TGF-α作为体-肺分流性肺动脉高压诊断生物标志物的研究
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摘要
目的评估转化生长因子α(transforming growth factorα, TGF-α)作为体-肺分流性肺动脉高压(pulmonary artery hypertension, PAH)诊断生物标志物的可行性。方法用联合手术(右肺动脉结扎+1周后建立颈部分流)的方法构建体-肺分流性PAH大鼠模型。纳入先天性心脏病(congenital heart disease, CHD)患者49例,其中CHD不合并PAH患者24例,CHD-PAH患者25例;同时纳入年龄、性别相匹配的健康志愿者(control, CON) 20例。酶联免疫吸附实验法检测分流性PAH大鼠和CHD-PAH患者血浆TGF-α的浓度。结果体-肺分流性PAH大鼠血浆中TGF-α的浓度较假手术组明显升高;Spearman相关性分析表明,大鼠血浆TGF-α的水平与肺血流动力学指标及右室肥厚指数均呈明显正相关。TGF-α的血浆浓度在CHD-PAH组较CHD及CON组均明显升高,而在CHD组与CON组之间差异无显著性;血浆TGF-α的浓度为314 ng·L~(-1)时,诊断CHD-PAH的敏感度为0.760,特异度为0.750,ROC曲线下面积0.895。结论 TGF-α的血浆浓度在体-肺分流性PAH发生、发展过程中表达逐渐升高,血浆中TGF-α的水平可能是诊断体-肺分流性PAH潜在的生物标志物。
Aim To determine the feasibility of transforming growth factor-α(TGF-α) as a diagnostic biomarker for systemic-to-pulmonary shunts induced pulmonary arterial hypertension(PAH).Methods Systemic-to-pulmonary shunts induced PAH was built by combined surgery(right pulmonary artery was ligated and a cervical shunt was established one week later). A total of 49 patients with congenital heart diseases were recruited, including 24 congenital heart disease patients without PAH(CHD) and 25 congenital heart disease patients with pulmonary arterial hypertension(CHD-PAH). Moreover, 20 healthy volunteersmatched by age and sex were also included. Enzyme linked immunosorbent assay( ELISA) was used to test TGF-α concentrations in plasma of systemic-to-pulmonary shunts induced PAH rats and CHD-PAH patients.Results ELISA results showed that TGF-α levels in plasma of systemic-to-pulmonary shunts induced PAH rats were significantly higher than those of sham operated group. Spearman correlation analysis showed that plasma TGF-α concentrations were positively associated with right ventricular systolic pressure,pulmonary arterial systolic pressure,mean pulmonary arterial pressure and right ventricular hypertrophy index. The plasma concentration of TGF-α in CHD-PAH patients was much higher than that of CHD patients and healthy vol-unteers( CON); however, there was no significant difference between CHD group and CON group; Using314 ng·L-1 as cutoff value of TGF-α for the diagnosis of CHD-PAH,the sensitivity,specificity and area under the cure was 0. 760,0. 750 and 0. 895,respectively. Conclusions Plasma concentration of TGF-α increases with the progression of systemic-to-pulmonary shunt induced PAH; the level of TGF-α in plasma may be a potential biomarker for the diagnosis of systemicto-pulmonary shunt induced PAH.
Aim To determine the feasibility of transforming growth factor-α(TGF-α) as a diagnostic biomarker for systemic-to-pulmonary shunts induced pulmonary arterial hypertension(PAH).Methods Systemic-to-pulmonary shunts induced PAH was built by combined surgery(right pulmonary artery was ligated and a cervical shunt was established one week later). A total of 49 patients with congenital heart diseases were recruited, including 24 congenital heart disease patients without PAH(CHD) and 25 congenital heart disease patients with pulmonary arterial hypertension(CHD-PAH). Moreover, 20 healthy volunteersmatched by age and sex were also included. Enzyme linked immunosorbent assay( ELISA) was used to test TGF-α concentrations in plasma of systemic-to-pulmonary shunts induced PAH rats and CHD-PAH patients.Results ELISA results showed that TGF-α levels in plasma of systemic-to-pulmonary shunts induced PAH rats were significantly higher than those of sham operated group. Spearman correlation analysis showed that plasma TGF-α concentrations were positively associated with right ventricular systolic pressure,pulmonary arterial systolic pressure,mean pulmonary arterial pressure and right ventricular hypertrophy index. The plasma concentration of TGF-α in CHD-PAH patients was much higher than that of CHD patients and healthy vol-unteers( CON); however, there was no significant difference between CHD group and CON group; Using314 ng·L-1 as cutoff value of TGF-α for the diagnosis of CHD-PAH,the sensitivity,specificity and area under the cure was 0. 760,0. 750 and 0. 895,respectively. Conclusions Plasma concentration of TGF-α increases with the progression of systemic-to-pulmonary shunt induced PAH; the level of TGF-α in plasma may be a potential biomarker for the diagnosis of systemicto-pulmonary shunt induced PAH.
引文
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[9] Hoeper M M. Definition, classification, and epidemiology of pulmonary arterial hypertension[J]. Semin Respir Crit Care Med,2009,30(4): 369-75.
[10] Nievergall E, Reynolds J, Kok C H, et al. TGF-alpha and IL-6 plasma levels selectively identify CML patients who fail to achieve an early molecular response or progress in the first year of therapy[J]. Leukemia,2016,30(6):1263-72.
[11] Tarhini A A, Lin Y, Yeku O, et al. A four-marker signature of TNF-RII, TGF-alpha, TIMP-1 and CRP is prognostic of worse survival in high-risk surgically resected melanoma[J]. J Transl Med,2014,12:19.
[12] Addison C L, Ding K, Zhao H, et al. Plasma transforming growth factor alpha and amphiregulin protein levels in NCIC clinical trials group BR.21[J]. J Clin Oncol,2010,28(36): 5247-56.
[13] Shim K S, Kim K H, Park B W, et al. Increased serum levels of transforming growth factor-alpha in patients with colorectal cancer[J]. Dis Colon Rectum,1998,41(2): 219-24.
[14] Moskal T L, Huang S, Ellis L M,et al. Serum levels of transforming growth factor alpha in gastrointestinal cancer patients[J]. Cancer Epidemiol Biomarkers Prev,1995, 4(2): 127-31.
[2] Lemarie C A, Tharaux P L, Esposito B, et al. Transforming growth factor-alpha mediates nuclear factor kappaB activation in strained arteries[J]. Circ Res, 2006, 99(4): 434-41
[3] Purba E R, Saita E I, Maruyama I N. Activation of the EGF receptor by ligand binding and oncogenic mutations: the "rotation model"[J]. Cells, 2017,6(2):13.
[4] Singh B, Coffey R J. From wavy hair to naked proteins: the role of transforming growth factor alpha in health and disease (Oxf)[J]. Semin Cell Dev Biol,2014, 28:12-21.
[5] Liu X, Meng L, Li J, et al. Secretory clusterin is upregulated in rats with pulmonary arterial hypertension induced by systemic-to-pulmonary shunts and exerts important roles in pulmonary artery smooth muscle cells[J]. Acta Physiol (Oxf), 2015,213(2): 505-18.
[6] Meng L, Liu X, Zheng Z, et al .Original rat model of high kinetic unilateral pulmonary hypertension surgically induced by combined surgery[J]. J Thorac Cardiovasc Surg,2013,146(5): 1220-6.
[7] 刘晓艳,孟刘坤,李君,等, 分泌型簇蛋白在肺动脉高压大鼠中的表达变化[J].中国药理学通报,2014, 30(6):764-8.
[7] Liu X Y, Meng L K, Li J, et al. Expression pattern of secreted clusterin in pulmonary arterial hypertesion rats[J]. Chin Pharmacol Bull, 2014, 30(6): 764-8.
[8] 潘永露,何淑芳,韩正怡,等. Fas/caspase-8/3和ERK信号通路在Fas siRNA减轻心肌细胞缺氧/复氧损伤中的作用[J].中国药理学通报,2018,34(8):1150-7.
[8] Pan Y L, He S F, Han Z Y, et al. Roles of Fas/caspase-8/3 and ERK signaling pathways in Fas siRNA induced reduction of hypoxia/reoxygenation injury to cardiomyocytes[J]. Chin Pharmacol Bull, 2018, 34(8): 1150-7.
[9] Hoeper M M. Definition, classification, and epidemiology of pulmonary arterial hypertension[J]. Semin Respir Crit Care Med,2009,30(4): 369-75.
[10] Nievergall E, Reynolds J, Kok C H, et al. TGF-alpha and IL-6 plasma levels selectively identify CML patients who fail to achieve an early molecular response or progress in the first year of therapy[J]. Leukemia,2016,30(6):1263-72.
[11] Tarhini A A, Lin Y, Yeku O, et al. A four-marker signature of TNF-RII, TGF-alpha, TIMP-1 and CRP is prognostic of worse survival in high-risk surgically resected melanoma[J]. J Transl Med,2014,12:19.
[12] Addison C L, Ding K, Zhao H, et al. Plasma transforming growth factor alpha and amphiregulin protein levels in NCIC clinical trials group BR.21[J]. J Clin Oncol,2010,28(36): 5247-56.
[13] Shim K S, Kim K H, Park B W, et al. Increased serum levels of transforming growth factor-alpha in patients with colorectal cancer[J]. Dis Colon Rectum,1998,41(2): 219-24.
[14] Moskal T L, Huang S, Ellis L M,et al. Serum levels of transforming growth factor alpha in gastrointestinal cancer patients[J]. Cancer Epidemiol Biomarkers Prev,1995, 4(2): 127-31.