Wnt/β-catenin信号通路在肺纤维化形成中的机制研究
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摘要
目的：特发性肺纤维化为致命的肺部疾病。其特点是肺上皮细胞损伤,肺成纤维细胞／肌成纤维细胞增殖和细胞外基质过渡沉积,造成肺结构破坏。但机制不明。最近的证据表明,Wnt信号通路在IPF患者异常活跃。本研究采用Wntl蛋白干预人胚肺成纤维细胞,探讨对细胞增殖、活化的影响；通过Wntl蛋白及β-catenin质粒干预A549细胞,探讨Wnt/β-catenin信号通路对肺上皮细胞-间质转变作用。通过模型鼠,观察肺纤维化形成过程中,β-catenin动态变化规律。用肺纤维化模型鼠的支气管肺泡灌洗液培养HEPF和A549细胞,探讨对细胞表型转变的影响,及与Wnt/β-catenin信号通路的相关性；用P-catenin基因siRNA干扰慢病毒沉默β-catenin,再用支气管肺泡灌洗液培养细胞,对细胞表型转变的影响,进一步揭示Wnt/β-catenin信号通路对成纤维细胞活化、增殖及肺上皮细胞-间质转变的作用。
方法：我们用不同浓度的Wntl干预人胚肺成纤维细胞,MTT检测细胞增殖率,RT-PCR及westen blot检测a-平滑肌肌动蛋白、波形蛋白、Ⅰ型胶原蛋白表达；不同浓度的Wntl干预A549细胞,RT-PCR及westen blot检测E-钙粘蛋白、a-平滑肌肌动蛋白、波形蛋白、Ⅰ型胶原蛋白表达；然后用P-catenin质粒转染A549细胞,光镜下观察细胞形态变化,RT-PCR及westen blot检测E-钙粘蛋白、α-平滑肌肌动蛋白、波形蛋白、Ⅰ型胶原蛋白表达。进一步我们用气管内滴入博莱霉素构建小鼠肺纤维化模型,于造模后的第3、7、14、28天,取肺组织苏木精-伊红及Masson染色观察肺组织炎症及纤维化程度,碱水解法检测肺组织内羟脯氨酸含量,免疫组织化学法及westen blot检测β-catenin蛋白的表达。用造模后第7天获取支气管肺泡灌洗液培养人胚肺成纤维细胞和A549细胞,RT-PCR及westen blot检测E-钙粘蛋白、α-平滑肌肌动蛋白、波形蛋白、Ⅰ型胶原蛋白及β-catenin mRNA及蛋白表达。进一步构建P-catenin基因RNA干扰慢病毒表达载体,筛选出高效特异性抑制P-atenin基因的shRNA'慢病毒载体。将β-catenin siRNA慢病毒转染人胚肺成纤维细胞和A549细胞,再用肺纤维化模型鼠支气管肺泡灌洗液培养细胞,RT-PCR及westen blot检测E-钙粘蛋白、α-平滑肌肌动蛋白、波形蛋白、Ⅰ型胶原蛋白mRNA及蛋白表达。
结果：不同浓度Wntl干预人胚肺成纤维细胞,促进细胞增值,尤其当浓度大于20μg/l,细胞增殖更明显,并且a-平滑肌肌动蛋白、波形蛋白、Ⅰ型胶原蛋白mRNA及蛋白表达增加,具有统计学意义（P<0.05)。Wntl干预A549细胞E-钙粘蛋白mRNA及蛋白表达减少,而α-平滑肌肌动蛋白、波形蛋白、Ⅰ型胶原蛋白mRNA及蛋白表达增加,尤其当Wntl浓度大于20μg/l时,变化更明显。β-catenin质粒转染A549细胞,细胞形态发生改变,由原来的鹅卵石状变成了梭型,同时E-钙粘蛋白mRNA及蛋白表达减少,而α-平滑肌肌动蛋白、波形蛋白、Ⅰ型胶原蛋白mRNA及蛋白表达增加。我们用博莱霉素气管内滴入,构建小鼠肺纤维化模型,与对照组比较,在纤维化形成过程中,肺组织中β-catenin蛋白表达第7天升高,表达高峰在第14天,第28天下降,但仍高于第7天。为了探讨肺泡上皮细胞损伤后诱导肺组织异常修复,在肺组织纤维化形成中与Wnt/β-catenin信号通路的关系,我们用肺纤维化模型鼠第7天支气管肺泡灌洗液培养人胚肺成纤维细胞,α-平滑肌肌动蛋白、波形蛋白、Ⅰ型胶原蛋白mRNA和蛋白的表达均显著增加,而且与β-catenin相关。转染慢病毒P-catenin siRNA的人胚肺成纤维细胞后,再用肺纤维化模型鼠支气管肺泡灌洗液培养细胞,a-平滑肌肌动蛋白、波形蛋白、Ⅰ型胶原蛋白mRNA和蛋白没有显著增加。我们又用小鼠肺纤维化模型第7天支气管肺泡灌洗液培养A549细胞,结果显示表达间质特异性标记物α-平滑肌肌动蛋白、波形蛋白、Ⅰ型胶原蛋白升高,而上皮标记物E-钙粘蛋白减低,与β-catenin升高有关。当我们预先用β-catenin siRNA慢病毒转染A549细胞,再用肺纤维化模型鼠的支气管肺泡灌洗液培养A549细胞,结果显示α-平滑肌肌动蛋白、波形蛋白、Ⅰ型胶原蛋白升高不明显,E-钙粘蛋白也无明显下降。
结论：我们的研究表明,Wnt/β-catenin信号通路可以促进人胚肺成纤维细胞增殖并诱导向肌成纤维细胞转变,促进细胞外基质沉积；Wnt/β-catenin信号通路可诱导肺上皮细胞间质转变,从而增加成纤维细胞／肌纤维细胞的数量；证实Wnt/β-catenin信号通路参与了早期肺纤维化的发生及发展过程；而抑制Wnt/β-catenin信号通路,减轻细胞表型转变,减少肺纤维化发生。此外,这些结果还表明,在损伤部位激活异常生物修复程序并保持这种反应持久存在是肺纤维化形成中的一个关键因素。Wnt/β-catenin信号通路在肺损伤及纤维化疾病的形成中起重要作用,可能为IPF的治疗提供一条新途径。
Objective:Idiopathic pulmonary fibrosis(IPF) is a lethal lung disease of unknown etiology. It is characterized by alterations of the alveolar epithelium, the expansion of the fibroblast/myofibroblast population and extracellular matrix (ECM)deposition, which results in an irreversible distortion of the lung architecture. Recent studies showed that abnormal activation of the Wnt/β-catenin signaling pathway occurs in lung tissue of patients with IPF. In the present study, we explored the role of wntl in human embryo pulmonary fibroblast (HEPF) proliferation, activation and myofibroblast differentiation of fibroblasts. A549cells were treated by Wntl and transfected by β-catenin plasmid cells to investigated the possible role of the Wnt signaling pathway in inducing epithelial-mesenchymal transitions (EMT) in lung epithelial cells. Pulmonary fibrosis was induced in mice by intraltracheal instillation of bleomycin,to explore the relationship with β-catenin. HEPF and A549cells were cultured by bronchoalveolar fluid (BALF) which conducted from bleomycin-induced murine model of pulmonary fibrosis, to investigate the effects on the cell proliferation and phenotype transformation, which were correlated with Wnt/β-catenin signaling pathway;The recombinant lentiviruses which express siRNA targeting β-catenin gene were transfected into HEPF and A549cells, and then cultured cells by BALF,to explore the effects on the cell phenotype transformation.
Methods:HEPF cells were stimulated with various concentrations of Wntl, the proliferation of HEPF cells observed by MTT method.Western blot analysis and qRT-PCR revealed that alpha-smooth muscle actin (a-SMA), vimentin and collagen I mRNA and protein expression. A549cells were stimulated with various concentrations of Wntl, western blot testing and qRT-PCR revealed that E-cadherinc (E-cad), vimentin, a-SMA, collagen I mRNA and protein expression. We used β-catenin plasmid-transfected A549cells,the cellular morphologic changes were observed by light microscope.Western blot analysis and qRT-PCR revealed that the expression of epithelial phenotypic marker E-cad and the mesenchymal marker a-SMA, vimentin and collagen I. Furthermore, we used intratracheal instillation of bleomycin as a model of pulmonary fibrosis,on the3rd,7th,14th and28th day after treatment with bleomycin, lung were dissected out, separated from other tissues. Hematoxylin and Eosin (H&E), Masson's Trichrome staining were used to detect the degrees of acute inflammation and fibrosis;Hydroxyproline (HYP) was tested by lung tissue alkaline hydrolysis. Western blot and immunohistochemical method was adopted to detect the protein of β-catenin. HEPF and A549cells cultured by BALF which was conducted on days7after bleomycin administration. qRT-PCR and westen blot were used to determine the mRNA and protein expression of E-cad, a-SMA, vimentin, collagen I and β-catenin.To clarify further the role of β-catenin in fibrosis, we constructed recombinant lentiviral vector expressing siRNA targeting β-catenin gene. The most effective sequence of siRNA was screened by efficiency of β-catenin gene knock-down in transfected HEPF cells. The recombinant lentiviruses were transfected into HEPF and A549cells, and then cultured cells by BALF coming from Mouse models. qRT-PCR and westen blot were used to determine the mRNA and protein expression of E-cad, a-SMA, vimentin, collagen I.
Results:The present study revealed that cell proliferation improved following stimulation using different concentrations of Wntl in a concentration-dependent manner. When the concentration exceeded20μg/l, cell proliferation was significant (P<0.05) and the cell expression of a-SMA, vimentin and collagen I mRNA, as well as protein expression, significantly increased (P<0.05); A549cells were treated by Wntl, the results showed that the mRNA and protein expression of vimentin, a-SMA and collagen I gradully increased, meanwhile those of E-cad gradully decreased in a concentration dependent manner. A549were transfected by β-catenin plasmid cells, showing a changes their phenotype from pebble-shaped to fusiform. The mRNA and protein expression of vimentin, a-SMA and collagen I increased significantly, whereas those of E-cad decreased significantly. We used intratracheal instillation of bleomycin as a model of acute lung injury and fibrosis, the expressions of β-catenin had the consistent increasing trends, increaseing on day7and peaking around day14. To explored that lung fibrosis induced by abnormal wound healing in response to alveolar epithelial cell injury were relationship with the Wnt/β-catenin signaling pathway. BALF was obtained from bleomycin-induced models of pulmonary fibrosis. HEPF cells were cultured with Dulbecco's modified Eagle's medium plus BALF. The mRNA and protein expression of a-SMA, vimentin and collagen I significantly increased and these increases were associated with β-catenin. Furthermore, following being infected with the lentivirus expressing β-catenin shRNA, HEPF cells were cultured with BALF. However, the mRNA and protein expression of a-SMA, vimentin and collagen I did not increase significantly. We also incubated A549cells by BALF from the intratracheal bleomycin mice model. We observed an increased expression of mesenchymal markers (a-SMA, vimentin and collagen I), a concomitant decreased expression of epithelial markers (E-cad), corresponding to an increased expression of P-catenin. When A549cells were infected with a lentivirus expressing P-catenin shRNA, the expression of mesenchymal cell markers did not increase significantly and E-cad expression did not decrease.
Conclusion:These findings show that the activation of the Wnt/β-catenin signaling pathway can increases the number of myofibroblasts and promotes fibroblasts to change into myofibroblasts,which leading to excessive ECM deposition. It also suggests that the activation of the Wnt signaling pathway can increase the number of myofibroblasts in pulmonary fibrosis through epithelial-mesenchymal transition. The Wnt/β-catenin signaling pathway is involved in the occurrence and development of pulmonary fibrosis,and the inhibition of Wnt/β-catenin signaling pathway suppresses the cell phenotype changed and pulmonary fibrosis.Furthermore, these results also demonstrated that the activation of a biological repair response and persistence at the injury site is a key factor in the formation of pulmonary fibrosis. The Wntl/β-catenin signalling pathway is important in the formation of fibrotic disease in lung injury and may provide opportunities for treatment and intervention in IPF.
方法：我们用不同浓度的Wntl干预人胚肺成纤维细胞,MTT检测细胞增殖率,RT-PCR及westen blot检测a-平滑肌肌动蛋白、波形蛋白、Ⅰ型胶原蛋白表达；不同浓度的Wntl干预A549细胞,RT-PCR及westen blot检测E-钙粘蛋白、a-平滑肌肌动蛋白、波形蛋白、Ⅰ型胶原蛋白表达；然后用P-catenin质粒转染A549细胞,光镜下观察细胞形态变化,RT-PCR及westen blot检测E-钙粘蛋白、α-平滑肌肌动蛋白、波形蛋白、Ⅰ型胶原蛋白表达。进一步我们用气管内滴入博莱霉素构建小鼠肺纤维化模型,于造模后的第3、7、14、28天,取肺组织苏木精-伊红及Masson染色观察肺组织炎症及纤维化程度,碱水解法检测肺组织内羟脯氨酸含量,免疫组织化学法及westen blot检测β-catenin蛋白的表达。用造模后第7天获取支气管肺泡灌洗液培养人胚肺成纤维细胞和A549细胞,RT-PCR及westen blot检测E-钙粘蛋白、α-平滑肌肌动蛋白、波形蛋白、Ⅰ型胶原蛋白及β-catenin mRNA及蛋白表达。进一步构建P-catenin基因RNA干扰慢病毒表达载体,筛选出高效特异性抑制P-atenin基因的shRNA'慢病毒载体。将β-catenin siRNA慢病毒转染人胚肺成纤维细胞和A549细胞,再用肺纤维化模型鼠支气管肺泡灌洗液培养细胞,RT-PCR及westen blot检测E-钙粘蛋白、α-平滑肌肌动蛋白、波形蛋白、Ⅰ型胶原蛋白mRNA及蛋白表达。
结果：不同浓度Wntl干预人胚肺成纤维细胞,促进细胞增值,尤其当浓度大于20μg/l,细胞增殖更明显,并且a-平滑肌肌动蛋白、波形蛋白、Ⅰ型胶原蛋白mRNA及蛋白表达增加,具有统计学意义（P<0.05)。Wntl干预A549细胞E-钙粘蛋白mRNA及蛋白表达减少,而α-平滑肌肌动蛋白、波形蛋白、Ⅰ型胶原蛋白mRNA及蛋白表达增加,尤其当Wntl浓度大于20μg/l时,变化更明显。β-catenin质粒转染A549细胞,细胞形态发生改变,由原来的鹅卵石状变成了梭型,同时E-钙粘蛋白mRNA及蛋白表达减少,而α-平滑肌肌动蛋白、波形蛋白、Ⅰ型胶原蛋白mRNA及蛋白表达增加。我们用博莱霉素气管内滴入,构建小鼠肺纤维化模型,与对照组比较,在纤维化形成过程中,肺组织中β-catenin蛋白表达第7天升高,表达高峰在第14天,第28天下降,但仍高于第7天。为了探讨肺泡上皮细胞损伤后诱导肺组织异常修复,在肺组织纤维化形成中与Wnt/β-catenin信号通路的关系,我们用肺纤维化模型鼠第7天支气管肺泡灌洗液培养人胚肺成纤维细胞,α-平滑肌肌动蛋白、波形蛋白、Ⅰ型胶原蛋白mRNA和蛋白的表达均显著增加,而且与β-catenin相关。转染慢病毒P-catenin siRNA的人胚肺成纤维细胞后,再用肺纤维化模型鼠支气管肺泡灌洗液培养细胞,a-平滑肌肌动蛋白、波形蛋白、Ⅰ型胶原蛋白mRNA和蛋白没有显著增加。我们又用小鼠肺纤维化模型第7天支气管肺泡灌洗液培养A549细胞,结果显示表达间质特异性标记物α-平滑肌肌动蛋白、波形蛋白、Ⅰ型胶原蛋白升高,而上皮标记物E-钙粘蛋白减低,与β-catenin升高有关。当我们预先用β-catenin siRNA慢病毒转染A549细胞,再用肺纤维化模型鼠的支气管肺泡灌洗液培养A549细胞,结果显示α-平滑肌肌动蛋白、波形蛋白、Ⅰ型胶原蛋白升高不明显,E-钙粘蛋白也无明显下降。
结论：我们的研究表明,Wnt/β-catenin信号通路可以促进人胚肺成纤维细胞增殖并诱导向肌成纤维细胞转变,促进细胞外基质沉积；Wnt/β-catenin信号通路可诱导肺上皮细胞间质转变,从而增加成纤维细胞／肌纤维细胞的数量；证实Wnt/β-catenin信号通路参与了早期肺纤维化的发生及发展过程；而抑制Wnt/β-catenin信号通路,减轻细胞表型转变,减少肺纤维化发生。此外,这些结果还表明,在损伤部位激活异常生物修复程序并保持这种反应持久存在是肺纤维化形成中的一个关键因素。Wnt/β-catenin信号通路在肺损伤及纤维化疾病的形成中起重要作用,可能为IPF的治疗提供一条新途径。
Objective:Idiopathic pulmonary fibrosis(IPF) is a lethal lung disease of unknown etiology. It is characterized by alterations of the alveolar epithelium, the expansion of the fibroblast/myofibroblast population and extracellular matrix (ECM)deposition, which results in an irreversible distortion of the lung architecture. Recent studies showed that abnormal activation of the Wnt/β-catenin signaling pathway occurs in lung tissue of patients with IPF. In the present study, we explored the role of wntl in human embryo pulmonary fibroblast (HEPF) proliferation, activation and myofibroblast differentiation of fibroblasts. A549cells were treated by Wntl and transfected by β-catenin plasmid cells to investigated the possible role of the Wnt signaling pathway in inducing epithelial-mesenchymal transitions (EMT) in lung epithelial cells. Pulmonary fibrosis was induced in mice by intraltracheal instillation of bleomycin,to explore the relationship with β-catenin. HEPF and A549cells were cultured by bronchoalveolar fluid (BALF) which conducted from bleomycin-induced murine model of pulmonary fibrosis, to investigate the effects on the cell proliferation and phenotype transformation, which were correlated with Wnt/β-catenin signaling pathway;The recombinant lentiviruses which express siRNA targeting β-catenin gene were transfected into HEPF and A549cells, and then cultured cells by BALF,to explore the effects on the cell phenotype transformation.
Methods:HEPF cells were stimulated with various concentrations of Wntl, the proliferation of HEPF cells observed by MTT method.Western blot analysis and qRT-PCR revealed that alpha-smooth muscle actin (a-SMA), vimentin and collagen I mRNA and protein expression. A549cells were stimulated with various concentrations of Wntl, western blot testing and qRT-PCR revealed that E-cadherinc (E-cad), vimentin, a-SMA, collagen I mRNA and protein expression. We used β-catenin plasmid-transfected A549cells,the cellular morphologic changes were observed by light microscope.Western blot analysis and qRT-PCR revealed that the expression of epithelial phenotypic marker E-cad and the mesenchymal marker a-SMA, vimentin and collagen I. Furthermore, we used intratracheal instillation of bleomycin as a model of pulmonary fibrosis,on the3rd,7th,14th and28th day after treatment with bleomycin, lung were dissected out, separated from other tissues. Hematoxylin and Eosin (H&E), Masson's Trichrome staining were used to detect the degrees of acute inflammation and fibrosis;Hydroxyproline (HYP) was tested by lung tissue alkaline hydrolysis. Western blot and immunohistochemical method was adopted to detect the protein of β-catenin. HEPF and A549cells cultured by BALF which was conducted on days7after bleomycin administration. qRT-PCR and westen blot were used to determine the mRNA and protein expression of E-cad, a-SMA, vimentin, collagen I and β-catenin.To clarify further the role of β-catenin in fibrosis, we constructed recombinant lentiviral vector expressing siRNA targeting β-catenin gene. The most effective sequence of siRNA was screened by efficiency of β-catenin gene knock-down in transfected HEPF cells. The recombinant lentiviruses were transfected into HEPF and A549cells, and then cultured cells by BALF coming from Mouse models. qRT-PCR and westen blot were used to determine the mRNA and protein expression of E-cad, a-SMA, vimentin, collagen I.
Results:The present study revealed that cell proliferation improved following stimulation using different concentrations of Wntl in a concentration-dependent manner. When the concentration exceeded20μg/l, cell proliferation was significant (P<0.05) and the cell expression of a-SMA, vimentin and collagen I mRNA, as well as protein expression, significantly increased (P<0.05); A549cells were treated by Wntl, the results showed that the mRNA and protein expression of vimentin, a-SMA and collagen I gradully increased, meanwhile those of E-cad gradully decreased in a concentration dependent manner. A549were transfected by β-catenin plasmid cells, showing a changes their phenotype from pebble-shaped to fusiform. The mRNA and protein expression of vimentin, a-SMA and collagen I increased significantly, whereas those of E-cad decreased significantly. We used intratracheal instillation of bleomycin as a model of acute lung injury and fibrosis, the expressions of β-catenin had the consistent increasing trends, increaseing on day7and peaking around day14. To explored that lung fibrosis induced by abnormal wound healing in response to alveolar epithelial cell injury were relationship with the Wnt/β-catenin signaling pathway. BALF was obtained from bleomycin-induced models of pulmonary fibrosis. HEPF cells were cultured with Dulbecco's modified Eagle's medium plus BALF. The mRNA and protein expression of a-SMA, vimentin and collagen I significantly increased and these increases were associated with β-catenin. Furthermore, following being infected with the lentivirus expressing β-catenin shRNA, HEPF cells were cultured with BALF. However, the mRNA and protein expression of a-SMA, vimentin and collagen I did not increase significantly. We also incubated A549cells by BALF from the intratracheal bleomycin mice model. We observed an increased expression of mesenchymal markers (a-SMA, vimentin and collagen I), a concomitant decreased expression of epithelial markers (E-cad), corresponding to an increased expression of P-catenin. When A549cells were infected with a lentivirus expressing P-catenin shRNA, the expression of mesenchymal cell markers did not increase significantly and E-cad expression did not decrease.
Conclusion:These findings show that the activation of the Wnt/β-catenin signaling pathway can increases the number of myofibroblasts and promotes fibroblasts to change into myofibroblasts,which leading to excessive ECM deposition. It also suggests that the activation of the Wnt signaling pathway can increase the number of myofibroblasts in pulmonary fibrosis through epithelial-mesenchymal transition. The Wnt/β-catenin signaling pathway is involved in the occurrence and development of pulmonary fibrosis,and the inhibition of Wnt/β-catenin signaling pathway suppresses the cell phenotype changed and pulmonary fibrosis.Furthermore, these results also demonstrated that the activation of a biological repair response and persistence at the injury site is a key factor in the formation of pulmonary fibrosis. The Wntl/β-catenin signalling pathway is important in the formation of fibrotic disease in lung injury and may provide opportunities for treatment and intervention in IPF.
引文
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