骨髓来源的纤维细胞在特发性肺纤维化中募集及相关信号的研究
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摘要
背景和目的
特发性肺纤维化(Idiopathic Pulmonary Fibrosis, IPF)是特发性间质性肺炎(Idiopathic Interstitial Pneumonias,ⅡPs)中最常见的一种类型,近年来发病率呈不断上升趋势。目前其发病机制尚不清楚。IPF的病理特征是肺内成纤维细胞(Fibroblast)／肌成纤维细胞(Myofibroblast)数量的扩增与纤维化病灶(Fibroblastic Foci)形成；肺内纤维化病灶主要由肌成纤维细胞组成。国内外研究认为骨髓来源的纤维细胞(Fibrocytes)可能募集到纤维化病灶中并分化为肌成纤维细胞。它们共同表达普通的白细胞抗原CD45、造血干细胞抗原CD34、间充质标记物如胶原-1(Collagen-Ⅰ)、纤维结合素(Fibronectin)、α-平滑肌肌动蛋白(a-SMA)、脯氨酰-4-羟化酶(prolyl-4-hydroxylase)等特有的细胞表面标记物。大部分Fibrocytes都表达趋化因子受体4(CXCR4),并认为CXCR4/CXCL12信号途径对Fibrocytes的募集十分重要。目前关于其研究都是在体外或实验动物模型中进行的,而在IPF患者中关于Fibrocytes促进了肺纤维化形成的研究还未见相关报道。
本次实验研究目的：①应用双重免疫荧光方法通过荧光显微镜分别观察实验组和对照组中的Fibrocytes;②通过对各组Fibrocytes数量的比较,在肺纤维化形成过程中探讨CXCR4/CXCL12信号途径对Fibrocytes募集的作用。旨在为Fibrocytes促进肺纤维化形成的发病机制提供理论基础；为更好的了解该病的发生发展和转归及靶向治疗提供分子生物学依据。
材料与方法
实验组20例,标本来自河南省人民医院行小切口开胸肺活检,最终病理证实为IPF的住院患者。对照组20例,标本来自河南省人民医院与河南省胸科医院因支气管扩张症行肺叶切除术的患者,所取肺组织标本距病变距离大于5cm,经病理证实为正常的肺组织。根据Fibrocytes所特有的不同的细胞表面标记物,按不同组合分成四组：①CXCR4/Collagen-Ⅰ,②CD34/a-SMA,③CD34/Collagen-Ⅰ,④CD45RO/Collagen-Ⅰ。通过荧光显微镜分别观察实验组和对照组中Fibrocytes,分别计数四组中Fibrocytes数百分率,结果采用SPSS12.0统计分析软件处理,各组数据之间的比较分析分别采用Kruskal-Wallis test及Mann-Whitney u,以a=0.05为检验水准。
结果
1.双重免疫荧光试验结果：实验组20例IPF患者中有19例肺组织发现Fibrocytes,而对照组中没有发现。
2.相关结果分析：本实验研究经统计学检测发现：通过荧光显微镜观察并分别计数IPF患者肺组织中上述四组的Fibrocytes数百分率,分别为(5.19±0.0152%)、(2.19±0.0083%)、(2.56±0.0109%)、(2.29±0.0082%)。①组分别与②组、③组、④组的数据比较差异具有统计学意义(P<0.001)。
结论
1.该实验研究发现在实验组肺组织存在Fibrocytes,而在对照组中则未发现。提示Fibrocytes在IPF的形成和发展过程中可能促进了肺纤维化形成。
2.该实验研究发现在人类间质性肺疾病中亦可能存在Fibrocytes。
3.该实验研究发现在实验组肺组织能检测更多CXCR4+的Fibrocytes,提示CXCR4+的Fibrocytes可能通过CXCR4/CXCL12信号途径募集IPF患者肺组织并促进了肺纤维化形成。
Background and Objective
Idiopathic Pulmonary Fibrosis(IPF) is the most common category of idiopathic interstitial pneumonias. The incidence of IPF seems to be increasing. The real mechanisms underlying the development of IPF still remain unknown. The pathologic hallmarks of IPF are Fibroblastic Foci, which are areas rich in mesenchymal cells and Extracellular Matrix (ECM). These Fibroblastic Foci, which consist of fibroblasts and myofibroblasts cell, are deemed to be a key element in the diagnosis of IPF. Fibrocytes have been suggested that they are a potential source of formation of myofibroblast. They co-express the common leukocyte antigen CD45, the hematopoietic stem cell antigen CD34, and mesenchymal markers such as Collagen-I, fibronectin, a-smooth muscle actin(a-SMA) and prolyl-4-hydroxylase. Most of them express the receptor CXCR4 supporting the concept that the CXCR4/CXCL12 pathway may be important for tissue recruitment. So far, fibrocytes have not been demonstrated in the lungs of patients with IPF or other human interstitial lung diseases.
The present study is designed in order to define the following points:to observe that there have fibrocytes in human lung tissue by immunofluorescence; fibrocytes are observed in lung tissues with combinations including CXCR4 or CD34 or CD45RO with mesenchymal markers; to analyze correlation of fibrocytes of different staining combination; to evaluate the effect of CXCR4/CXCL12 signal pathway on recruiting of fibrocytes and expansion of the fibroblast/myofibroblast population in IPF by immunofluorescence. The aim of our study is to evaluate the role of fibrocytes for the pathogenesy of IPF, and to provide evidence of molecular biology for better understanding evolution and development of IPF and potential therapeutic target of IPF.
Materials and methods
20 lung tissues were collected by open lung biopsies from patients with IPF. Lung tissue samples of the control group obtained from 20 patients undergoing thoracotomy for bronchiectasis. Patients in the control group had no other underlying lung disease and the specimens distanced 5 cm from the affections.The histologic diagnosis in these specimens was normal lung tissue. To observe that there have fibrocytes in lung tissue by immunofluorescence. Four groups respectively are①CXCR4/Collagen-Ⅰ,②CD34/a-SMA,③CD34/Collagen-Ⅰ,④CD45RO/Collagen-Ⅰby special cell surface markers. The numble of the double positive cell of four groups of all lung tissue samples is detected respectively by immunofluorescence.These dates are analysed by statistical software SPSS 12.0. Differences between the number of fibrocytes detected in lungs tissue samples are compared by using Kruskal-Wallis test and Mann-Whitney u test, a=0.05 is considered as the level of tests.
Result
Fibrocytes have been identified in tissues in 19 out of 20 IPF and not identified in lung of control group by immunofluorescence.
The number of four groups in lung of IPF respectively is (5.19±0.0152%), (2.19±0.0083%), (2.56±0.0109%), (2.29±0.0082%).Compared with others, the number of the double positive cell expressing for CXCR4/Collagen-I is much higher.(P< 0.001).
Conclusion
1. This study suggests that fibrocytes existed in the lung tissue of patients with IPF, but fibrocytes did not exist in lung of control group. Fibrocytes may facilitate to the expansion of the fibroblast/myofibroblast population in IPF.
2. Our study suggests that fibrocytes have been demonstrated in the lungs of patients with IPF or other human interstitial lung diseases.
3.There have more CXCR4 positive fibrocytes in lung of IPF, these findings indicate that these fibrocytes have been likely recruited through the CXCR4/CXCL12 axis, and may play a important role in evolution and development of IPF.
特发性肺纤维化(Idiopathic Pulmonary Fibrosis, IPF)是特发性间质性肺炎(Idiopathic Interstitial Pneumonias,ⅡPs)中最常见的一种类型,近年来发病率呈不断上升趋势。目前其发病机制尚不清楚。IPF的病理特征是肺内成纤维细胞(Fibroblast)／肌成纤维细胞(Myofibroblast)数量的扩增与纤维化病灶(Fibroblastic Foci)形成；肺内纤维化病灶主要由肌成纤维细胞组成。国内外研究认为骨髓来源的纤维细胞(Fibrocytes)可能募集到纤维化病灶中并分化为肌成纤维细胞。它们共同表达普通的白细胞抗原CD45、造血干细胞抗原CD34、间充质标记物如胶原-1(Collagen-Ⅰ)、纤维结合素(Fibronectin)、α-平滑肌肌动蛋白(a-SMA)、脯氨酰-4-羟化酶(prolyl-4-hydroxylase)等特有的细胞表面标记物。大部分Fibrocytes都表达趋化因子受体4(CXCR4),并认为CXCR4/CXCL12信号途径对Fibrocytes的募集十分重要。目前关于其研究都是在体外或实验动物模型中进行的,而在IPF患者中关于Fibrocytes促进了肺纤维化形成的研究还未见相关报道。
本次实验研究目的：①应用双重免疫荧光方法通过荧光显微镜分别观察实验组和对照组中的Fibrocytes;②通过对各组Fibrocytes数量的比较,在肺纤维化形成过程中探讨CXCR4/CXCL12信号途径对Fibrocytes募集的作用。旨在为Fibrocytes促进肺纤维化形成的发病机制提供理论基础；为更好的了解该病的发生发展和转归及靶向治疗提供分子生物学依据。
材料与方法
实验组20例,标本来自河南省人民医院行小切口开胸肺活检,最终病理证实为IPF的住院患者。对照组20例,标本来自河南省人民医院与河南省胸科医院因支气管扩张症行肺叶切除术的患者,所取肺组织标本距病变距离大于5cm,经病理证实为正常的肺组织。根据Fibrocytes所特有的不同的细胞表面标记物,按不同组合分成四组：①CXCR4/Collagen-Ⅰ,②CD34/a-SMA,③CD34/Collagen-Ⅰ,④CD45RO/Collagen-Ⅰ。通过荧光显微镜分别观察实验组和对照组中Fibrocytes,分别计数四组中Fibrocytes数百分率,结果采用SPSS12.0统计分析软件处理,各组数据之间的比较分析分别采用Kruskal-Wallis test及Mann-Whitney u,以a=0.05为检验水准。
结果
1.双重免疫荧光试验结果：实验组20例IPF患者中有19例肺组织发现Fibrocytes,而对照组中没有发现。
2.相关结果分析：本实验研究经统计学检测发现：通过荧光显微镜观察并分别计数IPF患者肺组织中上述四组的Fibrocytes数百分率,分别为(5.19±0.0152%)、(2.19±0.0083%)、(2.56±0.0109%)、(2.29±0.0082%)。①组分别与②组、③组、④组的数据比较差异具有统计学意义(P<0.001)。
结论
1.该实验研究发现在实验组肺组织存在Fibrocytes,而在对照组中则未发现。提示Fibrocytes在IPF的形成和发展过程中可能促进了肺纤维化形成。
2.该实验研究发现在人类间质性肺疾病中亦可能存在Fibrocytes。
3.该实验研究发现在实验组肺组织能检测更多CXCR4+的Fibrocytes,提示CXCR4+的Fibrocytes可能通过CXCR4/CXCL12信号途径募集IPF患者肺组织并促进了肺纤维化形成。
Background and Objective
Idiopathic Pulmonary Fibrosis(IPF) is the most common category of idiopathic interstitial pneumonias. The incidence of IPF seems to be increasing. The real mechanisms underlying the development of IPF still remain unknown. The pathologic hallmarks of IPF are Fibroblastic Foci, which are areas rich in mesenchymal cells and Extracellular Matrix (ECM). These Fibroblastic Foci, which consist of fibroblasts and myofibroblasts cell, are deemed to be a key element in the diagnosis of IPF. Fibrocytes have been suggested that they are a potential source of formation of myofibroblast. They co-express the common leukocyte antigen CD45, the hematopoietic stem cell antigen CD34, and mesenchymal markers such as Collagen-I, fibronectin, a-smooth muscle actin(a-SMA) and prolyl-4-hydroxylase. Most of them express the receptor CXCR4 supporting the concept that the CXCR4/CXCL12 pathway may be important for tissue recruitment. So far, fibrocytes have not been demonstrated in the lungs of patients with IPF or other human interstitial lung diseases.
The present study is designed in order to define the following points:to observe that there have fibrocytes in human lung tissue by immunofluorescence; fibrocytes are observed in lung tissues with combinations including CXCR4 or CD34 or CD45RO with mesenchymal markers; to analyze correlation of fibrocytes of different staining combination; to evaluate the effect of CXCR4/CXCL12 signal pathway on recruiting of fibrocytes and expansion of the fibroblast/myofibroblast population in IPF by immunofluorescence. The aim of our study is to evaluate the role of fibrocytes for the pathogenesy of IPF, and to provide evidence of molecular biology for better understanding evolution and development of IPF and potential therapeutic target of IPF.
Materials and methods
20 lung tissues were collected by open lung biopsies from patients with IPF. Lung tissue samples of the control group obtained from 20 patients undergoing thoracotomy for bronchiectasis. Patients in the control group had no other underlying lung disease and the specimens distanced 5 cm from the affections.The histologic diagnosis in these specimens was normal lung tissue. To observe that there have fibrocytes in lung tissue by immunofluorescence. Four groups respectively are①CXCR4/Collagen-Ⅰ,②CD34/a-SMA,③CD34/Collagen-Ⅰ,④CD45RO/Collagen-Ⅰby special cell surface markers. The numble of the double positive cell of four groups of all lung tissue samples is detected respectively by immunofluorescence.These dates are analysed by statistical software SPSS 12.0. Differences between the number of fibrocytes detected in lungs tissue samples are compared by using Kruskal-Wallis test and Mann-Whitney u test, a=0.05 is considered as the level of tests.
Result
Fibrocytes have been identified in tissues in 19 out of 20 IPF and not identified in lung of control group by immunofluorescence.
The number of four groups in lung of IPF respectively is (5.19±0.0152%), (2.19±0.0083%), (2.56±0.0109%), (2.29±0.0082%).Compared with others, the number of the double positive cell expressing for CXCR4/Collagen-I is much higher.(P< 0.001).
Conclusion
1. This study suggests that fibrocytes existed in the lung tissue of patients with IPF, but fibrocytes did not exist in lung of control group. Fibrocytes may facilitate to the expansion of the fibroblast/myofibroblast population in IPF.
2. Our study suggests that fibrocytes have been demonstrated in the lungs of patients with IPF or other human interstitial lung diseases.
3.There have more CXCR4 positive fibrocytes in lung of IPF, these findings indicate that these fibrocytes have been likely recruited through the CXCR4/CXCL12 axis, and may play a important role in evolution and development of IPF.
引文
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[1]Gross TJ, Hunninghake GW, Idiopathic pulmonary fibrosis. N Engl J Med, 2001,345(7):517-525
[2]King Jr TE, Schwarz MI, Brown K, et al. Idiopathic pulmonary fibrosis:relation between histopathologic features and mortality. Am J Respir Crit Med,2001,164 (6):1025-1032
[3]Quan, T. E., Cowper, S., Wu, S. P.,et al. Circulating fibrocytes:collagen-secreting cells of the peripheral blood. Int. J. Biochem. Cell. Biol.,2004,36,598-606
[4]Aiba, S.,& Tagami, H. Inverse correlation between CD34 expression and proline-4-hydroxylase immunoreactivity on spindle cells noted in hypertrophic scars and keloids. J. Cutan. Pathol.,1997,24,65-69
[5]Strieter, R. M., Gomperts, B. N.,& Keane, M. P. The role of CXC chemokines in pulmonary fibrosis. J. Clin. Invest.,2007,117,549-556
[6]Postlethwaite, A. E., Shigemitsu, H.,& Kanangat, S. Cellular origins of fibroblasts: possible implications for organ fibrosis in systemic sclerosis. Curr. Opin. Rheumatol., 2004,16,733-738
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