appl Pharmacol,2001,172( 1 ):75-82.
27 Corbett EL,Mozzato-Chamay N,Butterworth AE,et al.Polymorphisms in the tumor necrosis factor-alpha gene promoter may predispose to severe silicosis in black South African miners (J) .Am J Respir Crit Care Med,2002,165(5):690-693.
28 Mcmanus R,Wilson AG,Mansfield J, et al .TNF2,a poly morphism of the tumor necrosis-alpha gene promoter,is a component of the celiac disease major histocompatibility complex haplo type (J) .Eur J Immunol, 1996,26(9):2113-2118.
29 Yucesoy B.Vallyathan V,Landsittel DP,et al.Polymorphisms of the IL-1 gene complex in coal miners with silicosis (J) .Am J Ind Med,2001,39(3):286-291.
30 Baron R,Silverman ES,Grasemann H,et al. DNA sequence variants of the platelet-derived growth factor A-chain gene (J) .Cli Exp Aller,2001,31(10):1501-1508.
2 朱元钰，陈文彬．呼吸病学．北京：人民卫生出版社，2003．
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5 贾斌、徐爱霞，矽肺合并肺结核42例分析．职业与健康，2004年7月第20卷第7期．
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1 常家庆，夏来顺，程嘉瑾，汤永勇，矽肺发病机制与治疗．预防医学情报杂志1997年第13卷第4期．
2 郑荣梁：自由基生物学[M]．北京：高等教育出版社，1992．23—27．
3 何凤生：中华职业医学[M]．北京：人民卫生出版社，1999．812—813．
4 Poter DW, millecchia L, Robinson VA, et al. Enhanced nitric oxide and reactive oxygen species productions and damage after inhalation of silica [J]. Am J Physiol Lung Cell Mol Physiol, 2002, 283: LA85—493.
5 Fredetzky A, Grau V, Wieckenberg M, et al. Long term iNOS expression in thoracic lymph nodes of silicofic rats[J].Immunobiology, 2002,205:219—230.
6 王穆兰，刚葆琪．现代劳动卫生学[M]．北京：人民卫生出版社，1994．64—65．
7 张琪风，张群卫．尘肺病变对BAL排出物影响的实验研究[J]．工业卫生与职业病，1995，21(5)：266—268．
8 Caotranova V, Porter D, millecchia L, et al. Effect of inhaled crystalline silica in a rat modle: time course of pulmonary reactions [J]. Mol Cell Belchem, 2002, 234—235, 177—184.
9 杨青：大鼠矽肺BALF中DPPC与Ⅱ型细胞改变关系的研究[J]．中国工业医学杂志，1995，8(6)：324—325．
10．谢尔凡，杨宗诚．吸入尘粒对肺表面活性物质系统的作用[J]．中华预防医学杂志，1995，29(2)：108—110．
11 张尚明．羟自由基对人胚成纤维细胞的体外作用[J]．卫生研究，1994，23(4)：24—26．
12 George A. Modulation of fibroblast proliferation by oxygen free radical [J]. Biochem J. 1990, 265: 659—660.
13 陈元秀，等．[J]．生物化学杂志，1991，7：447—450．
14 陈亚萍，等．[J]．生物化学杂志，1993，9：65—69．
15 Kovacs E J, et al. [J]. Obstet Gynecol,1993,83:29—36.
16 Sunderkotter C, et al. [J].J Leukocyto Biol, 1994, 55: 410—422.
17 Battegay EJ, et al. [J]. Cell, 1990, 63: 515—524.
18 Piguet PF, et al. [J]. Cytokines,1993, 5: 57—61.
19 PiguetPF, et al. [J] .Nature, 1990,344(15):245- 247.
20 Varga J, et al. [J] .Ear J Clin Invest, 1990,20: 487-493.
21 KhaliltN.et al. [J] J Clin Invest,1993,92:1812-1818.
22 Denis M . [J] .Immunol, 1994,82(4):584-590.
23 Erin M C,Douglas PL,Berran Y, et al .Significance of genetic information in risk assessment and individual classification using silicosis as a case (J) .Ann OccupHyg,2002,46(4):375-381.
24 Koskinen H,Tiilikainen A,Nordman H. Increased prevalence of HLA-Aw19 and of the phenogroup Aw19,B18 in advanced silicosis (J) .Chest, 1983,83(6):848-852.
25 Rihs HP, Lipps P,May-Taube K, et al. Immunogenetic studies on HLA-DR in German coal miners with and without coal worker's pneumoconisis (J) .Lung,1994,172(6):347-354.
26 Yucesoy B,Vallyathan V,Landsittel DP,et al.Association of tumor necrosis factor -alpha and interleukin-1 gene polymorphisms with silicosis ( J ) .Toxicol Appl Pharmacol,2001,172( 1 ):75-82.
27 Corbett EL,Mozzato-Chamay N,Butterworth AE,et al.Polymorphisms in the tumor necrosis factor-alpha gene promoter may predispose to severe silicosis in black South African miners (J) .Am J Respir Crit Care Med,2002,165(5):690-693.
28 Mcmanus R,Wilson AG,Mansfield J, et al .TNF2,a poly morphism of the tumor necrosis-alpha gene promoter,is a component of the celiac disease major histocompatibility complex haplo type (J) .Eur J Immunol, 1996,26(9):2113-2118.
29 Yucesoy B.Vallyathan V,Landsittel DP,et al.Polymorphisms of the IL-1 gene complex in coal miners with silicosis (J) .Am J Ind Med,2001,39(3):286-291.
30 Baron R,Silverman ES,Grasemann H,et al. DNA sequence variants of the platelet-derived growth factor A-chain gene (J) .Cli Exp Aller,2001,31(10):1501-1508.