高血流肺血管重建中内皮细胞NF-κB的活性研究
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摘要
研究背景
先天性心脏病(congenital heart disease, CHD)是儿童常见的先天畸形之一,发病率为7‰～8‰,而肺动脉高压(pulmonary hypertension, PH)可发生于先天性心脏病演变过程的各个阶段,左向右分流型先天性心脏病导致肺动脉高压的治疗成为目前国内外备受关注的临床问题。左向右分流型先天性心脏病时,由于肺血流量增加,导致肺动脉切应力(shear stress,SS)增加,肺动脉内皮结构和功能发生改变,可引起明显的血管内皮受损。内皮细胞受损后,破坏了内皮的屏障作用以及内皮细胞和平滑肌细胞之间的肌—内皮连接,也损伤了内皮细胞对平滑肌细胞的调控作用,从而使血管平滑肌细胞(vascular smooth muscle cell,VSMC)失去控制而增殖,引起肺血管重建。肺血管重建是血管对外界环境变化的一种适应性改变,同时又是肺动脉高压发生的病理生理基础。血管内皮细胞(vascular endothelial cell, VEC)处于直接与血流接触的界面,对血管壁正常生理功能起屏障作用,又具有感受器功能,还是合成传导介质的中枢,将切应力刺激转化为细胞的生物效应,因此,血管内皮对调控血管张力和肺动脉压力起重要作用。如果增加的肺血流量(pulmonary flow, PF)超过一定限度,使血管的反应性增强损伤了内皮细胞对血管张力的调控机制,就可能导致肺动脉高压。
1986年,Sen和Baltimore首先从B淋巴细胞核抽提物中检测到一种能与免疫球蛋白κ轻链基因增强子κB序列(GGG ACT TTC)特异结合的核蛋白因子,称之为NF—κB。此后人们发现它存在于许多类型的细胞中,包括血管内皮细胞、平滑肌细胞和心肌细胞。该因子能够和许多基因上启动子区域的固定核苷酸序列(nucleotide sequence)结合而启动基因转录的功能,在机体的免疫应答、炎症反应及细胞的生长调控等方面发挥重要作用,与多种心血管疾病的发生和发展有关。NF—κB是细胞内最重要的核转录因子,在许多细胞刺激介导的细胞信息的转录调控中起核心作用,参与多种基因的表达和调控,是细胞激活的标志。能激活NF-κB的因素很多,包括各种应激性刺激、多种炎性细胞因子(如TNF-α、IL-1β)、有丝分裂原、氧自由基、蛋白激酶C等。当细胞受到上述刺激时,蛋白激酶被激活,使IκBα蛋白调节区的Sef32／36磷酸化,进而N端的2个赖氨酸残基与遍在蛋白结合而发生遍在蛋白化。最后在蛋白酶小体的作用下IκBα发生裂解,暴露出Rel蛋白上的核定位信号(NLS),导致NF-κB-IκB复合体解体,活化后的NF-κB即迅速从细胞质移位于细胞核,入核的NF-κB二聚体与靶基因上的K B位点发生特异性结合,从而启动和调控相关靶基因的转录。
研究证实,血管内皮细胞受到外界因子刺激后,首先会激活NF—κB,后者与细胞粘附分子基因结合,使其表达上调,这些粘附分子的基因都含有NF—κB的结合位点,在白细胞附着、侵入和迁移于血管中具有重要作用,NF—κB的激活被视为血管内皮细胞受损的始动机制之一。血管平滑肌细胞的增殖和游走受许多基因调控,NF—κB的激活同样是血管平滑肌的必经始动环节。我们研究高血流肺血管重建中内皮细胞NF—κB激活状态以及介导的细胞生物学作用对肺动脉高压形成的影响及其调控作用,将对了解肺动脉高压的成因和靶向性的干预治疗起重要作用。
研究目的
本研究通过检测高血流肺血管重建中肺动脉内皮细胞中NF—κB的活性及使用NF-κB阻断剂吡咯烷二硫基甲酸盐(PDTC)进行干预后的变化,有助于寻找高肺血流引起的肺动脉高压的病理生理成因,通过调节NF—κB的激活抑制肺血管平滑肌细胞的增殖,为肺动脉高压的预防和治疗提供理论依据和新的途径。
研究方法
50只4周龄Wistar大鼠编号,计算机随机分为4个组,其中,分流组Tn15只,手术后PDTC阻断组Ti15只,假手术对照组Co10只,正常对照组Cn10只。将Tn组和Ti组共30只大鼠通过套管连接法建立左侧颈总动脉-颈外静脉分流,其中PDTC阻断实验组(Ti)15只大鼠于术前1h开始腹腔注射PDTC,剂量为120mg·kg-1·d-1,术后持续注射2周,Co组大鼠除了不进行颈总动脉-颈外静脉吻合外,其余手术程序与实验组完全相同。连续饲养12周后,采用心导管术测量肺动脉收缩压(pulmonary arterial systolic pressure, PASP),计算Qp／Qs；测压后开胸取肺动脉、肺组织和心脏,计算右心室与左心室+室间隔[right ventricle/left ventricle+septum, RV/(LV+SP)]的重量之比,估计右心室肥厚程度。肺组织切片HE染色光镜下观察肺血管形态学改变,测量并计算中等血管中膜厚度所占管径百分比(MT%)；分离大鼠肺动脉内皮细胞,提取核蛋白,制备DNA引物,通过凝胶迁移率实验(EMSA)测定各组内皮细胞NF-κB与特定基因识别序列相结合的活性。
研究结果
①颈总动脉-颈外静脉分流导致肺循环血流量增加,Qp／Qs平均值为2.32±0.44；Tn组肺动脉收缩压(PASP)明显高于Cn组(P<0.01),Ti组PASP与Cn组相比差异无统计学意义(P>0.05),Co组与Cn组相比无明显差异。②与对照组(Co和Cn组)相比,Tn组肺动脉管腔狭窄或闭塞,内膜增厚,部分内膜脱落,平滑肌细胞排列紊乱、过度增生和肥大；Ti组内膜肿胀,部分脱落,中膜无明显肥厚；Cn组与Co组相比无明显差异。Co组MT%及RV／(LV+SP)与Cn组相比无差异,Tn组MT%及RV／(LV+SP)明显高于对照组(Co和Cn组)(P<0.01),Ti组MT%及RV／(LV+SP)与对照组(Co和Cn组)相比差异不明显(P>0.05)。③Tn组NF—κB活性明显高于Cn组(P<0.01),Ti组NF—κB活性低于Cn组(P<0.01),而Co组与Cn组相比无明显差异。
研究结论
高肺血流所致的大鼠肺血管收缩和结构重建与NF—κB的活性增强有关,阻断剂PDTC可以通过阻断高血流所致的NF—κB信号通路从而干预肺血管重建。
Background
Congenital heart disease is a common congenital malformation,with 7%o-8%o incidence.Pulmonary hypertension develop in every development stage of congenital heart disease,therefore, many clinical doctors, at home and abroad,pay close attention to the treatment of left-to-right shunt cogenital heart disease.Pulmonary flow increases in left-to-right shunt cogenital heart disease,which makes shear stress to pulmonary artery increase,lead to pathological changes of structure and function pulmonary in arterial endothelium,thus,vascular endothelium is markedly damaged.Close behind,the barrier function of endothelium and endothelial-mucular conjunction are damaged,meanwhile the mechnism of endothelium modulating vascular smooth muscle cells,which induce vascular endothelial cells to proliferate uncontrolledly.So,pulmonary vascular remolding happens.On the one hand,it is a adaptive change to enviroment,the other hand, it is the physiopathologic found of pulmonary hypertension.Vascular endothelial cell that lies on the surface layer sensing blood flow is a physiological barrier,a sensor and a centor of production of conductive mediators.It can convert stress to biological effect.Accordingly,vascular endothelium plays an important part in angiotasis and pulmonary artery pressure.If increased pulmonary flow exceeds a limit,which damages regulation mechnism of endothelium to angiotasis,pulmonary hypertension happens.
In 1986,Sen and Baltimore firstly detect a neucleoprotein factor which can specially bind to gene enhanserκB sequence(GGG ACT TTC) of immunoglobulinκL-chain,which is called NF-κB.After this,it is found in many kinds of cells,including vascular endothelial cells、smooth muscle cells and cardiac muscle cells. NF-κB can bind to specified nucleotide sequence of promotor domain,to start genetic transcription in immune response、inflammatory reaction and growth regulation of cells,which relate to diverse of onset and development of cardiovascular diseases. NF-κB is the most important nuclear factor in cells and plays a crucial part in signal transduction mediated by cell stimulus.Factors which can activate NF-κB are great deal,including various kinds of irritable stimulus,multiple cytokins(e.g.TNF-a,IL-1β),mitogen, oxygen free radical,protein kinase C,et al.When above-mentioned stimulus effect cells, protein kinases are activated, which make Sef32/36 of IκBa protein-regulation domain phosphorylates,and then 2 diaminocaproic acid residue of N-terminal bind to ubiquitin-ubiquitination. At last under the proteasome'function, IκBαschizolysis, nuclear localization signal on Rel protein snagged,lead to NF-κB-IκB-compound resolute,as result activated NF-κB rapidly enter into nucleus and specialy bind toκB site at target gene to start and regulate transcription of related target gene.
Study confirm that vascular endothelial cell suffer outside stimulus,then firstly activate NF-κB,the latter bind to cell adhesion molecule gene and make it expression up-regulate.These adhesion molecule genes contain binding sites of NF-κB,which play an important part in coherence,invasion and immagration to blood vessel of white blood cell.So, activation of NF-κB is deemed to one of the start-up mechnism of damage to vascular endothelial cell.We study NF-κB activated condition of endothelial cell and cytobiologic function mediated by it to influence on pulmonary hypertension and regulation,which play an important part in understanding cause and target intervention treatment of pulmonary hypertension.
Objective
Through detecting activation of NF-κB in pulmonary endothelial cells of pulmonary vacular remolding induced by high blood flow and changes after given a block agent (PDTC) of NF-κB,the study conduce to search for physiopathologic causes of pulmonary hypertension induced by high pulmonary blood and provide theory basis and new path to PH by regulating NF-κB pathway to inhibite proliferation of pulmonary vascular smooth muscle cells.
Research Methods
Number 50 Wistar rats,aged 4w,randomly group 4 by computer,shunt group (Tn) 15,blocked by PDTC after operation group(Ti) 15,sham operation control group(Co) 10,negative control group 10 (Cn).30 rats(Tn+Ti) are seted up left common carotid artery-left external jugular vein shunt by telescoped joint,of the total 15 rats(Ti group) are given PDTC by intraperitoneal injection before operation lh,dosage 12Omg·kg-1·d-1after this,continue 2w;except not undertaking shunt operation,Co group rats own the identical operative procedure.After conscutively raising 12w, cardiac catheterization are used to survey pulmonary arterial systolic pressure,to calculate Qp/Qs;After then, to open the chest and remove the lung and the heart;Calculate the weight ratio of right ventricle and left ventricle plus septum to estimate the hypertrophy of the right ventricle.Lung tissue slices dyed by HE are observed in morphologic change of pulmonary vessels by light microscope,measure and calculate MT%(percentage of tunica media thickness making for caliber) of medium vessles.Dissociate pulmonary arterial endothelial cells,extract neucleoprotein,prepare DNA primer,determine the binding activity of endothelial cells in every group and special gene recognition sequence by ESMA(electrophoretic mobility shift assay)
Research Results
①Left common carotid artery-left external jugular vein shunt lead to increase of pulmonary blood flow,the general average of Qp/Qs is 2.32±0.44.Compared to Cn group,PASP of Tn group significantly increases(P<0.01),the increase of Ti group'PASP have no statistical significance(P>0.05). Cn group and Co group have no significant difference.②Compared to control group, Tn group,pulmonary arterial lumina narrow or occlude;endomembranes thicken,part of them ablate;vacular smooth muscle cell array disorder,hyperplasia and hypertrophy;Ti group,endomembrane swells,some of them ablate,tunica media is not obviously thickening;Cn group and Co group have no significant difference.Tn group,MT% and RV/(LV+SP) significantly higher than control group (P<0.01);Ti group compared to control group, MT% and RV/(LV+SP) have no significant difference.③Ti group activation of NF-κB is significantly higher than control group (P<0.01),Tn group significantly lower than control (P＜0.01).
Conclusion
Rat pulmonary blood vessels construction and constructure remolding are related to augmented activaty of NF-κB.PDTC can interfere in pulmonary vascular remolding by blocking NF-κB signaling way induced by high blood flow.
先天性心脏病(congenital heart disease, CHD)是儿童常见的先天畸形之一,发病率为7‰～8‰,而肺动脉高压(pulmonary hypertension, PH)可发生于先天性心脏病演变过程的各个阶段,左向右分流型先天性心脏病导致肺动脉高压的治疗成为目前国内外备受关注的临床问题。左向右分流型先天性心脏病时,由于肺血流量增加,导致肺动脉切应力(shear stress,SS)增加,肺动脉内皮结构和功能发生改变,可引起明显的血管内皮受损。内皮细胞受损后,破坏了内皮的屏障作用以及内皮细胞和平滑肌细胞之间的肌—内皮连接,也损伤了内皮细胞对平滑肌细胞的调控作用,从而使血管平滑肌细胞(vascular smooth muscle cell,VSMC)失去控制而增殖,引起肺血管重建。肺血管重建是血管对外界环境变化的一种适应性改变,同时又是肺动脉高压发生的病理生理基础。血管内皮细胞(vascular endothelial cell, VEC)处于直接与血流接触的界面,对血管壁正常生理功能起屏障作用,又具有感受器功能,还是合成传导介质的中枢,将切应力刺激转化为细胞的生物效应,因此,血管内皮对调控血管张力和肺动脉压力起重要作用。如果增加的肺血流量(pulmonary flow, PF)超过一定限度,使血管的反应性增强损伤了内皮细胞对血管张力的调控机制,就可能导致肺动脉高压。
1986年,Sen和Baltimore首先从B淋巴细胞核抽提物中检测到一种能与免疫球蛋白κ轻链基因增强子κB序列(GGG ACT TTC)特异结合的核蛋白因子,称之为NF—κB。此后人们发现它存在于许多类型的细胞中,包括血管内皮细胞、平滑肌细胞和心肌细胞。该因子能够和许多基因上启动子区域的固定核苷酸序列(nucleotide sequence)结合而启动基因转录的功能,在机体的免疫应答、炎症反应及细胞的生长调控等方面发挥重要作用,与多种心血管疾病的发生和发展有关。NF—κB是细胞内最重要的核转录因子,在许多细胞刺激介导的细胞信息的转录调控中起核心作用,参与多种基因的表达和调控,是细胞激活的标志。能激活NF-κB的因素很多,包括各种应激性刺激、多种炎性细胞因子(如TNF-α、IL-1β)、有丝分裂原、氧自由基、蛋白激酶C等。当细胞受到上述刺激时,蛋白激酶被激活,使IκBα蛋白调节区的Sef32／36磷酸化,进而N端的2个赖氨酸残基与遍在蛋白结合而发生遍在蛋白化。最后在蛋白酶小体的作用下IκBα发生裂解,暴露出Rel蛋白上的核定位信号(NLS),导致NF-κB-IκB复合体解体,活化后的NF-κB即迅速从细胞质移位于细胞核,入核的NF-κB二聚体与靶基因上的K B位点发生特异性结合,从而启动和调控相关靶基因的转录。
研究证实,血管内皮细胞受到外界因子刺激后,首先会激活NF—κB,后者与细胞粘附分子基因结合,使其表达上调,这些粘附分子的基因都含有NF—κB的结合位点,在白细胞附着、侵入和迁移于血管中具有重要作用,NF—κB的激活被视为血管内皮细胞受损的始动机制之一。血管平滑肌细胞的增殖和游走受许多基因调控,NF—κB的激活同样是血管平滑肌的必经始动环节。我们研究高血流肺血管重建中内皮细胞NF—κB激活状态以及介导的细胞生物学作用对肺动脉高压形成的影响及其调控作用,将对了解肺动脉高压的成因和靶向性的干预治疗起重要作用。
研究目的
本研究通过检测高血流肺血管重建中肺动脉内皮细胞中NF—κB的活性及使用NF-κB阻断剂吡咯烷二硫基甲酸盐(PDTC)进行干预后的变化,有助于寻找高肺血流引起的肺动脉高压的病理生理成因,通过调节NF—κB的激活抑制肺血管平滑肌细胞的增殖,为肺动脉高压的预防和治疗提供理论依据和新的途径。
研究方法
50只4周龄Wistar大鼠编号,计算机随机分为4个组,其中,分流组Tn15只,手术后PDTC阻断组Ti15只,假手术对照组Co10只,正常对照组Cn10只。将Tn组和Ti组共30只大鼠通过套管连接法建立左侧颈总动脉-颈外静脉分流,其中PDTC阻断实验组(Ti)15只大鼠于术前1h开始腹腔注射PDTC,剂量为120mg·kg-1·d-1,术后持续注射2周,Co组大鼠除了不进行颈总动脉-颈外静脉吻合外,其余手术程序与实验组完全相同。连续饲养12周后,采用心导管术测量肺动脉收缩压(pulmonary arterial systolic pressure, PASP),计算Qp／Qs；测压后开胸取肺动脉、肺组织和心脏,计算右心室与左心室+室间隔[right ventricle/left ventricle+septum, RV/(LV+SP)]的重量之比,估计右心室肥厚程度。肺组织切片HE染色光镜下观察肺血管形态学改变,测量并计算中等血管中膜厚度所占管径百分比(MT%)；分离大鼠肺动脉内皮细胞,提取核蛋白,制备DNA引物,通过凝胶迁移率实验(EMSA)测定各组内皮细胞NF-κB与特定基因识别序列相结合的活性。
研究结果
①颈总动脉-颈外静脉分流导致肺循环血流量增加,Qp／Qs平均值为2.32±0.44；Tn组肺动脉收缩压(PASP)明显高于Cn组(P<0.01),Ti组PASP与Cn组相比差异无统计学意义(P>0.05),Co组与Cn组相比无明显差异。②与对照组(Co和Cn组)相比,Tn组肺动脉管腔狭窄或闭塞,内膜增厚,部分内膜脱落,平滑肌细胞排列紊乱、过度增生和肥大；Ti组内膜肿胀,部分脱落,中膜无明显肥厚；Cn组与Co组相比无明显差异。Co组MT%及RV／(LV+SP)与Cn组相比无差异,Tn组MT%及RV／(LV+SP)明显高于对照组(Co和Cn组)(P<0.01),Ti组MT%及RV／(LV+SP)与对照组(Co和Cn组)相比差异不明显(P>0.05)。③Tn组NF—κB活性明显高于Cn组(P<0.01),Ti组NF—κB活性低于Cn组(P<0.01),而Co组与Cn组相比无明显差异。
研究结论
高肺血流所致的大鼠肺血管收缩和结构重建与NF—κB的活性增强有关,阻断剂PDTC可以通过阻断高血流所致的NF—κB信号通路从而干预肺血管重建。
Background
Congenital heart disease is a common congenital malformation,with 7%o-8%o incidence.Pulmonary hypertension develop in every development stage of congenital heart disease,therefore, many clinical doctors, at home and abroad,pay close attention to the treatment of left-to-right shunt cogenital heart disease.Pulmonary flow increases in left-to-right shunt cogenital heart disease,which makes shear stress to pulmonary artery increase,lead to pathological changes of structure and function pulmonary in arterial endothelium,thus,vascular endothelium is markedly damaged.Close behind,the barrier function of endothelium and endothelial-mucular conjunction are damaged,meanwhile the mechnism of endothelium modulating vascular smooth muscle cells,which induce vascular endothelial cells to proliferate uncontrolledly.So,pulmonary vascular remolding happens.On the one hand,it is a adaptive change to enviroment,the other hand, it is the physiopathologic found of pulmonary hypertension.Vascular endothelial cell that lies on the surface layer sensing blood flow is a physiological barrier,a sensor and a centor of production of conductive mediators.It can convert stress to biological effect.Accordingly,vascular endothelium plays an important part in angiotasis and pulmonary artery pressure.If increased pulmonary flow exceeds a limit,which damages regulation mechnism of endothelium to angiotasis,pulmonary hypertension happens.
In 1986,Sen and Baltimore firstly detect a neucleoprotein factor which can specially bind to gene enhanserκB sequence(GGG ACT TTC) of immunoglobulinκL-chain,which is called NF-κB.After this,it is found in many kinds of cells,including vascular endothelial cells、smooth muscle cells and cardiac muscle cells. NF-κB can bind to specified nucleotide sequence of promotor domain,to start genetic transcription in immune response、inflammatory reaction and growth regulation of cells,which relate to diverse of onset and development of cardiovascular diseases. NF-κB is the most important nuclear factor in cells and plays a crucial part in signal transduction mediated by cell stimulus.Factors which can activate NF-κB are great deal,including various kinds of irritable stimulus,multiple cytokins(e.g.TNF-a,IL-1β),mitogen, oxygen free radical,protein kinase C,et al.When above-mentioned stimulus effect cells, protein kinases are activated, which make Sef32/36 of IκBa protein-regulation domain phosphorylates,and then 2 diaminocaproic acid residue of N-terminal bind to ubiquitin-ubiquitination. At last under the proteasome'function, IκBαschizolysis, nuclear localization signal on Rel protein snagged,lead to NF-κB-IκB-compound resolute,as result activated NF-κB rapidly enter into nucleus and specialy bind toκB site at target gene to start and regulate transcription of related target gene.
Study confirm that vascular endothelial cell suffer outside stimulus,then firstly activate NF-κB,the latter bind to cell adhesion molecule gene and make it expression up-regulate.These adhesion molecule genes contain binding sites of NF-κB,which play an important part in coherence,invasion and immagration to blood vessel of white blood cell.So, activation of NF-κB is deemed to one of the start-up mechnism of damage to vascular endothelial cell.We study NF-κB activated condition of endothelial cell and cytobiologic function mediated by it to influence on pulmonary hypertension and regulation,which play an important part in understanding cause and target intervention treatment of pulmonary hypertension.
Objective
Through detecting activation of NF-κB in pulmonary endothelial cells of pulmonary vacular remolding induced by high blood flow and changes after given a block agent (PDTC) of NF-κB,the study conduce to search for physiopathologic causes of pulmonary hypertension induced by high pulmonary blood and provide theory basis and new path to PH by regulating NF-κB pathway to inhibite proliferation of pulmonary vascular smooth muscle cells.
Research Methods
Number 50 Wistar rats,aged 4w,randomly group 4 by computer,shunt group (Tn) 15,blocked by PDTC after operation group(Ti) 15,sham operation control group(Co) 10,negative control group 10 (Cn).30 rats(Tn+Ti) are seted up left common carotid artery-left external jugular vein shunt by telescoped joint,of the total 15 rats(Ti group) are given PDTC by intraperitoneal injection before operation lh,dosage 12Omg·kg-1·d-1after this,continue 2w;except not undertaking shunt operation,Co group rats own the identical operative procedure.After conscutively raising 12w, cardiac catheterization are used to survey pulmonary arterial systolic pressure,to calculate Qp/Qs;After then, to open the chest and remove the lung and the heart;Calculate the weight ratio of right ventricle and left ventricle plus septum to estimate the hypertrophy of the right ventricle.Lung tissue slices dyed by HE are observed in morphologic change of pulmonary vessels by light microscope,measure and calculate MT%(percentage of tunica media thickness making for caliber) of medium vessles.Dissociate pulmonary arterial endothelial cells,extract neucleoprotein,prepare DNA primer,determine the binding activity of endothelial cells in every group and special gene recognition sequence by ESMA(electrophoretic mobility shift assay)
Research Results
①Left common carotid artery-left external jugular vein shunt lead to increase of pulmonary blood flow,the general average of Qp/Qs is 2.32±0.44.Compared to Cn group,PASP of Tn group significantly increases(P<0.01),the increase of Ti group'PASP have no statistical significance(P>0.05). Cn group and Co group have no significant difference.②Compared to control group, Tn group,pulmonary arterial lumina narrow or occlude;endomembranes thicken,part of them ablate;vacular smooth muscle cell array disorder,hyperplasia and hypertrophy;Ti group,endomembrane swells,some of them ablate,tunica media is not obviously thickening;Cn group and Co group have no significant difference.Tn group,MT% and RV/(LV+SP) significantly higher than control group (P<0.01);Ti group compared to control group, MT% and RV/(LV+SP) have no significant difference.③Ti group activation of NF-κB is significantly higher than control group (P<0.01),Tn group significantly lower than control (P＜0.01).
Conclusion
Rat pulmonary blood vessels construction and constructure remolding are related to augmented activaty of NF-κB.PDTC can interfere in pulmonary vascular remolding by blocking NF-κB signaling way induced by high blood flow.
引文
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[12]杨杰,王一彪.小儿心脏病学理论与实践[M].北京：人民军医出版社,2009：
242-254.
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