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  • Title: [Role of CTGF and PI3K/Akt signaling pathway in paraquat-induced mesenchymal changes in alveolar epithelial cells].
    Author: Su YW, Li GZ, Fang WX, Zhang JW, Liu YM, Wang Z.
    Journal: Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi; 2024 Jun 20; 42(6):401-407. PubMed ID: 38964903.
    Abstract:
    Objective: To investigate the role of connective tissue growth factor (CTGF) and PI3K/Akt signaling pathways in paraquat (PQ) -induced alterations in alveolar epithelial cell mesenchymalization (EMT) . Methods: In February 2023, RLE-6TN cells were divided into 2 groups, which were set as uncontaminated group and contaminated group (200 μmol/L PQ), and cellular EMT alteration, CTGF and PI3K/Akt signaling pathway related molecules expression were detected by cell scratch assay, qRT-PCR and western-blot assay. Using shRNA interference technology to specifically inhibit the expression of CTGF, RLE-6TN cells were divided into four groups: control group, PQ group (200 μmol/L PQ), interference group (transfected with a plasmid with shRNA-CTGF+200 μmol/L PQ), and null-loaded group (transfected with a plasmid with scramble- CTGF+200 μmol/L PQ), qRT-PCR and western blot were used to examine the alteration of the cellular EMT and the expression of molecules related to the activity of PI3K/Akt pathway. The PI3K/Akt signaling pathway was blocked by the PI3K inhibitor LY294002, and the expression of EMT-related molecules in cells of the control group, PQ group (200 μmol/L PQ), and inhibitor group (200 μmol/L PQ+20 μmol/L LY294002) was examined by qRT-PCR and western blot.The t-test was used to compare the differences between the two groups, while the analysis of variance (ANOVA) was applied to compare the differences among multiple groups. For further pairwise comparisons, the Bonferroni method was adopted. Results: The results of cell scratch test showed that compared with the uncontaminated group, RLE-6TN cells in the contaminated group had faster migration rate, lower mRNA and protein expression levels of E-Cadherin, and higher mRNA and protein expression levels of α-SMA, CTGF, PI3K and Akt, with statistical significance (P<0.05). After specific inhibition of CTGF expression, the mRNA and protein expression of CTGF, PI3K, Akt, and α-SMA in the cells of the interference group were significantly lower than that of the PQ group and the null-loaded group (P<0.05/6), whereas that of E-Cadherin was higher than that of the PQ group and the null-loaded group (P<0.05/6). Specifically blocking the PI3K/Akt signaling pathway, the mRNA and protein expression of PI3K, Akt and α-SMA in the cells of the inhibitor group was decreased compared with that of the PQ group (P<0.05/3), while the expression of E-Cadherin was elevated compared with that of the PQ group (P<0.05/3) . Conclusion: CTGF may promote PQ-induced alveolar epithelial cell EMT through activation of the PI3K/Akt signaling pathway. Inhibition of CTGF expression or blockade of PI3K/Akt signaling pathway activity can alleviate the extent of PQ-induced alveolar epithelial cell EMT. 目的： 探讨结缔组织生长因子（CTGF）及磷脂酰肌醇3-激酶/丝氨酸/苏氨酸激酶（PI3K/Akt）信号通路在百草枯（PQ）致肺泡上皮细胞上皮-间充质化（EMT）改变的作用。 方法： 于2023年2月，将RLE-6TN细胞分成2组，设为未染毒组和染毒组（200 μmol/L PQ），采用细胞划痕实验、qRT-PCR和Western-blot法检测细胞EMT改变、CTGF及PI3K/Akt信号通路相关分子表达情况。利用shRNA干扰技术特异性抑制CTGF的表达，将RLE-6TN细胞分成4组，分别为对照组、PQ组（200 μmol/L PQ）、干扰组（转染含shRNA-CTGF质粒+200 μmol/L PQ）和空载组（转染含CTGF-scramble质粒+200 μmol/L PQ），qRT-PCR和Western-blot法检测细胞EMT改变及PI3K/Akt通路活性相关分子的表达情况。使用PI3K抑制剂LY294002阻断PI3K/Akt信号通路，运用qRT-PCR和Western-blot法检测对照组、PQ组（200 μmol/L PQ）、抑制剂组（200 μmol/L PQ+20 μmol/L LY294002）细胞EMT相关分子表达情况。两组间差异比较采用t检验，多组间差异比较采用方差分析，进一步两两比较采用Bonferroni法。 结果： 细胞划痕实验结果显示，与未染毒组比较，PQ染毒组RLE-6TN细胞迁移速度更快，E-钙黏蛋白（E-Cadherin）的mRNA和蛋白表达量更低，α-平滑肌肌动蛋白（α-SMA）、CTGF、PI3K、Akt的mRNA和蛋白表达量更高，差异均有统计学意义（P<0.05）。特异性抑制CTGF表达后，干扰组细胞CTGF、PI3K、Akt、α-SMA的mRNA和蛋白表达量明显低于PQ组和空载组（P<0.05/6），E-Cadherin的mRNA和蛋白表达量高于PQ组和空载组（P<0.05/6）。特异性阻断PI3K/Akt信号通路，抑制剂组细胞PI3K、Akt和α-SMA的mRNA和蛋白表达量较PQ组降低（P<0.05/3），E-Cadherin表达量较PQ组升高（P<0.05/3）。 结论： CTGF可能通过激活PI3K/Akt信号通路促进PQ致肺泡上皮细胞EMT改变，抑制CTGF的表达或阻断PI3K/Akt信号通路活性，可减轻PQ所致肺泡上皮细胞EMT的程度。.
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