分泌型蛋白质NBL1在体—肺分流性肺动脉高压中的作用
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摘要
第一部分：新型单侧高动力性肺动脉高压模型的建立
目的：现有大鼠分流模型仅能导致肺血管产生Ⅰ级病变,而先天性心脏畸形患者肺组织内典型的肺血管重构改变至今尚未在大鼠分流模型中再现。本研究通过分期手术的方法,建立了一种新型单侧肺动脉高压大鼠模型,以诱导出更为严重的肺血管病变。
方法：经右侧肋间如胸腔,结扎右肺动脉,一周后,建立颈部分流。术后即刻,8周,12周通过右心导管评估此模型对肺血流动力学的即刻和长期作用。肺组织行HE染色和Weigert's染色来评估肺血管系统形态学改变情况。同时做了右室肥厚指数计算和血气分析。
结果：颈部分流完成瞬间肺循环即成循环高压状态,且随着病程的进展,逐步发展至临界态。肺血管病理学显示术后8周出现可逆病变(Ⅰ-Ⅱ级肺血管病变：中膜肌化,内膜增生),术后12周出现不可逆病变(Ⅲ级肺血管病变：内膜纤维化,血管腔闭塞)。同时伴有显著的右心室肥厚和氧分压的降低。
结论：此分流模型成功诱导了肺循环的高压状态,在相对较短的时间内再现了肺血管病变由可逆状态向不可逆状态的典型转变过程。因此,本研究可为分流性肺动脉高压潜在机制的研究提供一个死亡率低,可重复强的模型选择。
第二部分：分泌型蛋白质NBL1在体肺分流性肺动脉高压中的作用
背景：正常情况下主要表达于肺组织,而在体肺分流性肺动脉高压时发生特征性改变的蛋白质将是先天性心脏病肺动脉高压研究的新靶点。因此,本研究旨在发现在先天性心脏病性肺动脉高压发生发展过程中发生显著改变的分泌型蛋白质。
方法：对5例先天性心脏并合并重度肺动脉高压的病人和5例先天性心脏病且肺动脉压力正常的病人外周血进行抗体芯片的测试。筛选出变化显著的分泌型蛋白质,选择分泌型蛋白质NBL1作为进一步研究的靶点蛋白。Elisa的方法验证分泌型蛋白质NBL1在大样本的临床病例中的变化趋势及分泌型蛋白质NBL1的血浆浓度和肺血流动力学的相关性；应用RT-PCR, Western-blot及组织化学的方法在我们新近构建的大鼠体肺分流模型中进一步验证,以明确分泌型蛋白质NBL1在肺组织中的分布,表达情况及在肺动脉高压性肺组织中的变化；在肺动脉内皮细胞和肺动脉平滑肌细胞中验证NBL1的来源及重组NBL1蛋白对肺动脉内皮细胞和肺动脉平滑肌细胞增殖的影响；最后在体肺分流模型持续补充重组蛋白NBL1。
结果：抗体蛋白芯片结果发现一些分泌型蛋白质在先天性心脏病合并肺动脉高压的病人和先天性心脏病无肺动脉高压的病人间有显著的统计学差异。我们选择NBL1进行下一步验证。RT-PCR分析发现NBL1主要特异性的表达在正常肺组织且其：mRNA水平在体肺分流大鼠模型中呈时间依赖性的下降；Western-blot分析显示NBL1在正常肺组织中高表达且在体肺分流性肺组织中亦呈时间依赖性的表达下降；组织化学显示NBL1在正常肺组织中高表达,而在体肺分流性肺组织中低水平表达。而且,细胞学研究发现肺动脉内皮细胞和肺动脉平滑肌细胞均能分泌NBL1,且这种分泌行为伴随着细胞表型和细胞周期分布的改变,另外NBL1能特异的拮抗BMP2/4对肺动脉内皮细胞和肺动脉平滑肌细胞增殖的抑制作用。先天性心脏病病人和体肺分流性SD大鼠的外周血Elisa结果发现血浆NBL1水平随着肺动脉高压程度的加重而逐渐降低；而持续补充重组NBL1蛋白使体肺分流性SD大鼠肺动脉压力进一步升高,肺血管重构程度进一步加重。
结论：分泌型蛋白质NBL1主要高表达于正常肺组织。体肺分流性肺动脉高压性肺组织中NBL1的表达水平降低且血浆NBL1浓度和肺动脉高压的程度负相关。因此,NBL1或是先天性心脏病肺动脉高压的一个新的治疗靶点和候选生物标记物。
Part I:An original rat model of highkinetic unilateral pulmonary hypertension surgically induced by combined surgery
Background:Characteristic morphological lesions observed in lungs of patients with congenital cardiac anomalies have not been closely generated in rat shunt-related models except reversible grade one change. This study presented an original rat model of unilateral pulmonary arterial hypertension (PAH) surgically induced by combined surgery to reproduce more advanced pulmonary vascular lesions.
Methods:Right pulmonary artery was ligated through a right posterolateral thoracotomy; subsequently, a cervical shunt was established one week later. Immediate and chronic effects on pulmonary hemodynamics were evaluated through right heart catheterization immediately after and an interval of8,12weeks. Morphological changes in pulmonary vasculature were analyzed after staining with hematoxylin-eosin and modified Weighert's method. Right ventricular hypertrophy index and artery blood gas analysis were also calculated and performed.
Results:Pulmonary hypertensive status was successfully induced immediately after cervical surgery and progressively aggravated into a borderline state with the course advancing. Pulmonary vasculopathy demonstrated a transition from reversibility (muscularization, intimal proliferation-grade one, two) at the8th week to irreversibility (intimal fibrosis, entirely luminal occlusion-grade three) at the12week. Conspicuous right ventricular hypertrophy and descending partial arterial pressure of oxygen were also observed.
Conclusions:This shunt-related model successfully simulated a hypertensive status in pulmonary circulation and reproduced the characteristic transition of pulmonary vasculopathy from reversibility to irreversibility within a relatively short period. Thus, this model may offer an alternative with low mortality and high reproducibility for investigations on the underling mechanisms of shunt-related PAH. PartⅡ:Secreted protein NBL1exerts a critical role in pulmonary arterial hypertension associated with systemic-to-pulmonary shunts
Background:Proteins mainly expressed in normal lungs and characteristically changed in lungs suffering from systemic-to-pulmonary shunts will be useful research targets for pulmonary arterial hypertension in patients with congenital heart diseases(PAH/CHD). Thus, this study aimed to identify secreted proteins that significantly altered during the genesis and progression of PAH/CHD.
Methods:An antibody microarrary procedure was performed to detect proteins whose plasma levels specifically changed in patients with congenital intracardiac shunts. Then, significantly changed proteins were identified and the target protein NBL1was determined. Real-time quantitative PCR (RT-PCR), western-blot analysis and immunohistochemistry were performed to further examine the expression changes and location of NBL1in lungs from patients and rats with systemic-to-pulmonary shunts; the potentially biological role of NBL1on HPASMCs and HPAECs proliferation were also explored. The plasma NBL1concentration in a set of120patients with or without PAH was assessed by a commercially available enzyme-linked immunosorbent assay.
Results:The antibody microarrary procedure derived several proteins with s tatistically significant differences between patients with or without PAH. Secreted protein NBLl, which appeared as a valuable candidate for molecular markers of PAH, was selected for validation. Quantitative RT-PCR analysis revealed that NBL1was expressed with much higher specificity in normal lung tissues than in other systemic organ tissues, and the mRAN level was downregulated in a time-related modus in lungs suffering from systemic-to-pulmonary shunts; Western blot analysis revealed that NBL1was highly expressed in normal lung tissues and similarly a time-related reduction was also observed in pulmonary hypertensive lungs; Immunohistochemical analysis showed that NBL1was highly detected in normal lung tissues and was significantly down-regulated with the progression of PAH. Furthermore, NBL1could specially reverse the inhibitory effect of BMP2/4on HPASMCs and HPAECs proliferation; Elisa-kit also determined a detectable level of NBL1in the supernatants of culture media of the HPASMCs and HPAECs. Finally, plasma NBL1concentration was significantly downregulated according to the PAH/CHD stage.
Conclusion:NBLl is a secreted protein that is highly and mainly expressed in lungs. Downregulation of NBL1correlated with the severity of PAH. NBL1might be a candidate biomarker and a novel therapeutic target for PAH/CHD.
目的：现有大鼠分流模型仅能导致肺血管产生Ⅰ级病变,而先天性心脏畸形患者肺组织内典型的肺血管重构改变至今尚未在大鼠分流模型中再现。本研究通过分期手术的方法,建立了一种新型单侧肺动脉高压大鼠模型,以诱导出更为严重的肺血管病变。
方法：经右侧肋间如胸腔,结扎右肺动脉,一周后,建立颈部分流。术后即刻,8周,12周通过右心导管评估此模型对肺血流动力学的即刻和长期作用。肺组织行HE染色和Weigert's染色来评估肺血管系统形态学改变情况。同时做了右室肥厚指数计算和血气分析。
结果：颈部分流完成瞬间肺循环即成循环高压状态,且随着病程的进展,逐步发展至临界态。肺血管病理学显示术后8周出现可逆病变(Ⅰ-Ⅱ级肺血管病变：中膜肌化,内膜增生),术后12周出现不可逆病变(Ⅲ级肺血管病变：内膜纤维化,血管腔闭塞)。同时伴有显著的右心室肥厚和氧分压的降低。
结论：此分流模型成功诱导了肺循环的高压状态,在相对较短的时间内再现了肺血管病变由可逆状态向不可逆状态的典型转变过程。因此,本研究可为分流性肺动脉高压潜在机制的研究提供一个死亡率低,可重复强的模型选择。
第二部分：分泌型蛋白质NBL1在体肺分流性肺动脉高压中的作用
背景：正常情况下主要表达于肺组织,而在体肺分流性肺动脉高压时发生特征性改变的蛋白质将是先天性心脏病肺动脉高压研究的新靶点。因此,本研究旨在发现在先天性心脏病性肺动脉高压发生发展过程中发生显著改变的分泌型蛋白质。
方法：对5例先天性心脏并合并重度肺动脉高压的病人和5例先天性心脏病且肺动脉压力正常的病人外周血进行抗体芯片的测试。筛选出变化显著的分泌型蛋白质,选择分泌型蛋白质NBL1作为进一步研究的靶点蛋白。Elisa的方法验证分泌型蛋白质NBL1在大样本的临床病例中的变化趋势及分泌型蛋白质NBL1的血浆浓度和肺血流动力学的相关性；应用RT-PCR, Western-blot及组织化学的方法在我们新近构建的大鼠体肺分流模型中进一步验证,以明确分泌型蛋白质NBL1在肺组织中的分布,表达情况及在肺动脉高压性肺组织中的变化；在肺动脉内皮细胞和肺动脉平滑肌细胞中验证NBL1的来源及重组NBL1蛋白对肺动脉内皮细胞和肺动脉平滑肌细胞增殖的影响；最后在体肺分流模型持续补充重组蛋白NBL1。
结果：抗体蛋白芯片结果发现一些分泌型蛋白质在先天性心脏病合并肺动脉高压的病人和先天性心脏病无肺动脉高压的病人间有显著的统计学差异。我们选择NBL1进行下一步验证。RT-PCR分析发现NBL1主要特异性的表达在正常肺组织且其：mRNA水平在体肺分流大鼠模型中呈时间依赖性的下降；Western-blot分析显示NBL1在正常肺组织中高表达且在体肺分流性肺组织中亦呈时间依赖性的表达下降；组织化学显示NBL1在正常肺组织中高表达,而在体肺分流性肺组织中低水平表达。而且,细胞学研究发现肺动脉内皮细胞和肺动脉平滑肌细胞均能分泌NBL1,且这种分泌行为伴随着细胞表型和细胞周期分布的改变,另外NBL1能特异的拮抗BMP2/4对肺动脉内皮细胞和肺动脉平滑肌细胞增殖的抑制作用。先天性心脏病病人和体肺分流性SD大鼠的外周血Elisa结果发现血浆NBL1水平随着肺动脉高压程度的加重而逐渐降低；而持续补充重组NBL1蛋白使体肺分流性SD大鼠肺动脉压力进一步升高,肺血管重构程度进一步加重。
结论：分泌型蛋白质NBL1主要高表达于正常肺组织。体肺分流性肺动脉高压性肺组织中NBL1的表达水平降低且血浆NBL1浓度和肺动脉高压的程度负相关。因此,NBL1或是先天性心脏病肺动脉高压的一个新的治疗靶点和候选生物标记物。
Part I:An original rat model of highkinetic unilateral pulmonary hypertension surgically induced by combined surgery
Background:Characteristic morphological lesions observed in lungs of patients with congenital cardiac anomalies have not been closely generated in rat shunt-related models except reversible grade one change. This study presented an original rat model of unilateral pulmonary arterial hypertension (PAH) surgically induced by combined surgery to reproduce more advanced pulmonary vascular lesions.
Methods:Right pulmonary artery was ligated through a right posterolateral thoracotomy; subsequently, a cervical shunt was established one week later. Immediate and chronic effects on pulmonary hemodynamics were evaluated through right heart catheterization immediately after and an interval of8,12weeks. Morphological changes in pulmonary vasculature were analyzed after staining with hematoxylin-eosin and modified Weighert's method. Right ventricular hypertrophy index and artery blood gas analysis were also calculated and performed.
Results:Pulmonary hypertensive status was successfully induced immediately after cervical surgery and progressively aggravated into a borderline state with the course advancing. Pulmonary vasculopathy demonstrated a transition from reversibility (muscularization, intimal proliferation-grade one, two) at the8th week to irreversibility (intimal fibrosis, entirely luminal occlusion-grade three) at the12week. Conspicuous right ventricular hypertrophy and descending partial arterial pressure of oxygen were also observed.
Conclusions:This shunt-related model successfully simulated a hypertensive status in pulmonary circulation and reproduced the characteristic transition of pulmonary vasculopathy from reversibility to irreversibility within a relatively short period. Thus, this model may offer an alternative with low mortality and high reproducibility for investigations on the underling mechanisms of shunt-related PAH. PartⅡ:Secreted protein NBL1exerts a critical role in pulmonary arterial hypertension associated with systemic-to-pulmonary shunts
Background:Proteins mainly expressed in normal lungs and characteristically changed in lungs suffering from systemic-to-pulmonary shunts will be useful research targets for pulmonary arterial hypertension in patients with congenital heart diseases(PAH/CHD). Thus, this study aimed to identify secreted proteins that significantly altered during the genesis and progression of PAH/CHD.
Methods:An antibody microarrary procedure was performed to detect proteins whose plasma levels specifically changed in patients with congenital intracardiac shunts. Then, significantly changed proteins were identified and the target protein NBL1was determined. Real-time quantitative PCR (RT-PCR), western-blot analysis and immunohistochemistry were performed to further examine the expression changes and location of NBL1in lungs from patients and rats with systemic-to-pulmonary shunts; the potentially biological role of NBL1on HPASMCs and HPAECs proliferation were also explored. The plasma NBL1concentration in a set of120patients with or without PAH was assessed by a commercially available enzyme-linked immunosorbent assay.
Results:The antibody microarrary procedure derived several proteins with s tatistically significant differences between patients with or without PAH. Secreted protein NBLl, which appeared as a valuable candidate for molecular markers of PAH, was selected for validation. Quantitative RT-PCR analysis revealed that NBL1was expressed with much higher specificity in normal lung tissues than in other systemic organ tissues, and the mRAN level was downregulated in a time-related modus in lungs suffering from systemic-to-pulmonary shunts; Western blot analysis revealed that NBL1was highly expressed in normal lung tissues and similarly a time-related reduction was also observed in pulmonary hypertensive lungs; Immunohistochemical analysis showed that NBL1was highly detected in normal lung tissues and was significantly down-regulated with the progression of PAH. Furthermore, NBL1could specially reverse the inhibitory effect of BMP2/4on HPASMCs and HPAECs proliferation; Elisa-kit also determined a detectable level of NBL1in the supernatants of culture media of the HPASMCs and HPAECs. Finally, plasma NBL1concentration was significantly downregulated according to the PAH/CHD stage.
Conclusion:NBLl is a secreted protein that is highly and mainly expressed in lungs. Downregulation of NBL1correlated with the severity of PAH. NBL1might be a candidate biomarker and a novel therapeutic target for PAH/CHD.
引文
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5. Li XH, Jin HF, Bin G, Wang L, Tang C, Du J. Endogenous hydrogen sulfide regulates pulmonary artery collagen remodeling in rats with high pulmonary blood flow. Exp Biol Med 2009; 234(5):504-512.
6. Fullerton DA, Mitchell MB, Jone DN, Maki A, Mcintyre RC Jr. Pulmonary vasomotor dysfunction is produced with chronically high pulmonary blood flow. J Thorac Cardiovasc Surg 1996;111 (1):190-197.
7. Rondelet B, Dewachter C, Kerbaul F, Kang X, Fesler P, Brimioulle S, et al. Prolonged overcirculation-induced pulmonary arterial hypertension as a cause of right ventricular failure. Eur Heart J 2012;33(8):1017-26.
8. Wang W, Liu R, Cao G, Zhang F, Zhang Y, Zhang Z, et al. A reliable rabbit model for hyperkinetic pulmonary hypertension. J Thorac Cardiovasc Surg 2010;140(2):395-399.
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