结缔组织病相关肺动脉高压的生物标记物研究
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摘要
[目的]
肺动脉高压的发病受到多种因素的影响,与炎症反应密切相关。系统性硬化症和系统性红斑狼疮是最常见合并肺动脉高压的结缔组织病。目前仍然缺乏有效的生物标记物用于肺动脉高压的诊断、评估和分析预后。本文研究了红细胞分布宽度、抗膜突蛋白抗体以及内皮素-1的血清水平在结缔组织病相关肺动脉高压中的临床意义,探索不同患者外周血单个核细胞中膜突蛋白表达情况的差异,以及抗膜突蛋白抗体与膜突蛋白表达情况的相关性。
[方法]
1)入组79名健康受试者、77名系统性硬化症患者和89位系统性红斑狼疮患者,整理患者的临床表现和实验室检查等资料,包括红细胞分布宽度和右心导管术检查结果。
2)应用酶联免疫吸附测定方法检测系统性红斑狼疮、系统性硬皮病及健康人群外周血中抗膜突蛋白抗体和内皮素-1的血清水平。
3)应用流式细胞术方法检测系统性红斑狼疮、系统性硬皮病及健康人群外周血单个核细胞表面及细胞内表达膜突蛋白的水平。
[结果]
1)与未合并肺动脉高压的患者相比,结缔组织病相关肺动脉高压患者红细胞分布宽度显著上升(P=0.013)。WHO功能分级越高的患者,红细胞分布宽度水平越高(P=0.002)。红细胞分布宽度与六分钟步行试验距离(P=0.025,r=0.241)及血清脑钠肽水平显著正相关(P=0.038,r=0.466)。
2)抗膜突蛋白抗体的阳性率在结缔组织病相关肺动脉高压患者中显著上升(P=0.000)。绘制受试者工作特征曲线分析,曲线下面积为0.624,其诊断肺动脉高压的灵敏度为47%,特异度为87%。
3)外周血单个核细胞膜突蛋白表达总量在结缔组织病相关肺动脉高压患者中显著高于未合并肺动脉高压的结缔组织病患者(P=0.033)。外周血单个核细胞胞外膜突蛋白表达量与血清抗膜突蛋白抗体水平具有显著正相关性(P=0.045,r=0.564)。
4)在系统性红斑狼疮合并肺动脉高压患者中血清内皮素水平显著上升(P=0.018)。绘制受试者工作特征曲线分析,曲线下面积为0.704,其诊断效能优于红细胞分布宽度及抗膜突蛋白抗体。
[结论]
1)红细胞分布宽度可能成为结缔组织病相关肺动脉高压患者不良预后的预测因子。
2)抗膜突蛋白抗体及内皮素-1血清水平的检测可以分别用于结缔组织病相关肺动脉高压和系统性红斑狼疮相关肺动脉高压的诊断。
3)结缔组织病患者血清抗膜突蛋白抗体水平上升,可能与患者外周血单个核细胞胞外膜突蛋白表达总量上升有关。
[Objective]
The association between autoimmunity and pulmonary artery hypertension(PAH) has been appreciated for>40years, but biomarkers for the diagnosis of this disease is not yet known. Here we examined the serum levels of RDW, anti-moesin antibody, and endothelin-1in patients with systemic lupus erythematosus (SLE) or systemic sclerosis (SSc), two popular research models of connective tissue disease(CTD) associated PAH (CTD-PAH). We also studied the expression of moesin on peripheral blood mononuclear cells (PBMC) and its relationship with anti-moesin antibodies.
[Methods]
1) Hemodynamic variables, along with demographic, clinical, laboratory, and red cell distribution width (RDW) were recorded from77SSc patients and89SLE patients in Peking Union Medical College Hospital.79health controls' blood samples were collected from the Laboratory department.
2) Enzyme-linked immunosorbent assay was used to determine the serum levels of anti-moesin antibody and endothelin-1.
3) Flow cytometry was used to detect changes in moesin expression on the surface of PBMC, as well as the total amount of moesin in PBMC.
[Results]
1) RDW level were raised in patients with PAH (P=0.013). It correlated significantly with WHO functional class (P=0.002), six minutes walk distance (P=0.025) and NT-BNP(P=0.038).
2) Anti-moesin antibody was significantly raised in CTD-PAH (P=0.000). It detected PAH with47%sensitivity and87%specificity (area under the curve=0.624).
3) The total amount of moesin in PBMC was significantly higher in CTD-PAH patients (P=0.033). Surface expression of moesin was correlated with serum anti-moesin antibody (P=0.045, r=0.564).
4) In SLE-PAH, endothelin-1outperformed other biomarkers in receiver operating characteristic analysis (AUC=0.704).
[Conclusion]
1) These results suggested that RDW served as a prognostic indicator in CTD-PAH.
2) Anti-moesin antibody and endothelin-1may become diagnostic biomarkers for CTD-PAH and SLE-PAH respectively.
3) There were indications that the serum level of anti-moesin antibody was raised in CTD-PAH partly as a result of the overexpression of moesin on the surface of PBMC.
肺动脉高压的发病受到多种因素的影响,与炎症反应密切相关。系统性硬化症和系统性红斑狼疮是最常见合并肺动脉高压的结缔组织病。目前仍然缺乏有效的生物标记物用于肺动脉高压的诊断、评估和分析预后。本文研究了红细胞分布宽度、抗膜突蛋白抗体以及内皮素-1的血清水平在结缔组织病相关肺动脉高压中的临床意义,探索不同患者外周血单个核细胞中膜突蛋白表达情况的差异,以及抗膜突蛋白抗体与膜突蛋白表达情况的相关性。
[方法]
1)入组79名健康受试者、77名系统性硬化症患者和89位系统性红斑狼疮患者,整理患者的临床表现和实验室检查等资料,包括红细胞分布宽度和右心导管术检查结果。
2)应用酶联免疫吸附测定方法检测系统性红斑狼疮、系统性硬皮病及健康人群外周血中抗膜突蛋白抗体和内皮素-1的血清水平。
3)应用流式细胞术方法检测系统性红斑狼疮、系统性硬皮病及健康人群外周血单个核细胞表面及细胞内表达膜突蛋白的水平。
[结果]
1)与未合并肺动脉高压的患者相比,结缔组织病相关肺动脉高压患者红细胞分布宽度显著上升(P=0.013)。WHO功能分级越高的患者,红细胞分布宽度水平越高(P=0.002)。红细胞分布宽度与六分钟步行试验距离(P=0.025,r=0.241)及血清脑钠肽水平显著正相关(P=0.038,r=0.466)。
2)抗膜突蛋白抗体的阳性率在结缔组织病相关肺动脉高压患者中显著上升(P=0.000)。绘制受试者工作特征曲线分析,曲线下面积为0.624,其诊断肺动脉高压的灵敏度为47%,特异度为87%。
3)外周血单个核细胞膜突蛋白表达总量在结缔组织病相关肺动脉高压患者中显著高于未合并肺动脉高压的结缔组织病患者(P=0.033)。外周血单个核细胞胞外膜突蛋白表达量与血清抗膜突蛋白抗体水平具有显著正相关性(P=0.045,r=0.564)。
4)在系统性红斑狼疮合并肺动脉高压患者中血清内皮素水平显著上升(P=0.018)。绘制受试者工作特征曲线分析,曲线下面积为0.704,其诊断效能优于红细胞分布宽度及抗膜突蛋白抗体。
[结论]
1)红细胞分布宽度可能成为结缔组织病相关肺动脉高压患者不良预后的预测因子。
2)抗膜突蛋白抗体及内皮素-1血清水平的检测可以分别用于结缔组织病相关肺动脉高压和系统性红斑狼疮相关肺动脉高压的诊断。
3)结缔组织病患者血清抗膜突蛋白抗体水平上升,可能与患者外周血单个核细胞胞外膜突蛋白表达总量上升有关。
[Objective]
The association between autoimmunity and pulmonary artery hypertension(PAH) has been appreciated for>40years, but biomarkers for the diagnosis of this disease is not yet known. Here we examined the serum levels of RDW, anti-moesin antibody, and endothelin-1in patients with systemic lupus erythematosus (SLE) or systemic sclerosis (SSc), two popular research models of connective tissue disease(CTD) associated PAH (CTD-PAH). We also studied the expression of moesin on peripheral blood mononuclear cells (PBMC) and its relationship with anti-moesin antibodies.
[Methods]
1) Hemodynamic variables, along with demographic, clinical, laboratory, and red cell distribution width (RDW) were recorded from77SSc patients and89SLE patients in Peking Union Medical College Hospital.79health controls' blood samples were collected from the Laboratory department.
2) Enzyme-linked immunosorbent assay was used to determine the serum levels of anti-moesin antibody and endothelin-1.
3) Flow cytometry was used to detect changes in moesin expression on the surface of PBMC, as well as the total amount of moesin in PBMC.
[Results]
1) RDW level were raised in patients with PAH (P=0.013). It correlated significantly with WHO functional class (P=0.002), six minutes walk distance (P=0.025) and NT-BNP(P=0.038).
2) Anti-moesin antibody was significantly raised in CTD-PAH (P=0.000). It detected PAH with47%sensitivity and87%specificity (area under the curve=0.624).
3) The total amount of moesin in PBMC was significantly higher in CTD-PAH patients (P=0.033). Surface expression of moesin was correlated with serum anti-moesin antibody (P=0.045, r=0.564).
4) In SLE-PAH, endothelin-1outperformed other biomarkers in receiver operating characteristic analysis (AUC=0.704).
[Conclusion]
1) These results suggested that RDW served as a prognostic indicator in CTD-PAH.
2) Anti-moesin antibody and endothelin-1may become diagnostic biomarkers for CTD-PAH and SLE-PAH respectively.
3) There were indications that the serum level of anti-moesin antibody was raised in CTD-PAH partly as a result of the overexpression of moesin on the surface of PBMC.
引文
[1]Cojocaru M., Cojocaru I.M., Silosi I., et al. Associated pulmonary arterial hypertension in connective tissue diseases[J]. Maedica (Buchar),2011,6(2):141-5.
[2]Tamosiuniene R., Tian W., Dhillon G., et al. Regulatory T cells limit vascular endothelial injury and prevent pulmonary hypertension[J]. Circ Res,2011,109(8):867-79.
[3]Pullamsetti S.S., Savai R., Janssen W., et al. Inflammation, immunological reaction and role of infection in pulmonary hypertension [J]. Clin Microbiol Infect,2011,17(1):7-14.
[4]Cuttica M.J., Langenickel T., Noguchi A., et al. Perivascular T-cell infiltration leads to sustained pulmonary artery remodeling after endothelial cell damage[J]. Am J Respir Cell Mol Biol,2011, 45(1):62-71.
[5]Nicolls M.R., Taraseviciene-Stewart L, Rai P.R., et al. Autoimmunity and pulmonary hypertension: a perspective[J]. Eur Respir J,2005,26(6):1110-8.
[6]McMurtry M.S., Bonnet S., Wu X., et al. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis[J]. Circ Res,2004,95(8): 830-40.
[7]Risbano M.G., Meadows C.A., Coldren C.D., et al. Altered immune phenotype in peripheral blood cells of patients with scleroderma-associated pulmonary hypertension [J]. Clin Transl Sci,2010, 3(5):210-8.
[8]Austin E.D., Rock M.T., Mosse C.A., et al. T lymphocyte subset abnormalities in the blood and lung in pulmonary arterial hypertension[J]. Respir Med,2010,104(3):454-62.
[9]Daley E., Emson C., Guignabert C., et al. Pulmonary arterial remodeling induced by a Th2 immune response[J]. J Exp Med,2008,205(2):361-72.
[10]Taraseviciene-Stewart L., Nicolls M.R., Kraskauskas D., et al. Absence of T cells confers increased pulmonary arterial hypertension and vascular remodeling[J]. Am J Respir Crit Care Med,2007, 175(12):1280-9.
[11]Runo J.R. and Loyd J.E. Primary pulmonary hypertension[J]. Lancet,2003,361(9368):1533-44.
[12]lannone F., Riccardi M.T., Guiducci S., et al. Bosentan regulates the expression of adhesion molecules on circulating T cells and serum soluble adhesion molecules in systemic sclerosis-associated pulmonary arterial hypertension[J]. Annals of the Rheumatic Diseases,2008, 67(8):1121-6.
[13]Giaid A., Yanagisawa M., Langleben D., et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension[J]. N Engl J Med,1993,328(24):1732-9.
[14]Galie N., Hoeper M.M., Humbert M., et al. Guidelines for the diagnosis and treatment of pulmonary hypertension:the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT)[J]. Eur Heart J,2009,30(20):2493-537.
[15]Hampole C.V., Mehrotra A.K., Thenappan T, et al. Usefulness of red cell distribution width as a prognostic marker in pulmonary hypertension [J]. Am J Cardiol,2009,104(6):868-72.
[16]Rhodes C.J., Wharton J., Howard L.S., et al. Red cell distribution width outperforms other potential circulating biomarkers in predicting survival in idiopathic pulmonary arterial hypertension[J]. Heart,2011,97(13):1054-60.
[17]Hashimoto S., Amaya F., Matsuyama H., et al. Dysregulation of lung injury and repair in moesin-deficient mice treated with intratracheal bleomycin[J]. Am J Physiol Lung Cell Mol Physiol, 2008,295(4):L566-74.
[18]Amieva M.R. and Furthmayr H. Subcellular localization of moesin in dynamic filopodia, retraction fibers, and other structures involved in substrate exploration, attachment, and cell-cell contacts[J]. Exp Cell Res,1995,219(1):180-96.
[19]Berryman M., Franck Z., and Bretscher A. Ezrin is concentrated in the apical microvilli of a wide variety of epithelial cells whereas moesin is found primarily in endothelial cells[J]. J Cell Sci,1993, 105 (Pt 4):1025-43.
[20]Lee J.H., Katakai T, Hara T., et al. Roles of p-ERM and Rho-ROCK signaling in lymphocyte polarity and uropod formation[J]. J Cell Biol,2004,167(2):327-37.
[21]Bretscher A., Edwards K., and Fehon R.G. ERM proteins and merlin:integrators at the cell cortex[J]. Nat Rev Mol Cell Biol,2002,3(8):586-99.
[22]Wagatsuma M., Kimura M., Suzuki R., et al. Ezrin, radixin and moesin are possible auto-immune antigens in rheumatoid arthritis[J]. Mol Immunol,1996,33(15):1171-6.
[23]Takamatsu H., Feng X., Chuhjo T., et al. Specific antibodies to moesin, a membrane-cytoskeleton linker protein, are frequently detected in patients with acquired aplastic anemia[J]. Blood,2007, 109(6):2514-2520.
[24]尹雷,李梦涛,田庄,et al.结缔组织病相关肺动脉高压抗内皮细胞抗体检测及其靶抗原研究[J].中华风湿病学杂志,2010,14(5)：297-300.
[25]李梦涛,尹雷,王迁,et al.膜突蛋白及其抗体对人肺微血管内皮细胞损伤机制的研究[J].中华风湿病学杂志,2010,14(4)：232-235.
[26]Tsokos G.C., Overview of cellular immune function in systemic lupus erythematosus [M], in Systemic Lupus Erythematosus, San Diego:Elsevier.2003,29-92.
[27]Delon J., Kaibuchi K., and Germain R.N. Exclusion of CD43 from the immunological synapse is mediated by phosphorylation-regulated relocation of the cytoskeletal adaptor moesin[J]. Immunity,2001,15(5):691-701.
[28]Li Y., Harada T., Juang Y.T., et al. Phosphorylated ERM is responsible for increased T cell polarization, adhesion, and migration in patients with systemic lupus erythematosus[J]. Journal of Immunology,2007,178(3):1938-1947.
[29]Bhattacharyya S., Wei J., and Varga J. Understanding fibrosis in systemic sclerosis:shifting paradigms, emerging opportunities[J]. Nat Rev Rheumatol,2012,8(1):42-54.
[30]Yurovsky V.V., Sutton P.A., Schulze D.H., et al. Expansion of selected V delta 1+ gamma delta T cells in systemic sclerosis patients[J]. J Immunol,1994,153(2):881-91.
[31]Giacomelli R., Matucci-Cerinic M., Cipriani P., et al. Circulating Vdeltal+ T cells are activated and accumulate in the skin of systemic sclerosis patients[J]. Arthritis Rheum,1998,41(2):327-34.
[32]Waldburg N., Kahne T., Reisenauer A., et al. Clinical proteomics in lung diseases[J]. Pathol Res Pract,2004,200(2):147-54.
[33]王迁,赵久良,李梦涛,et al.抗膜突蛋白抗体与系统性硬化病相关肺间质病变的临床相关性研究[J].中华风湿病学杂志,2010,14(6)：364-367.
[34]Pernot J., Puzenat E., Magy-Bertrand N., et al. Detection of Interstitial Lung Disease in Systemic Sclerosis through Partitioning of Lung Transfer for Carbon Monoxide[J]. Respiration,2012.
[35]Gulati M. Diagnostic assessment of patients with interstitial lung disease[J]. Prim Care Respir J, 2011,20(2):120-7.
[36]Bussone G. and Mouthon L. Interstitial lung disease in systemic sclerosis[J]. Autoimmun Rev,2011, 10(5):248-55.
[37]Verschakelen J.A. The role of high-resolution computed tomography in the work-up of interstitial lung disease[J]. Curr Opin Pulm Med,2010,16(5):503-10.
[38]Felker G.M., Allen L.A., Pocock S.J., et al. Red cell distribution width as a novel prognostic marker in heart failure:data from the CHARM Program and the Duke Databank[J]. J Am Coll Cardiol,2007, 50(1):40-7.
[39]Tonelli M., Sacks F., Arnold M., et al. Relation Between Red Blood Cell Distribution Width and Cardiovascular Event Rate in People With Coronary Disease[J]. Circulation,2008,117(2):163-168.
[40]王为.结缔组织病相关肺动脉高压的血清标记物研究[D].北京：北京协和医学院,2010：
[41]Laget M.P., Defossez P.A., Albagli O., et al. Two functionally distinct domains responsible for transactivation by the Ets family member ERM[J]. Oncogene,1996,12(6):1325-36.
[42]Matsui T., Maeda M., Doi Y., et al. Rho-kinase phosphorylates COOH-terminal threonines of ezrin/radixin/moesin (ERM) proteins and regulates their head-to-tail association [J]. J Cell Biol, 1998,140(3):647-57.
[43]Finnerty C.M., Chambers D., Ingraffea J., et al. The EBP50-moesin interaction involves a binding site regulated by direct masking on the FERM domain[J]. J Cell Sci,2004,117(Pt 8):1547-52.
[44]Ivetic A. and Ridley A.J. Ezrin/radixin/moesin proteins and Rho GTPase signalling in leucocytes[J]. Immunology,2004,112(2):165-76.
[45]Rabinovitch M. Autoimmune disease and unexplained pulmonary hypertension[J]. Circulation, 1992,85(1):380-1.
[46]Mouthon L, Guillevin L, and Humbert M. Pulmonary arterial hypertension:an autoimmune disease?[J]. Eur Respir J,2005,26(6):986-8.
[47]Ohta-Ogo K., Hao H., Ishibashi-Ueda H., et al. CD44 expression in plexiform lesions of idiopathic pulmonary arterial hypertension[J]. Pathol Int,2012,62(4):219-25.
[48]Fehon R.G., McClatchey A.I., and Bretscher A. Organizing the cell cortex:the role of ERM proteins[J]. Nat Rev Mol Cell Biol,2010,11(4):276-87.
[49]Sutendra G., Dromparis P., Bonnet S., et al. Pyruvate dehydrogenase inhibition by the inflammatory cytokine TNFalpha contributes to the pathogenesis of pulmonary arterial hypertension [J]. J Mol Med (Berl),2011,89(8):771-83.
[50]Koss M., Pfeiffer li G.R., Wang Y., et al. Ezrin/radixin/moesin proteins are phosphorylated by TNF-(alpha) and modulate permeability increases in human pulmonary microvascular endothelial cells[J]. Journal of Immunology,2006,176(2):1218-1227.
[51]Galie N., Manes A., and Branzi A. The endothelin system in pulmonary arterial hypertension [J]. Cardiovasc Res,2004,61(2):227-37.
[52]Garncarczyk A., Jurzak Mv and Gojniczek K. [Characteristic of the endogenous peptides-endothelins and their role in the connective tissue fibrosis][J]. Wiadomosci Lekarskie, 2008,61(4-6):126-34.
[53]Xu S.W., Howat S.L, Renzoni E.A., et al. Endothelin-1 induces expression of matrix-associated genes in lung fibroblasts through MEK/ERK[J]. J Biol Chem,2004,279(22):23098-103.
[54]Coral-Alvarado P., Quintana G., Garces M.F., et al. Potential biomarkers for detecting pulmonary arterial hypertension in patients with systemic sclerosis[J]. Rheumatology International,2009, 29(9):1017-24.
[55]Rubin L.J., Badesch D.B., Barst R.J., et al. Bosentan therapy for pulmonary arterial hypertension[J]. N Engl J Med,2002,346(12):896-903.
[1]Amieva M.R. and Furthmayr H. Subcellular localization of moesin in dynamic filopodia, retraction fibers, and other structures involved in substrate exploration, attachment, and cell-cell contacts[J]. Exp Cell Res,1995,219(1):180-96.
[2]Fehon R.G., McClatchey A.I., and Bretscher A. Organizing the cell cortex:the role of ERM proteins[J]. Nat Rev Mol Cell Biol,2010,11(4):276-87.
[3]Wagatsuma M., Kimura M., Suzuki R., et al. Ezrin, radixin and moesin are possible auto-immune antigens in rheumatoid arthritis[J]. Mol Immunol,1996,33(15):1171-6.
[4]Takamatsu H., Espinoza J.L, Lu X., et al. Anti-moesin antibodies in the serum of patients with aplastic anemia stimulate peripheral blood mononuclear cells to secrete TNF-(alpha) and IFN-(gamma)[J]. Journal of Immunology,2009,182(1):703-710.
[5]Takamatsu H., Feng X., Chuhjo T., et al. Specific antibodies to moesin, a membrane-cytoskeleton linker protein, are frequently detected in patients with acquired aplastic anemia[J]. Blood,2007, 109(6):2514-2520.
[6]Espinoza J.L, Takamatsu H., Lu X., et al. Anti-moesin antibodies derived from patients with aplastic anemia stimulate monocytic cells to secrete TNF-alpha through an ERK1/2-dependent pathway[J]. Int Immunol,2009,21(8):913-23.
[7]Koss M., Pfeiffer li G.R., Wang Y., et al. Ezrin/radixin/moesin proteins are phosphorylated by TNF-(alpha) and modulate permeability increases in human pulmonary microvascular endothelial cells[J]. Journal of Immunology,2006,176(2):1218-1227.
[8]Lee J.H., Katakai T., Hara T., et al. Roles of p-ERM and Rho-ROCK signaling in lymphocyte polarity and uropod formation[J]. J Cell Biol,2004,167(2):327-37.
[9]Li Y., Harada T., Juang Y.T., et al. Phosphorylated ERM is responsible for increased T cell polarization, adhesion, and migration in patients with systemic lupus erythematosus[J]. Journal of Immunology,2007,178(3):1938-1947.
[10]Cines D.B., Bussel J.B., Liebman H.A., et al. The ITP syndrome:pathogenic and clinical diversity[J]. Blood,2009,113(26):6511-21.
[11]Nakamura F., Amieva M.R., and Furthmayr H. Phosphorylation of threonine 558 in the carboxyl-terminal actin-binding domain of moesin by thrombin activation of human platelets[J). J Biol Chem,1995,270(52):31377-85.
[12]Bhattacharyya S., Wei J., and Varga J. Understanding fibrosis in systemic sclerosis:shifting paradigms, emerging opportunities[J]. Nat Rev Rheumatol,2012,8(1):42-54.
[13]Berryman M., Franck Z., and Bretscher A. Ezrin is concentrated in the apical microvilli of a wide variety of epithelial cells whereas moesin is found primarily in endothelial cells[J]. J Cell Sci,1993, 105 (Pt 4):1025-43.
[14]Hashimoto S., Amaya F., Matsuyama H., et al. Dysregulation of lung injury and repair in moesin-deficient mice treated with intratracheal bleomycin[J]. Am J Physiol Lung Cell Mol Physiol, 2008,295(4):L566-74.
[15]Waldburg N., Kahne T., Reisenauer A., et al. Clinical proteomics in lung diseases[J]. Pathol Res Pract,2004,200(2):147-54.
[16]Shi-Wen X., Chen Y., Denton C.P., et al. Endothelin-1 promotes myofibroblast induction through the ETA receptor via a rac/phosphoinositide 3-kinase/Akt-dependent pathway and is essential for the enhanced contractile phenotype of fibrotic fibroblasts[J]. Mol Biol Cell,2004,15(6):2707-19.
[17]Xu S.W., Howat S.L., Renzoni E.A., et al. Endothelin-1 induces expression of matrix-associated genes in lung fibroblasts through MEK/ERK[J]. J Biol Chem,2004,279(22):23098-103.
[18]King T.E., Jr., Brown K.K., Raghu G., et al. BUILD-3:a randomized, controlled trial of bosentan in idiopathic pulmonary fibrosis[J]. Am J Respir Crit Care Med,2011,184(1):92-9.
[19]王迁,赵久良,李梦涛,et al.抗膜突蛋白抗体与系统性硬化病相关肺间质病变的临床相关性研究[J].中华风湿病学杂志,2010,14(6)：364-367.
[20]Galie N., Hoeper M.M., Humbert M., et al. Guidelines for the diagnosis and treatment of pulmonary hypertension:the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT)[J]. Eur Heart J,2009,30(20):2493-537.
[21]Runo J.R. and Loyd J.E. Primary pulmonary hypertension [J]. Lancet,2003,361(9368):1533-44.
[22]Rubin L.J., Badesch D.B., Barst R.J., et al. Bosentan therapy for pulmonary arterial hypertension[J]. N Engl J Med,2002,346(12):896-903.
[23]Rhodes C.J., Wharton J., Howard L.S., et al. Red cell distribution width outperforms other potential circulating biomarkers in predicting survival in idiopathic pulmonary arterial hypertension[J]. Heart,2011,97(13):1054-60.
[24]Hampole C.V., Mehrotra A.K., Thenappan T., et al. Usefulness of red cell distribution width as a prognostic marker in pulmonary hypertension[J]. Am J Cardiol,2009,104(6):868-72.
[25]尹雷,李梦涛,田庄,et al.结缔组织病相关肺动脉高压抗内皮细胞抗体检测及其靶抗原研究[J].中华风湿病学杂志,2010,14(5)：297-300.
[26]李梦涛,尹雷,王迁,et al.膜突蛋白及其抗体对人肺微血管内皮细胞损伤机制的研究[J].中华风湿病学杂志,2010,14(4)：232-235.
[27]王为.结缔组织病相关肺动脉高压的血清标记物研究[D].北京：北京协和医学院,2010：
[2]Tamosiuniene R., Tian W., Dhillon G., et al. Regulatory T cells limit vascular endothelial injury and prevent pulmonary hypertension[J]. Circ Res,2011,109(8):867-79.
[3]Pullamsetti S.S., Savai R., Janssen W., et al. Inflammation, immunological reaction and role of infection in pulmonary hypertension [J]. Clin Microbiol Infect,2011,17(1):7-14.
[4]Cuttica M.J., Langenickel T., Noguchi A., et al. Perivascular T-cell infiltration leads to sustained pulmonary artery remodeling after endothelial cell damage[J]. Am J Respir Cell Mol Biol,2011, 45(1):62-71.
[5]Nicolls M.R., Taraseviciene-Stewart L, Rai P.R., et al. Autoimmunity and pulmonary hypertension: a perspective[J]. Eur Respir J,2005,26(6):1110-8.
[6]McMurtry M.S., Bonnet S., Wu X., et al. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis[J]. Circ Res,2004,95(8): 830-40.
[7]Risbano M.G., Meadows C.A., Coldren C.D., et al. Altered immune phenotype in peripheral blood cells of patients with scleroderma-associated pulmonary hypertension [J]. Clin Transl Sci,2010, 3(5):210-8.
[8]Austin E.D., Rock M.T., Mosse C.A., et al. T lymphocyte subset abnormalities in the blood and lung in pulmonary arterial hypertension[J]. Respir Med,2010,104(3):454-62.
[9]Daley E., Emson C., Guignabert C., et al. Pulmonary arterial remodeling induced by a Th2 immune response[J]. J Exp Med,2008,205(2):361-72.
[10]Taraseviciene-Stewart L., Nicolls M.R., Kraskauskas D., et al. Absence of T cells confers increased pulmonary arterial hypertension and vascular remodeling[J]. Am J Respir Crit Care Med,2007, 175(12):1280-9.
[11]Runo J.R. and Loyd J.E. Primary pulmonary hypertension[J]. Lancet,2003,361(9368):1533-44.
[12]lannone F., Riccardi M.T., Guiducci S., et al. Bosentan regulates the expression of adhesion molecules on circulating T cells and serum soluble adhesion molecules in systemic sclerosis-associated pulmonary arterial hypertension[J]. Annals of the Rheumatic Diseases,2008, 67(8):1121-6.
[13]Giaid A., Yanagisawa M., Langleben D., et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension[J]. N Engl J Med,1993,328(24):1732-9.
[14]Galie N., Hoeper M.M., Humbert M., et al. Guidelines for the diagnosis and treatment of pulmonary hypertension:the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT)[J]. Eur Heart J,2009,30(20):2493-537.
[15]Hampole C.V., Mehrotra A.K., Thenappan T, et al. Usefulness of red cell distribution width as a prognostic marker in pulmonary hypertension [J]. Am J Cardiol,2009,104(6):868-72.
[16]Rhodes C.J., Wharton J., Howard L.S., et al. Red cell distribution width outperforms other potential circulating biomarkers in predicting survival in idiopathic pulmonary arterial hypertension[J]. Heart,2011,97(13):1054-60.
[17]Hashimoto S., Amaya F., Matsuyama H., et al. Dysregulation of lung injury and repair in moesin-deficient mice treated with intratracheal bleomycin[J]. Am J Physiol Lung Cell Mol Physiol, 2008,295(4):L566-74.
[18]Amieva M.R. and Furthmayr H. Subcellular localization of moesin in dynamic filopodia, retraction fibers, and other structures involved in substrate exploration, attachment, and cell-cell contacts[J]. Exp Cell Res,1995,219(1):180-96.
[19]Berryman M., Franck Z., and Bretscher A. Ezrin is concentrated in the apical microvilli of a wide variety of epithelial cells whereas moesin is found primarily in endothelial cells[J]. J Cell Sci,1993, 105 (Pt 4):1025-43.
[20]Lee J.H., Katakai T, Hara T., et al. Roles of p-ERM and Rho-ROCK signaling in lymphocyte polarity and uropod formation[J]. J Cell Biol,2004,167(2):327-37.
[21]Bretscher A., Edwards K., and Fehon R.G. ERM proteins and merlin:integrators at the cell cortex[J]. Nat Rev Mol Cell Biol,2002,3(8):586-99.
[22]Wagatsuma M., Kimura M., Suzuki R., et al. Ezrin, radixin and moesin are possible auto-immune antigens in rheumatoid arthritis[J]. Mol Immunol,1996,33(15):1171-6.
[23]Takamatsu H., Feng X., Chuhjo T., et al. Specific antibodies to moesin, a membrane-cytoskeleton linker protein, are frequently detected in patients with acquired aplastic anemia[J]. Blood,2007, 109(6):2514-2520.
[24]尹雷,李梦涛,田庄,et al.结缔组织病相关肺动脉高压抗内皮细胞抗体检测及其靶抗原研究[J].中华风湿病学杂志,2010,14(5)：297-300.
[25]李梦涛,尹雷,王迁,et al.膜突蛋白及其抗体对人肺微血管内皮细胞损伤机制的研究[J].中华风湿病学杂志,2010,14(4)：232-235.
[26]Tsokos G.C., Overview of cellular immune function in systemic lupus erythematosus [M], in Systemic Lupus Erythematosus, San Diego:Elsevier.2003,29-92.
[27]Delon J., Kaibuchi K., and Germain R.N. Exclusion of CD43 from the immunological synapse is mediated by phosphorylation-regulated relocation of the cytoskeletal adaptor moesin[J]. Immunity,2001,15(5):691-701.
[28]Li Y., Harada T., Juang Y.T., et al. Phosphorylated ERM is responsible for increased T cell polarization, adhesion, and migration in patients with systemic lupus erythematosus[J]. Journal of Immunology,2007,178(3):1938-1947.
[29]Bhattacharyya S., Wei J., and Varga J. Understanding fibrosis in systemic sclerosis:shifting paradigms, emerging opportunities[J]. Nat Rev Rheumatol,2012,8(1):42-54.
[30]Yurovsky V.V., Sutton P.A., Schulze D.H., et al. Expansion of selected V delta 1+ gamma delta T cells in systemic sclerosis patients[J]. J Immunol,1994,153(2):881-91.
[31]Giacomelli R., Matucci-Cerinic M., Cipriani P., et al. Circulating Vdeltal+ T cells are activated and accumulate in the skin of systemic sclerosis patients[J]. Arthritis Rheum,1998,41(2):327-34.
[32]Waldburg N., Kahne T., Reisenauer A., et al. Clinical proteomics in lung diseases[J]. Pathol Res Pract,2004,200(2):147-54.
[33]王迁,赵久良,李梦涛,et al.抗膜突蛋白抗体与系统性硬化病相关肺间质病变的临床相关性研究[J].中华风湿病学杂志,2010,14(6)：364-367.
[34]Pernot J., Puzenat E., Magy-Bertrand N., et al. Detection of Interstitial Lung Disease in Systemic Sclerosis through Partitioning of Lung Transfer for Carbon Monoxide[J]. Respiration,2012.
[35]Gulati M. Diagnostic assessment of patients with interstitial lung disease[J]. Prim Care Respir J, 2011,20(2):120-7.
[36]Bussone G. and Mouthon L. Interstitial lung disease in systemic sclerosis[J]. Autoimmun Rev,2011, 10(5):248-55.
[37]Verschakelen J.A. The role of high-resolution computed tomography in the work-up of interstitial lung disease[J]. Curr Opin Pulm Med,2010,16(5):503-10.
[38]Felker G.M., Allen L.A., Pocock S.J., et al. Red cell distribution width as a novel prognostic marker in heart failure:data from the CHARM Program and the Duke Databank[J]. J Am Coll Cardiol,2007, 50(1):40-7.
[39]Tonelli M., Sacks F., Arnold M., et al. Relation Between Red Blood Cell Distribution Width and Cardiovascular Event Rate in People With Coronary Disease[J]. Circulation,2008,117(2):163-168.
[40]王为.结缔组织病相关肺动脉高压的血清标记物研究[D].北京：北京协和医学院,2010：
[41]Laget M.P., Defossez P.A., Albagli O., et al. Two functionally distinct domains responsible for transactivation by the Ets family member ERM[J]. Oncogene,1996,12(6):1325-36.
[42]Matsui T., Maeda M., Doi Y., et al. Rho-kinase phosphorylates COOH-terminal threonines of ezrin/radixin/moesin (ERM) proteins and regulates their head-to-tail association [J]. J Cell Biol, 1998,140(3):647-57.
[43]Finnerty C.M., Chambers D., Ingraffea J., et al. The EBP50-moesin interaction involves a binding site regulated by direct masking on the FERM domain[J]. J Cell Sci,2004,117(Pt 8):1547-52.
[44]Ivetic A. and Ridley A.J. Ezrin/radixin/moesin proteins and Rho GTPase signalling in leucocytes[J]. Immunology,2004,112(2):165-76.
[45]Rabinovitch M. Autoimmune disease and unexplained pulmonary hypertension[J]. Circulation, 1992,85(1):380-1.
[46]Mouthon L, Guillevin L, and Humbert M. Pulmonary arterial hypertension:an autoimmune disease?[J]. Eur Respir J,2005,26(6):986-8.
[47]Ohta-Ogo K., Hao H., Ishibashi-Ueda H., et al. CD44 expression in plexiform lesions of idiopathic pulmonary arterial hypertension[J]. Pathol Int,2012,62(4):219-25.
[48]Fehon R.G., McClatchey A.I., and Bretscher A. Organizing the cell cortex:the role of ERM proteins[J]. Nat Rev Mol Cell Biol,2010,11(4):276-87.
[49]Sutendra G., Dromparis P., Bonnet S., et al. Pyruvate dehydrogenase inhibition by the inflammatory cytokine TNFalpha contributes to the pathogenesis of pulmonary arterial hypertension [J]. J Mol Med (Berl),2011,89(8):771-83.
[50]Koss M., Pfeiffer li G.R., Wang Y., et al. Ezrin/radixin/moesin proteins are phosphorylated by TNF-(alpha) and modulate permeability increases in human pulmonary microvascular endothelial cells[J]. Journal of Immunology,2006,176(2):1218-1227.
[51]Galie N., Manes A., and Branzi A. The endothelin system in pulmonary arterial hypertension [J]. Cardiovasc Res,2004,61(2):227-37.
[52]Garncarczyk A., Jurzak Mv and Gojniczek K. [Characteristic of the endogenous peptides-endothelins and their role in the connective tissue fibrosis][J]. Wiadomosci Lekarskie, 2008,61(4-6):126-34.
[53]Xu S.W., Howat S.L, Renzoni E.A., et al. Endothelin-1 induces expression of matrix-associated genes in lung fibroblasts through MEK/ERK[J]. J Biol Chem,2004,279(22):23098-103.
[54]Coral-Alvarado P., Quintana G., Garces M.F., et al. Potential biomarkers for detecting pulmonary arterial hypertension in patients with systemic sclerosis[J]. Rheumatology International,2009, 29(9):1017-24.
[55]Rubin L.J., Badesch D.B., Barst R.J., et al. Bosentan therapy for pulmonary arterial hypertension[J]. N Engl J Med,2002,346(12):896-903.
[1]Amieva M.R. and Furthmayr H. Subcellular localization of moesin in dynamic filopodia, retraction fibers, and other structures involved in substrate exploration, attachment, and cell-cell contacts[J]. Exp Cell Res,1995,219(1):180-96.
[2]Fehon R.G., McClatchey A.I., and Bretscher A. Organizing the cell cortex:the role of ERM proteins[J]. Nat Rev Mol Cell Biol,2010,11(4):276-87.
[3]Wagatsuma M., Kimura M., Suzuki R., et al. Ezrin, radixin and moesin are possible auto-immune antigens in rheumatoid arthritis[J]. Mol Immunol,1996,33(15):1171-6.
[4]Takamatsu H., Espinoza J.L, Lu X., et al. Anti-moesin antibodies in the serum of patients with aplastic anemia stimulate peripheral blood mononuclear cells to secrete TNF-(alpha) and IFN-(gamma)[J]. Journal of Immunology,2009,182(1):703-710.
[5]Takamatsu H., Feng X., Chuhjo T., et al. Specific antibodies to moesin, a membrane-cytoskeleton linker protein, are frequently detected in patients with acquired aplastic anemia[J]. Blood,2007, 109(6):2514-2520.
[6]Espinoza J.L, Takamatsu H., Lu X., et al. Anti-moesin antibodies derived from patients with aplastic anemia stimulate monocytic cells to secrete TNF-alpha through an ERK1/2-dependent pathway[J]. Int Immunol,2009,21(8):913-23.
[7]Koss M., Pfeiffer li G.R., Wang Y., et al. Ezrin/radixin/moesin proteins are phosphorylated by TNF-(alpha) and modulate permeability increases in human pulmonary microvascular endothelial cells[J]. Journal of Immunology,2006,176(2):1218-1227.
[8]Lee J.H., Katakai T., Hara T., et al. Roles of p-ERM and Rho-ROCK signaling in lymphocyte polarity and uropod formation[J]. J Cell Biol,2004,167(2):327-37.
[9]Li Y., Harada T., Juang Y.T., et al. Phosphorylated ERM is responsible for increased T cell polarization, adhesion, and migration in patients with systemic lupus erythematosus[J]. Journal of Immunology,2007,178(3):1938-1947.
[10]Cines D.B., Bussel J.B., Liebman H.A., et al. The ITP syndrome:pathogenic and clinical diversity[J]. Blood,2009,113(26):6511-21.
[11]Nakamura F., Amieva M.R., and Furthmayr H. Phosphorylation of threonine 558 in the carboxyl-terminal actin-binding domain of moesin by thrombin activation of human platelets[J). J Biol Chem,1995,270(52):31377-85.
[12]Bhattacharyya S., Wei J., and Varga J. Understanding fibrosis in systemic sclerosis:shifting paradigms, emerging opportunities[J]. Nat Rev Rheumatol,2012,8(1):42-54.
[13]Berryman M., Franck Z., and Bretscher A. Ezrin is concentrated in the apical microvilli of a wide variety of epithelial cells whereas moesin is found primarily in endothelial cells[J]. J Cell Sci,1993, 105 (Pt 4):1025-43.
[14]Hashimoto S., Amaya F., Matsuyama H., et al. Dysregulation of lung injury and repair in moesin-deficient mice treated with intratracheal bleomycin[J]. Am J Physiol Lung Cell Mol Physiol, 2008,295(4):L566-74.
[15]Waldburg N., Kahne T., Reisenauer A., et al. Clinical proteomics in lung diseases[J]. Pathol Res Pract,2004,200(2):147-54.
[16]Shi-Wen X., Chen Y., Denton C.P., et al. Endothelin-1 promotes myofibroblast induction through the ETA receptor via a rac/phosphoinositide 3-kinase/Akt-dependent pathway and is essential for the enhanced contractile phenotype of fibrotic fibroblasts[J]. Mol Biol Cell,2004,15(6):2707-19.
[17]Xu S.W., Howat S.L., Renzoni E.A., et al. Endothelin-1 induces expression of matrix-associated genes in lung fibroblasts through MEK/ERK[J]. J Biol Chem,2004,279(22):23098-103.
[18]King T.E., Jr., Brown K.K., Raghu G., et al. BUILD-3:a randomized, controlled trial of bosentan in idiopathic pulmonary fibrosis[J]. Am J Respir Crit Care Med,2011,184(1):92-9.
[19]王迁,赵久良,李梦涛,et al.抗膜突蛋白抗体与系统性硬化病相关肺间质病变的临床相关性研究[J].中华风湿病学杂志,2010,14(6)：364-367.
[20]Galie N., Hoeper M.M., Humbert M., et al. Guidelines for the diagnosis and treatment of pulmonary hypertension:the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT)[J]. Eur Heart J,2009,30(20):2493-537.
[21]Runo J.R. and Loyd J.E. Primary pulmonary hypertension [J]. Lancet,2003,361(9368):1533-44.
[22]Rubin L.J., Badesch D.B., Barst R.J., et al. Bosentan therapy for pulmonary arterial hypertension[J]. N Engl J Med,2002,346(12):896-903.
[23]Rhodes C.J., Wharton J., Howard L.S., et al. Red cell distribution width outperforms other potential circulating biomarkers in predicting survival in idiopathic pulmonary arterial hypertension[J]. Heart,2011,97(13):1054-60.
[24]Hampole C.V., Mehrotra A.K., Thenappan T., et al. Usefulness of red cell distribution width as a prognostic marker in pulmonary hypertension[J]. Am J Cardiol,2009,104(6):868-72.
[25]尹雷,李梦涛,田庄,et al.结缔组织病相关肺动脉高压抗内皮细胞抗体检测及其靶抗原研究[J].中华风湿病学杂志,2010,14(5)：297-300.
[26]李梦涛,尹雷,王迁,et al.膜突蛋白及其抗体对人肺微血管内皮细胞损伤机制的研究[J].中华风湿病学杂志,2010,14(4)：232-235.
[27]王为.结缔组织病相关肺动脉高压的血清标记物研究[D].北京：北京协和医学院,2010：