IGF-1在类风湿关节炎发病中作用机制的探讨
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摘要
前言
类风湿关节炎(Rheumatoid Arthritis，RA)是一种以关节组织慢性炎症性病变为主要表现的自身免疫性疾病，常伴有系统性血管炎的改变。众多的炎性细胞因子参与了疾病的病理过程，其中肿瘤坏死因子(Tumor Necrosis Factor-α，TNF-α)和白细胞介素-1(Interleukin-1，IL-1)被公认为是介导类风湿关节炎发生发展，造成滑膜损害和组织破坏的主要因素。胰岛素样生长因子(Insulin-like Growth Factor，IGFs)是一类结构上类似胰岛素原的多肽，在细胞的生长、分化及代谢的调节中起重要作用。体内几乎所有免疫细胞均存在IGF-1受体，对IGF-1的刺激产生反应。在RA的进展过程中，常存在周身脏器的受累，故推测IGF-1可能在RA的发病中特别是在伴有系统性损害的患者中起到相应的作用。本实验通过酶联免疫吸附法检测了RA患者血清IGF-1的水平，并分析其与血清TNF-α及其它化验指标之间的相互关系，探讨其在RA特别是在伴有系统性病变中的作用，为揭示RA的病因及拓展新的治疗途径提供一些新的思路。
材料与方法
RA患者39例，根据外周血中血小板数量分为血小板增高组及血小板正常组。选择20例参加健康体检的正常人作为正常对照组，两组性别、年龄之间具有可比性。试验组全部患者均采集清晨空腹静脉血3毫升，离心后取上清，保存于-80℃冰箱同批检测，血清IGF-1水平及TNF-α水平测定采用双抗体夹心ELISA法，同时采血测定肝功，血常规，血沉，免疫球蛋白，凝血三项，蛋白
电泳等相关指标。实验数据采用R。S表示，组间差异性比较应用
SPSS统计处理软件进行t检验及直线相关分析。
结 果
一sA患者血清 IGF—且平均水平为 102．66 t 83．85 ＂g／Inl，
明显高于对照组 37．46。74．08ng／Inl，p＝0．005＜0．of，其血小板
升高组（132．17。80．7In牙Inl）较血小板正常组（7．62。78．69n牙
Inl）及对照组血清IGF八平均水平明显升高，p＜0．05，血小板正
常组血清IGF一二平均水平与正常对照组比没有显著差异。
二、RA患者血清规F－a平均水平为1．15土0．妇n牙d，明
显高于对月组 0．27 i 0．olong／llilP一口．001＜0．of，有显著差异。
其血小板升高组血清 TNF一口水平 l．34。0．30n牙M血小板正常
组血清 TNF－a平均水平0 96 t 0．46n吵Inl，两者与正常对照组相
＊均有显著差异，P＝0．见二＜0．of。
5、RA患者血清mF—l水平与其血清TNF—Q水平呈显著
正相关，r＝0．521，P＝0．001＜0．01。
四、RA患者其他的与本实验相关指标的分析显示血清
IGF一水平与凝血酶原时间相关；血清TNF—口与血沉、血小板
数、a。一球蛋白呈显著正相关，p分别为0·036＜0·05；0·004＜
0．01；0．019＜0．05。
五、在39例RA患者中，进行常规胸部X一线检查者共34例，
其中经肺超薄CT及肺功能等进一步检查证实出现肺间质性改变
者共13 例，占38．2呢，其血清IGF－1水平为155．4。98．50
＂g／Inl，与不伴肺间质病变者相比 p＝0．off＜0．05，与正常对照组
相比较，P＝0．001＜0刀1，均有显著差异；其血清＊＊F－a水平为
1．22。0．57fig／all，与无肺间质病变者相比 P＝0．408＞0．05，而两
者与正常对照组相比较小均小于0．01，存在显著性差异。
·2·
六、将 RA患者按病程分为小于等于 24个月和大于 24个月
两组。前者血清 IGF一呈水平门31．05 t 84．78ng／Inl）较后者
（7．75。69．77fig／Inl）明显增才，P二 0．029＜0．05，h者有统计学
差异；而血清TNF一口水平则与病程无明显相关。
讨 论
RA是一组以累及周围关节为主的多系统炎症性的自身免疫
性疾病，系统性血管炎的出现常常成为影响预后的重要因素。RA
患者体内持续存在的自身免疫反应是其发病和病情迁延的中心环
节。现已知多种细胞因子参与了RA的病变过程，其中TNF－a
是研究较多的细胞因子，是启动炎症反应的关键细胞因子，在产生
RA的滑膜炎及周身病变的细胞因子网络中发挥重要作用。它除
了抑制基质中大分子物质合成外，对内皮细胞活化、血管增生、纤
维化、巨噬细胞激活等均起到促进作用。近年相关研究证实
IGF－1作为一种极其活跃的细胞因子参与了神经再生，骨的生
长、修复、改建，烧伤组织的修复，免疫系统的功能，糖尿病，肾间质
性疾病及肿瘤的发生发展过程。由于IGF一互受体可在几乎所有
兔疫细胞上表达，故推测IGF一二在RA的系统病变的发病中可能
起到相应的作用。已有相关报道显示在正常的血管内膜下组织有
IGF则 表达，特别在生长的血管、损伤动脉的再生内皮细胞
中显著增高。IGF－1能促进血管壁损伤后的血管平滑肌细胞的
增殖和迁移反应，刺激血管平滑肌细胞肥大并分泌细胞外基质。
血小板升高在RA患者中常提示疾病处于活动期，且往往同时合
并有血管炎的存在。凝血酶原时间是反映外源性凝血途径的常用
筛选试验之一。本实验结果显示血清IGF－l在RA特别是血小
板升高患者中有明显增高趋势且与凝血
Rheumatoid arthritis ( RA) is a heterogenous disease, which is characterized by symmetrical multiarthritis in clinic and is a progressive invasive autoimmune disease with systemic vasculitis usually. At prsent, studies have proved RA has obvious relationship with the net of immune regulation. As pre - inflammatory factors, TNF - acan increase the functions of neutrophils and eosinophils and make them produce superoxide and release Lyososome, inducing expression of other cellular factors and inflammatory factors. TNF - ais one of important nosogenetic factors of RA. Insulin - like Growth Factor - 1 (IGF - 1) is a kind of polypeptid, which has similar structure to insulinogen. It plays an important role in development, differentiation and metabolism of cells. Recently, some studies had make sure that IGF - 1 and IGF-2 expressed in different develop stage of many tissue cells. In vivo, IGF ?1 receptors almost exists all of immune cells, which reflects on stimulation of IGF - 1, So it conferred that IGF - 1 pla
yed some kind of role in RA, especially in the patients with systemic pathological changes. This experiment examined serum IGF - 1 and TNF - a in RA by ELISA and analyzed the relationship between them and other indexes, approached the role of them in RA, especially with systematic pathological changes and offered some new thoughtfulness for posting the pathogeny and exploiting new therapeutic means of RA.
Method
Selected 39RA patients, divided them into high -platelet group and normal - platelet group according to the amount of platelets in pe-ripherol blood. Selected 20 healthy people as control group, age and gender have no difference from patients group. The patients in experimental group were sampled 3ml vein blood of limosis in early morning, collected super serum after centrifugation and keeped in ?0^ in refrigeratory and measuring in the same term. At the same time, examined liver function, blood routine, erythrocyte sedimentation rate, immunoglobulins, coagulant three items, protein electrophoresis et al and analyzed by ELISA. Experimental data was dealed with SPSS and done t ?test and relativity analysis. Its results were expressed by x±s.
Results
1. Serum level of IGF - 1 in RA patients is 102. 66 ±83. 85ng/ ml, 37.46 ±74. 08ng/ml in control. IGF - 1 in RA group was higher than that of control group ( p = 0. 005 < 0. 01). In RA group, IGF - 1 in high - platelet group was higher than that of normal - platelet group (p = 0. 03 < 0. 05 ) and control group ( p < 0. 01). There is no obvious difference between normal ?platelet group and control group.
2. serum TNF - am RA group is 1. 15 ±0. 43ng/ml, which is greatly higher than that of control group (0. 27 ±0. 10ng/ml) ,p < 0.01. In RA group, serum TNF - aand IGF - 1 showed an remarkably positive correlation, r = 0. 521 p = 0. 001 < 0. 01.
3. In the analysis of other relative indexes in RA group, serum IGF - 1 had relationship with prothrombin time, serum TNF - a, ESR, amount of platelet and a.2 - globulin showed a positive correlation . 34 patients were examined by X - ray chest in RA group. 13 of them proved to be pulmonary interstitial pathological changes 38. 2% , IGF- 1 in them is 155. 4 ±98. 50ng/ml and compared with control group,p = 0. 001 < 0. 01; TNF - am them was 1. 22 ± 0. 57ng/ml, compared with control group p =0.003 <0.01.
4. RA patients were divided into two groups according to the course of disease; one group was less than 2 years, the anthor was more than 2 years. Serum level of IGF - 1 in short - course group was greatly higher than that of the other group, p =0. 029 <0. 05, which was statistical difference.
Disscussion
RA is an autoimmune disease, which is multisystem inflammation involved peripheral arthritis and systemic vaculitis often influenced its prognosis. At the present, we have known that many cellular factors took part in pathological process of RA, TNF - awas studied more widely, called pre - inflammatory factors and was vital cellular factors to start inflammatory reaction, play
类风湿关节炎(Rheumatoid Arthritis，RA)是一种以关节组织慢性炎症性病变为主要表现的自身免疫性疾病，常伴有系统性血管炎的改变。众多的炎性细胞因子参与了疾病的病理过程，其中肿瘤坏死因子(Tumor Necrosis Factor-α，TNF-α)和白细胞介素-1(Interleukin-1，IL-1)被公认为是介导类风湿关节炎发生发展，造成滑膜损害和组织破坏的主要因素。胰岛素样生长因子(Insulin-like Growth Factor，IGFs)是一类结构上类似胰岛素原的多肽，在细胞的生长、分化及代谢的调节中起重要作用。体内几乎所有免疫细胞均存在IGF-1受体，对IGF-1的刺激产生反应。在RA的进展过程中，常存在周身脏器的受累，故推测IGF-1可能在RA的发病中特别是在伴有系统性损害的患者中起到相应的作用。本实验通过酶联免疫吸附法检测了RA患者血清IGF-1的水平，并分析其与血清TNF-α及其它化验指标之间的相互关系，探讨其在RA特别是在伴有系统性病变中的作用，为揭示RA的病因及拓展新的治疗途径提供一些新的思路。
材料与方法
RA患者39例，根据外周血中血小板数量分为血小板增高组及血小板正常组。选择20例参加健康体检的正常人作为正常对照组，两组性别、年龄之间具有可比性。试验组全部患者均采集清晨空腹静脉血3毫升，离心后取上清，保存于-80℃冰箱同批检测，血清IGF-1水平及TNF-α水平测定采用双抗体夹心ELISA法，同时采血测定肝功，血常规，血沉，免疫球蛋白，凝血三项，蛋白
电泳等相关指标。实验数据采用R。S表示，组间差异性比较应用
SPSS统计处理软件进行t检验及直线相关分析。
结 果
一sA患者血清 IGF—且平均水平为 102．66 t 83．85 ＂g／Inl，
明显高于对照组 37．46。74．08ng／Inl，p＝0．005＜0．of，其血小板
升高组（132．17。80．7In牙Inl）较血小板正常组（7．62。78．69n牙
Inl）及对照组血清IGF八平均水平明显升高，p＜0．05，血小板正
常组血清IGF一二平均水平与正常对照组比没有显著差异。
二、RA患者血清规F－a平均水平为1．15土0．妇n牙d，明
显高于对月组 0．27 i 0．olong／llilP一口．001＜0．of，有显著差异。
其血小板升高组血清 TNF一口水平 l．34。0．30n牙M血小板正常
组血清 TNF－a平均水平0 96 t 0．46n吵Inl，两者与正常对照组相
＊均有显著差异，P＝0．见二＜0．of。
5、RA患者血清mF—l水平与其血清TNF—Q水平呈显著
正相关，r＝0．521，P＝0．001＜0．01。
四、RA患者其他的与本实验相关指标的分析显示血清
IGF一水平与凝血酶原时间相关；血清TNF—口与血沉、血小板
数、a。一球蛋白呈显著正相关，p分别为0·036＜0·05；0·004＜
0．01；0．019＜0．05。
五、在39例RA患者中，进行常规胸部X一线检查者共34例，
其中经肺超薄CT及肺功能等进一步检查证实出现肺间质性改变
者共13 例，占38．2呢，其血清IGF－1水平为155．4。98．50
＂g／Inl，与不伴肺间质病变者相比 p＝0．off＜0．05，与正常对照组
相比较，P＝0．001＜0刀1，均有显著差异；其血清＊＊F－a水平为
1．22。0．57fig／all，与无肺间质病变者相比 P＝0．408＞0．05，而两
者与正常对照组相比较小均小于0．01，存在显著性差异。
·2·
六、将 RA患者按病程分为小于等于 24个月和大于 24个月
两组。前者血清 IGF一呈水平门31．05 t 84．78ng／Inl）较后者
（7．75。69．77fig／Inl）明显增才，P二 0．029＜0．05，h者有统计学
差异；而血清TNF一口水平则与病程无明显相关。
讨 论
RA是一组以累及周围关节为主的多系统炎症性的自身免疫
性疾病，系统性血管炎的出现常常成为影响预后的重要因素。RA
患者体内持续存在的自身免疫反应是其发病和病情迁延的中心环
节。现已知多种细胞因子参与了RA的病变过程，其中TNF－a
是研究较多的细胞因子，是启动炎症反应的关键细胞因子，在产生
RA的滑膜炎及周身病变的细胞因子网络中发挥重要作用。它除
了抑制基质中大分子物质合成外，对内皮细胞活化、血管增生、纤
维化、巨噬细胞激活等均起到促进作用。近年相关研究证实
IGF－1作为一种极其活跃的细胞因子参与了神经再生，骨的生
长、修复、改建，烧伤组织的修复，免疫系统的功能，糖尿病，肾间质
性疾病及肿瘤的发生发展过程。由于IGF一互受体可在几乎所有
兔疫细胞上表达，故推测IGF一二在RA的系统病变的发病中可能
起到相应的作用。已有相关报道显示在正常的血管内膜下组织有
IGF则 表达，特别在生长的血管、损伤动脉的再生内皮细胞
中显著增高。IGF－1能促进血管壁损伤后的血管平滑肌细胞的
增殖和迁移反应，刺激血管平滑肌细胞肥大并分泌细胞外基质。
血小板升高在RA患者中常提示疾病处于活动期，且往往同时合
并有血管炎的存在。凝血酶原时间是反映外源性凝血途径的常用
筛选试验之一。本实验结果显示血清IGF－l在RA特别是血小
板升高患者中有明显增高趋势且与凝血
Rheumatoid arthritis ( RA) is a heterogenous disease, which is characterized by symmetrical multiarthritis in clinic and is a progressive invasive autoimmune disease with systemic vasculitis usually. At prsent, studies have proved RA has obvious relationship with the net of immune regulation. As pre - inflammatory factors, TNF - acan increase the functions of neutrophils and eosinophils and make them produce superoxide and release Lyososome, inducing expression of other cellular factors and inflammatory factors. TNF - ais one of important nosogenetic factors of RA. Insulin - like Growth Factor - 1 (IGF - 1) is a kind of polypeptid, which has similar structure to insulinogen. It plays an important role in development, differentiation and metabolism of cells. Recently, some studies had make sure that IGF - 1 and IGF-2 expressed in different develop stage of many tissue cells. In vivo, IGF ?1 receptors almost exists all of immune cells, which reflects on stimulation of IGF - 1, So it conferred that IGF - 1 pla
yed some kind of role in RA, especially in the patients with systemic pathological changes. This experiment examined serum IGF - 1 and TNF - a in RA by ELISA and analyzed the relationship between them and other indexes, approached the role of them in RA, especially with systematic pathological changes and offered some new thoughtfulness for posting the pathogeny and exploiting new therapeutic means of RA.
Method
Selected 39RA patients, divided them into high -platelet group and normal - platelet group according to the amount of platelets in pe-ripherol blood. Selected 20 healthy people as control group, age and gender have no difference from patients group. The patients in experimental group were sampled 3ml vein blood of limosis in early morning, collected super serum after centrifugation and keeped in ?0^ in refrigeratory and measuring in the same term. At the same time, examined liver function, blood routine, erythrocyte sedimentation rate, immunoglobulins, coagulant three items, protein electrophoresis et al and analyzed by ELISA. Experimental data was dealed with SPSS and done t ?test and relativity analysis. Its results were expressed by x±s.
Results
1. Serum level of IGF - 1 in RA patients is 102. 66 ±83. 85ng/ ml, 37.46 ±74. 08ng/ml in control. IGF - 1 in RA group was higher than that of control group ( p = 0. 005 < 0. 01). In RA group, IGF - 1 in high - platelet group was higher than that of normal - platelet group (p = 0. 03 < 0. 05 ) and control group ( p < 0. 01). There is no obvious difference between normal ?platelet group and control group.
2. serum TNF - am RA group is 1. 15 ±0. 43ng/ml, which is greatly higher than that of control group (0. 27 ±0. 10ng/ml) ,p < 0.01. In RA group, serum TNF - aand IGF - 1 showed an remarkably positive correlation, r = 0. 521 p = 0. 001 < 0. 01.
3. In the analysis of other relative indexes in RA group, serum IGF - 1 had relationship with prothrombin time, serum TNF - a, ESR, amount of platelet and a.2 - globulin showed a positive correlation . 34 patients were examined by X - ray chest in RA group. 13 of them proved to be pulmonary interstitial pathological changes 38. 2% , IGF- 1 in them is 155. 4 ±98. 50ng/ml and compared with control group,p = 0. 001 < 0. 01; TNF - am them was 1. 22 ± 0. 57ng/ml, compared with control group p =0.003 <0.01.
4. RA patients were divided into two groups according to the course of disease; one group was less than 2 years, the anthor was more than 2 years. Serum level of IGF - 1 in short - course group was greatly higher than that of the other group, p =0. 029 <0. 05, which was statistical difference.
Disscussion
RA is an autoimmune disease, which is multisystem inflammation involved peripheral arthritis and systemic vaculitis often influenced its prognosis. At the present, we have known that many cellular factors took part in pathological process of RA, TNF - awas studied more widely, called pre - inflammatory factors and was vital cellular factors to start inflammatory reaction, play
引文
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13. Grant MB, Wargovich TJ, Ellis EA, et al. Localization of Insulin-like growth factor I and inhibition of coronary smooth muscle cells.A potential treatment for restenosis? Circulation.1994 Apr;89(4):1511 -7.
14. Lee TC, Gold LI, Ileibman J, et al.Immunhistochemical localization of transforming growth factor-beta and Insulin-like growth factor I in asbestosis in the sheep model.Int Arch occup Environ Health.1997; 69 (3): 157-64.
15. Noveral JP, Bhala A, Hintz RL, et al. Insulin - like growth factor axis in airway smooth muscle cells. Am J Physiol. 1994 Dee; 267 (6 Pt 1): L761 -5.
16. Schins RP, Bonn PJ. Plasma levels of soluble tumor necrosis factor receptors are increased in coal miners with pneumoconiosis.Eur Respir J. 1995 Oct;8(10):1658 -63.
17. Wu Y, Tewari M, Cui S, et al. Activation of the Insulin -like growth factor I receptor inhibits tumor necrosis factor - induced cell death. J Cell Physiol. 1996 Sep; 168(3): 499 -509.
18. Melloni B, Lesur O, Bouhadiba T, et al. Effect of exposure to silica on human alveolar macrophages in supporting growth activity in type Ⅱ epithelial cells. Thorax. 1996 Aug; 51 (8): 781 -6.
19．陈非，邓鸿业，丁桂凤等．染矽尘大鼠肺泡巨噬细胞胰岛素样生长因子的研究．中华劳动卫生职业病杂志。1993；11：257-60．
20. Maeda A, Hiyama K, Yamakido H, et al. Increased expression of platelet- derived growth factor A and Insulin -like growth factor I in BAL cells during the development of bleomycin - induced pul- monary fibrosis in mice. Chest. 1996 Mar; 109(30) ;780 -6.
21. Vanhee D, Gosset P, Wallaert B, et al. Mechanisms of fibrosis in coal workers' pneumoconiosis. Increased production of platelet- derived growth factor, Insulin-like growth factor type I, and transforming growth factor-beta and relationship to disease severity. Am J Respir Crit Care Med. 1994 Oct; 150(4): 1049 -55.
22. Lemmev A, Maddison P, Breslin A, et al. Association between Insulin- like growth factor status and physical activity levels in rheumatoid arthritis. J rheumatol. 2001 Jan; 28 (1):29-34.