CTNNAL1表达的应答性调控及其在哮喘及气道上皮中的作用
摘要
目的:
关于哮喘发病机制,气道上皮缺陷理论已成为主流观点之一。哮喘的病理特征之一表现为支气管上皮损伤、脱落,提示哮喘患者的气道上皮对损伤应激的修复反应可能出现缺陷。已知上皮细胞通过表达不同类型的粘附分子实现“粘附”和“锚定”是发挥正常功能的先决条件。国内外及本实验室多项研究证实,粘附分子在气道炎症及损伤修复中发挥重要作用。为了确定与哮喘易感性相关的粘附分子表达特征,本实验室在先前的研究中应用基因芯片及生物信息学方法筛选了人外周血差异表达粘附分子,发现连环素(catenin)家族中的CTNNAL1(catenin alpha-like 1)基因在哮喘病人中表达下调。由于目前对于CTNNAL1功能意义的直接研究极少,其在支气管上皮及肺组织中的作用尚未见报道。本课题围绕CTNNAL1与哮喘发病的关系、CTNNAL1对支气管肺组织功能的影响及CTNNAL1基因表达调控进行了一系列研究。
方法与结果:
1) CTNNAL1与哮喘相关性分析
本实验室在先前的研究中应用基因芯片及生物信息学方法筛选了人外周血哮喘差异表达粘附分子,结果显示多个基因表达水平改变。本研究选择在所有哮喘病人中均下调的CTNNAL1(catenin alpha-like1)基因,应用荧光定量RT-PCR进一步证实结果的可靠性;收集正常人及哮喘病人的支气管粘膜,并构建经典的OVA致敏的小鼠哮喘模型,探讨CTNNAL1在支气管肺组织的分布情况及其与哮喘的关系。
荧光定量RT-PCR结果显示成年哮喘病人与正常成年人相比CTNNAL1表达水平明显降低。哮喘儿童病人CTNNAL1表达水平似比正常儿童低,但P＞0.05,尚不能认为有统计学意义,需扩大样本量进一步证实。
免疫组化和原位杂交显示,CTNNAL1广泛分布于支气管柱状纤毛细胞、细支气管分泌细胞、间质细胞、血管内皮细胞及肺泡上皮细胞。CTNNAL1在哮喘病人支气管粘膜及哮喘模型小鼠的支气管肺组织表达均下调,哮喘模型组小鼠气道阻力显著高于正常组,且CTNNAL1 mRNA水平与气道阻力呈负相关。以上结果证实CTNNAL1与哮喘发病相关。
2) CTNNAL1在气道上皮中的生物学效应
本实验利用吸入臭氧建立Balb/c小鼠支气管肺组织应激损伤模型。结果显示,臭氧应激导致明显的杯状细胞增生和上皮缺损。原位杂交实验和荧光定量RT-PCR显示臭氧应激可上调小鼠支气管肺组织CTNNAL1 mRNA表达,于应激的第二天达到高峰,但是随着臭氧应激时间的延长,CTNNAL1 mRNA表达缓慢下降。培养的人BEC细胞株爬片细胞原位杂交显示,未受臭氧应激组BEC阳性细胞数较少,胞浆呈浅黄色,臭氧攻击培养的人BEC 30 min后,阳性细胞数明显增多,染色明显加深,呈深黄色。荧光定量RT-PCR结果与原位杂交一致。提示CTNNAL1参与BEC应激反应,其表达水平受应激调控。
为阐明CTNNAL1在急性应激下上调的功能意义,我们利用CTNNAL1表达质粒和CTNNAL1反义寡核苷酸(ASO)建立CTNNAL1高表达或阻抑手段,籍此观察CTNNAL1在气道上皮中的生物学作用。损伤修复测定采用机械损伤在融合的支气管上皮细胞单层上造成一小面积不规则缺损,用显微视频分析系统每隔4h测量缺损面积一次,绘制时间与修复面积的直线回归方程,直线的斜率为损伤修复指数,斜率越大,损伤修复速度越快。增殖采用MTT法。结果显示CTNNAL1可促进细胞的损伤修复和增殖。CTNNAL1 mRNA在损伤修复边缘的活跃细胞高表达,有利于上皮细胞的修复。
我们还初步观察了CTNNAL1在细胞外基质纤维连接蛋白(Fibronectin,Fn)激活与细胞迁移运动有关的激酶中的作用。利用Western blot技术观察到CTNNAL1 ASO单独处理不影响FAK磷酸化,但CTNNAL1 ASO处理可降低Fn促FAK磷酸化效应,提示CTNNAL1在Fn促损伤修复与增殖效应的FAK磷酸化途径中发挥作用。
以上结果提示CTNNAL1参与维持气道上皮的完整性,CTNNAL1表达下调可能导致上皮功能缺陷及完整性破坏,从而与哮喘发病相关。我们认为,急性应激条件下CTNNAL1表达上调是一种保护性应答,哮喘病人可能出现了这种应答机制的缺陷。
3) CTNNAL1基因表达调控研究
为了进一步认识CTNNAL1基因表达调控机制,本研究对CTNNAL1的转录因子调节谱进行筛选。利用启动子分析软件PromoterScan和Transfac对CTNNAL1基因5′非编码区进行分析,推测启动子所在范围在-552～-152 from ATG。TESS软件(Transcription ElementSearch System)分析该区域内可能的转录因子结合位点,据此设计8条探针,覆盖所有的转录因子结合位点,应用凝胶阻滞电泳(electrophoretic mobility shift assays,EMSA)筛选调控CTNNAL1表达的转录因子,结果显示探针1,2,3,5,8有与蛋白结合形成的滞后带,能被100倍未标记探针所竞争,为特异性结合。通过突变探针结合试验、抗体超迁移试验,证实与探针结合的转录因子分别为LEF-1、AP-2α和CREB。染色质免疫共沉淀实验显示,LEF-1和AP-2α可特异性与CTNNAL1启动子结合。
紧接着,我们用基因定点突变技术观察LEF-1和AP-2α对CTNNAL1启动子活性的影响,结果显示LEF-1与AP-2α的结合位点突变后,CTNNAL1启动子活性下降。
进一步,我们用EMSA观察到LEF-1与AP-2α在臭氧应激30min后的活化情况,结果显示臭氧应激后LEF-1活化增加,在应激后1h达到高峰,AP-2α的活化发生在0-1h之间,于应激后30 min达到高峰。CTNNAL1 mRNA的表达与两种转录因子的激活一致。提示在臭氧应激条件下,LEF-1与AP-2α特异性与CTNNAL1结合,共同调控CTNNAL1的表达。
结论:
LEF-1与AP-2α特异性与CTNNAL1结合,共同调控CTNNAL1的表达。急性应激条件下CTNNAL1表达上调,促进支气管上皮细胞损伤修复与增殖,参与维持气道上皮的完整性。CTNNAL1在哮喘病人及哮喘模型小鼠表达下调,可能导致上皮功能缺陷及完整性破坏,从而与哮喘发病相关。
Objectives:
Destruction in airway epithelium structure and integrity,which is often induced by flaws of constitutive adhesion,is the essential link of asthma pathogenicity.During the course of AHR or airway inflammation, airway epithelial cells express adhesion molecules to arrest leucocytes and evoke an inflammation reaction in airway.Airway epithelial cells anchored to extracellular matrix through intergrins and sustained the ability of against injury,repair and integrity in structure or in function of human bronchial epithelial cells(BEC).Therefore it can be reasonably speculated that abnormal expression of adhesive molecules in airway epithelial cells, which might be possibly due to either correspond coding gene alteration or imbalance expression among various kind of adhesion molecules, contribute to aberrant susceptibility to asthma.Based on the result of asthma-associated adhesion molecules expression spectrum,CTNNAL1, whose expression was down regulated in asthma patients,was selected as a candidate in this present study for a further functional investigation.Up to now,there is very little known about the pulmonary biological effects, gene expression modulation of CTNNAL1.The present study was designed to identity the association of CTNNAL 1 with asthma,observe the pulmonary biological effects and gene expression modulation of CTNNAL1.
Contents:
1.Identity the association of CTNNAL 1 with asthma
Our previous study used a cDNA microarray to screen the differential expression of adhesion molecules in human peripheral blood leucocytes, and found that an alpha-catenin-related protein,catenin alpha-like 1 (CTNNAL1) was downregulated in asthma patients.In this study,Real time PCR was used to further confirm the expression of CTNNAL1 in asthm.Immunohistochemistry was used to verified CTNNAL1 expression on tunica mucosa bronchiorum of normal person and asthma patients. Using a well-characterized OVA-sensitized Balb/c mice asthma model,we carried out a time course study of the expression of CTNNAL1 in lung following the AHR progression.
Results:In situ hybridizition showed CTNNAL1 was predominantly localized in the ciliated columnar epithelium of bronchioles,secretory cells of terminal bronchioles,vascular endothelial cells and alveolar cells.The expression of CTNNAL1 mRNA was significantly down regulated in the peripheral blood leucocyte and tunica mucosa bronchiorum.Real-time PCR showed the mRNA level of CTNNAL1 was decreased in asthma animals.There was a negative correlation between the pulmonary resistance(R_L) in asthma mice and the levels of CTNNAL1 mRNA.This present study demonstrated that CTNNAL1 is highly correlated with asthma.
2.Function study of CTNNAL1 on airway epithelium
Balb/c mice were inhaled a mixture of 2.0ppm ozone and fresh air for one,two,four,and eight days respectively to establish a airway stressed animal model and the time and spatial expression of CTNNAL1 were examined by ISH and Real-time PCR.The results showed inflammationary infiltration,mucosal exudation,cavitary stricture and bronchial epithelial denudation were observed in the ozone-stressed group.The expression of CTNNAL1 mRNA was increased with the ozone stress,peaked on the second day,and then reduced.The results also showed that expression of CTNNAL1 mRNA was explicitly increased in ozone-stressed BEC.
To investigate function of CTNNAL1 in asthma,we established a CTNNAL1 expression plasmid and designed CTNNAL1 antisense oligonucleotide(ASO) to promoter or hinder the expression of CTNNAL1. Then we use them to observe the effect of CTNNAL1 on the repair and proliferation of BEC.
A small wound was made in the confluent monolayer by mechanical scraping and the remaining wound area was measured serially per 4 hours in 24h by video microscopy.A linear regression equation of the remaining wound area to time was obtained and the slope was used to judge the repair speed of BECs.The proliferation of BECs was assayed by MTT.The results showed that the wound repair and proliferation of BECs were accelerated by CTNNAL1.
We also detect the effect of CTNNAL1,a member of vinculin family, on Fn mediated wound repair,cell proliferation and focal adhesion kinase phosphorylation.Western blot showed that Fn could promote FAK phosphorylation in a transient time-dependent manner.CTNNAL1 ASO alone did not cause FAK phosphorylation.However,it could inhibit FAK phosphorylation induced by Fn,indicating that CTNNAL1 might have a role in modulating migration and proliferation via FAK phosphorylation signal transduction from Fn.Our results showed a novel link between CTNNAL1 with Fn mediated cell-extracellular matrix adhesion.
These results raise the possibility that the down regulation of CTNNAL1 might contribute to the asthma development because of the attenuated cell-cell and cell-matrix adhesion,which lead to the bronchial epithelium desquamated and asthma.
3.Study gene expression modulation of CTNNAL1
In the present study,we determined molecular mechanisms of CTNNAL1 regulation in human BEC.8 oligonucleotide probes corresponding to various regions of the CTNNAL1 promoter were used in EMSA(electrophoretic mobilityshift assays).5 were found to have an enhanced mobility shift with extracts from BECs.On the basis of the assay of mutated probes and antibody supershift,they were verified as LEF-1, AP-2αand CREB.Next,ChIP(chromatin immunoprecipitation) assay was used to observe the interaction between these transcription factors and CTNNAL1 promoter.Only AP-2αand LEF-1 show the binding on CTNNAL1 promoter.By site-directed mutagenesis of putative transcription-factor-binding sites within pGL3/CTNNAL1/luc,we observed a reduction in human CTNNAL1 promoter activity of mutants of both AP-2αand LEF-1 sites.Our data suggest that AP-2αand LEF-1 may be involved in regulation of CTNNAL1 expression.
The time courses of AP-2αand LEF-1 activation,followed by CTNNAL1 expression were also examined.It was shown that ozone stress can activate the AP-2αand LEF-1 with one hour,ozone-inducible CTNNAL1 expression and AP-2αand LEF-1 binding activity correlated during a-16 hour time course.
Conclusion:
The present study demonstrates a robust transcriptional CTNNAL1 up-regulation occurs during acute ozone-induced stress and is mediated at least in part by ozone-induced recruitment of LEF-1 and AP-2αto the human CTNNAL1 promoter thereby accelerated wound repair and proliferation of BEC,which ameliorating the effects of lung injury.The down-regulation of CTNNAL1 in asthma patients or asthma animal model may lead to the bronchial epithelium desquamated and AHR.
关于哮喘发病机制,气道上皮缺陷理论已成为主流观点之一。哮喘的病理特征之一表现为支气管上皮损伤、脱落,提示哮喘患者的气道上皮对损伤应激的修复反应可能出现缺陷。已知上皮细胞通过表达不同类型的粘附分子实现“粘附”和“锚定”是发挥正常功能的先决条件。国内外及本实验室多项研究证实,粘附分子在气道炎症及损伤修复中发挥重要作用。为了确定与哮喘易感性相关的粘附分子表达特征,本实验室在先前的研究中应用基因芯片及生物信息学方法筛选了人外周血差异表达粘附分子,发现连环素(catenin)家族中的CTNNAL1(catenin alpha-like 1)基因在哮喘病人中表达下调。由于目前对于CTNNAL1功能意义的直接研究极少,其在支气管上皮及肺组织中的作用尚未见报道。本课题围绕CTNNAL1与哮喘发病的关系、CTNNAL1对支气管肺组织功能的影响及CTNNAL1基因表达调控进行了一系列研究。
方法与结果:
1) CTNNAL1与哮喘相关性分析
本实验室在先前的研究中应用基因芯片及生物信息学方法筛选了人外周血哮喘差异表达粘附分子,结果显示多个基因表达水平改变。本研究选择在所有哮喘病人中均下调的CTNNAL1(catenin alpha-like1)基因,应用荧光定量RT-PCR进一步证实结果的可靠性;收集正常人及哮喘病人的支气管粘膜,并构建经典的OVA致敏的小鼠哮喘模型,探讨CTNNAL1在支气管肺组织的分布情况及其与哮喘的关系。
荧光定量RT-PCR结果显示成年哮喘病人与正常成年人相比CTNNAL1表达水平明显降低。哮喘儿童病人CTNNAL1表达水平似比正常儿童低,但P＞0.05,尚不能认为有统计学意义,需扩大样本量进一步证实。
免疫组化和原位杂交显示,CTNNAL1广泛分布于支气管柱状纤毛细胞、细支气管分泌细胞、间质细胞、血管内皮细胞及肺泡上皮细胞。CTNNAL1在哮喘病人支气管粘膜及哮喘模型小鼠的支气管肺组织表达均下调,哮喘模型组小鼠气道阻力显著高于正常组,且CTNNAL1 mRNA水平与气道阻力呈负相关。以上结果证实CTNNAL1与哮喘发病相关。
2) CTNNAL1在气道上皮中的生物学效应
本实验利用吸入臭氧建立Balb/c小鼠支气管肺组织应激损伤模型。结果显示,臭氧应激导致明显的杯状细胞增生和上皮缺损。原位杂交实验和荧光定量RT-PCR显示臭氧应激可上调小鼠支气管肺组织CTNNAL1 mRNA表达,于应激的第二天达到高峰,但是随着臭氧应激时间的延长,CTNNAL1 mRNA表达缓慢下降。培养的人BEC细胞株爬片细胞原位杂交显示,未受臭氧应激组BEC阳性细胞数较少,胞浆呈浅黄色,臭氧攻击培养的人BEC 30 min后,阳性细胞数明显增多,染色明显加深,呈深黄色。荧光定量RT-PCR结果与原位杂交一致。提示CTNNAL1参与BEC应激反应,其表达水平受应激调控。
为阐明CTNNAL1在急性应激下上调的功能意义,我们利用CTNNAL1表达质粒和CTNNAL1反义寡核苷酸(ASO)建立CTNNAL1高表达或阻抑手段,籍此观察CTNNAL1在气道上皮中的生物学作用。损伤修复测定采用机械损伤在融合的支气管上皮细胞单层上造成一小面积不规则缺损,用显微视频分析系统每隔4h测量缺损面积一次,绘制时间与修复面积的直线回归方程,直线的斜率为损伤修复指数,斜率越大,损伤修复速度越快。增殖采用MTT法。结果显示CTNNAL1可促进细胞的损伤修复和增殖。CTNNAL1 mRNA在损伤修复边缘的活跃细胞高表达,有利于上皮细胞的修复。
我们还初步观察了CTNNAL1在细胞外基质纤维连接蛋白(Fibronectin,Fn)激活与细胞迁移运动有关的激酶中的作用。利用Western blot技术观察到CTNNAL1 ASO单独处理不影响FAK磷酸化,但CTNNAL1 ASO处理可降低Fn促FAK磷酸化效应,提示CTNNAL1在Fn促损伤修复与增殖效应的FAK磷酸化途径中发挥作用。
以上结果提示CTNNAL1参与维持气道上皮的完整性,CTNNAL1表达下调可能导致上皮功能缺陷及完整性破坏,从而与哮喘发病相关。我们认为,急性应激条件下CTNNAL1表达上调是一种保护性应答,哮喘病人可能出现了这种应答机制的缺陷。
3) CTNNAL1基因表达调控研究
为了进一步认识CTNNAL1基因表达调控机制,本研究对CTNNAL1的转录因子调节谱进行筛选。利用启动子分析软件PromoterScan和Transfac对CTNNAL1基因5′非编码区进行分析,推测启动子所在范围在-552～-152 from ATG。TESS软件(Transcription ElementSearch System)分析该区域内可能的转录因子结合位点,据此设计8条探针,覆盖所有的转录因子结合位点,应用凝胶阻滞电泳(electrophoretic mobility shift assays,EMSA)筛选调控CTNNAL1表达的转录因子,结果显示探针1,2,3,5,8有与蛋白结合形成的滞后带,能被100倍未标记探针所竞争,为特异性结合。通过突变探针结合试验、抗体超迁移试验,证实与探针结合的转录因子分别为LEF-1、AP-2α和CREB。染色质免疫共沉淀实验显示,LEF-1和AP-2α可特异性与CTNNAL1启动子结合。
紧接着,我们用基因定点突变技术观察LEF-1和AP-2α对CTNNAL1启动子活性的影响,结果显示LEF-1与AP-2α的结合位点突变后,CTNNAL1启动子活性下降。
进一步,我们用EMSA观察到LEF-1与AP-2α在臭氧应激30min后的活化情况,结果显示臭氧应激后LEF-1活化增加,在应激后1h达到高峰,AP-2α的活化发生在0-1h之间,于应激后30 min达到高峰。CTNNAL1 mRNA的表达与两种转录因子的激活一致。提示在臭氧应激条件下,LEF-1与AP-2α特异性与CTNNAL1结合,共同调控CTNNAL1的表达。
结论:
LEF-1与AP-2α特异性与CTNNAL1结合,共同调控CTNNAL1的表达。急性应激条件下CTNNAL1表达上调,促进支气管上皮细胞损伤修复与增殖,参与维持气道上皮的完整性。CTNNAL1在哮喘病人及哮喘模型小鼠表达下调,可能导致上皮功能缺陷及完整性破坏,从而与哮喘发病相关。
Objectives:
Destruction in airway epithelium structure and integrity,which is often induced by flaws of constitutive adhesion,is the essential link of asthma pathogenicity.During the course of AHR or airway inflammation, airway epithelial cells express adhesion molecules to arrest leucocytes and evoke an inflammation reaction in airway.Airway epithelial cells anchored to extracellular matrix through intergrins and sustained the ability of against injury,repair and integrity in structure or in function of human bronchial epithelial cells(BEC).Therefore it can be reasonably speculated that abnormal expression of adhesive molecules in airway epithelial cells, which might be possibly due to either correspond coding gene alteration or imbalance expression among various kind of adhesion molecules, contribute to aberrant susceptibility to asthma.Based on the result of asthma-associated adhesion molecules expression spectrum,CTNNAL1, whose expression was down regulated in asthma patients,was selected as a candidate in this present study for a further functional investigation.Up to now,there is very little known about the pulmonary biological effects, gene expression modulation of CTNNAL1.The present study was designed to identity the association of CTNNAL 1 with asthma,observe the pulmonary biological effects and gene expression modulation of CTNNAL1.
Contents:
1.Identity the association of CTNNAL 1 with asthma
Our previous study used a cDNA microarray to screen the differential expression of adhesion molecules in human peripheral blood leucocytes, and found that an alpha-catenin-related protein,catenin alpha-like 1 (CTNNAL1) was downregulated in asthma patients.In this study,Real time PCR was used to further confirm the expression of CTNNAL1 in asthm.Immunohistochemistry was used to verified CTNNAL1 expression on tunica mucosa bronchiorum of normal person and asthma patients. Using a well-characterized OVA-sensitized Balb/c mice asthma model,we carried out a time course study of the expression of CTNNAL1 in lung following the AHR progression.
Results:In situ hybridizition showed CTNNAL1 was predominantly localized in the ciliated columnar epithelium of bronchioles,secretory cells of terminal bronchioles,vascular endothelial cells and alveolar cells.The expression of CTNNAL1 mRNA was significantly down regulated in the peripheral blood leucocyte and tunica mucosa bronchiorum.Real-time PCR showed the mRNA level of CTNNAL1 was decreased in asthma animals.There was a negative correlation between the pulmonary resistance(R_L) in asthma mice and the levels of CTNNAL1 mRNA.This present study demonstrated that CTNNAL1 is highly correlated with asthma.
2.Function study of CTNNAL1 on airway epithelium
Balb/c mice were inhaled a mixture of 2.0ppm ozone and fresh air for one,two,four,and eight days respectively to establish a airway stressed animal model and the time and spatial expression of CTNNAL1 were examined by ISH and Real-time PCR.The results showed inflammationary infiltration,mucosal exudation,cavitary stricture and bronchial epithelial denudation were observed in the ozone-stressed group.The expression of CTNNAL1 mRNA was increased with the ozone stress,peaked on the second day,and then reduced.The results also showed that expression of CTNNAL1 mRNA was explicitly increased in ozone-stressed BEC.
To investigate function of CTNNAL1 in asthma,we established a CTNNAL1 expression plasmid and designed CTNNAL1 antisense oligonucleotide(ASO) to promoter or hinder the expression of CTNNAL1. Then we use them to observe the effect of CTNNAL1 on the repair and proliferation of BEC.
A small wound was made in the confluent monolayer by mechanical scraping and the remaining wound area was measured serially per 4 hours in 24h by video microscopy.A linear regression equation of the remaining wound area to time was obtained and the slope was used to judge the repair speed of BECs.The proliferation of BECs was assayed by MTT.The results showed that the wound repair and proliferation of BECs were accelerated by CTNNAL1.
We also detect the effect of CTNNAL1,a member of vinculin family, on Fn mediated wound repair,cell proliferation and focal adhesion kinase phosphorylation.Western blot showed that Fn could promote FAK phosphorylation in a transient time-dependent manner.CTNNAL1 ASO alone did not cause FAK phosphorylation.However,it could inhibit FAK phosphorylation induced by Fn,indicating that CTNNAL1 might have a role in modulating migration and proliferation via FAK phosphorylation signal transduction from Fn.Our results showed a novel link between CTNNAL1 with Fn mediated cell-extracellular matrix adhesion.
These results raise the possibility that the down regulation of CTNNAL1 might contribute to the asthma development because of the attenuated cell-cell and cell-matrix adhesion,which lead to the bronchial epithelium desquamated and asthma.
3.Study gene expression modulation of CTNNAL1
In the present study,we determined molecular mechanisms of CTNNAL1 regulation in human BEC.8 oligonucleotide probes corresponding to various regions of the CTNNAL1 promoter were used in EMSA(electrophoretic mobilityshift assays).5 were found to have an enhanced mobility shift with extracts from BECs.On the basis of the assay of mutated probes and antibody supershift,they were verified as LEF-1, AP-2αand CREB.Next,ChIP(chromatin immunoprecipitation) assay was used to observe the interaction between these transcription factors and CTNNAL1 promoter.Only AP-2αand LEF-1 show the binding on CTNNAL1 promoter.By site-directed mutagenesis of putative transcription-factor-binding sites within pGL3/CTNNAL1/luc,we observed a reduction in human CTNNAL1 promoter activity of mutants of both AP-2αand LEF-1 sites.Our data suggest that AP-2αand LEF-1 may be involved in regulation of CTNNAL1 expression.
The time courses of AP-2αand LEF-1 activation,followed by CTNNAL1 expression were also examined.It was shown that ozone stress can activate the AP-2αand LEF-1 with one hour,ozone-inducible CTNNAL1 expression and AP-2αand LEF-1 binding activity correlated during a-16 hour time course.
Conclusion:
The present study demonstrates a robust transcriptional CTNNAL1 up-regulation occurs during acute ozone-induced stress and is mediated at least in part by ozone-induced recruitment of LEF-1 and AP-2αto the human CTNNAL1 promoter thereby accelerated wound repair and proliferation of BEC,which ameliorating the effects of lung injury.The down-regulation of CTNNAL1 in asthma patients or asthma animal model may lead to the bronchial epithelium desquamated and AHR.
引文
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