己酮可可碱对慢性吸烟小鼠肺免疫病理学的作用及其可能机制
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摘要
【研究背景】肺内炎症细胞的活化和免疫效应细胞的趋化是导致吸烟肺气肿形成和发展的中心环节，同时一些信号通路也在其中起着重要的作用。我们的前期研究发现，已酮可可碱(PTX)干预可抑制豚鼠慢性吸烟肺气肿的发生，并可能导致动物发生肺纤维化。Wnt／β-catenin信号通路是调控细胞生长、增殖和凋亡的关键途径，该途径的激活与人特发性肺间质纤维化-寻常型间质性肺炎(IPF／UIP)病变，以及肺纤维化的中心环节上皮-间充质转化(EMT)过程密切相关。PTX对小鼠是否也有类似的抑制吸烟肺气肿形成和导致肺纤维化的作用，PTX抑制吸烟肺气肿形成的免疫机制，以及PTX对Wnt／β-catenin信号通路的调控与其导致吸烟肺纤维化的关系尚未得到揭示。
【目的】探讨PTX对慢性吸烟BALB／c小鼠肺组织病理学改变的影响及与IFN-γ／IL-4因子表达的关系；探讨PTX对干扰素诱导蛋白(IP-10)介导的CXCR3~+Th1和Tc1细胞向吸烟动物肺内趋化的影响；探讨PTX对慢性吸烟小鼠肺内Wnt／β-catenin信号通路表达的影响及与肺纤维化的关系。
【方法】慢性吸烟和PTX干预BALB／c小鼠，观察肺组织病理学改变。ELISA法检测慢性吸烟和PTX干预动物肺泡灌沈液IFN-γ、IL-4、IP-10表达和肺组织TGF-β1表达。ELISA法检测PTX对香烟烟雾提取物刺激体外培养RAW264.7细胞表达IP-10的影响。免疫组织化学法检测肺组织CXCR3阳性细胞。免疫组织化学染色和Western blot法检测β-catenin蛋白在动物肺组织内的表达。RT-PCR法检测TCF-1和LEF-1表达。Western blot法检测a-平滑肌肌动蛋白(a-SMA)表达变化。
【结果】PTX干预可导致慢性(4月)吸烟BALB／c小鼠发生肺纤维化，伴有IFN-β／IL-4因子比例逆转。PTX干预可抑制吸烟(1周)BALB／c小鼠肺内IFN-γ和IP-10表达，减少CXCR3~+Th1和Tc1细胞数量，抑制吸烟对RAW264.7细胞表达IFN-γ和IP-10的活化作用。PTX可活化β-catenin蛋白在肺组织的表达和向胞浆内转运，促进LEF-1基因和TGF-β1表达，但对cyclinD1蛋白表达和TCF-1基因表达水平无显著影响。
【结论】PTX可阻抑慢性吸烟BALB／c小鼠形成肺气肿，并在部分动物导致肺纤维化形成。该作用可能与调控Th1／Th2细胞因子平衡、抑制IP-10介导的CXCR3~+Th1和Tc1细胞向肺内趋化，以及激活Wnt／β-catenin信号通路有关。
Background Two of the cardinal points in smoke-induced emphysema (SIE), isexcessive activation of inflammatory cells and chemotaxis of immunoreactant Cellsinto the lung, while chemoreactants and certain signaling pathways are playing anessential role in the process of SIE.In previous research, we have discovered thatadministration of pentoxifylline (PTX) may prevent Guinea pigs from SIE, and that insome animals PTX even leads to a fibrotic phenotype.Wnt/β-catenin signalingpathway is a key regulatory pathway which determines growth, differentiation,proliferation and apoptosis in cells, activation of which has been identified to beassociated with human idiopathic pulmonary fibrosis-usual interstitial pneumonia(IPF/UIP) and epithelial-mesenchymal transition, the key events of pulmonaryfibrosis.However, it's not clear whether PTX could prevent SIE or lead to pulmonaryfibrosis in BALB/c mice, yet it's not clear whether and how PTX regulates theimmune mechanisms and Wnt/β-catenin signaling.
Objective To investigate the effect of PTX on pulmonary pathology inBALB/c mice and its correlations with expression of interferon-g (IFN-γ) and interleukin-4 (IL-4), on interferon-γ-inducible protein-10 (IP-10)-mediatedchemotaxis of CXCR3+Th1 and Tc1 cells, and on Wnt/β-catenin signaling。
Methods Using Hematoxylin and eosin staining to observe the pathologicalchanges in BALB/c mice chronically exposed to cigarette smoke and oral PTX.Usingenzyme-linked immunnoabsorbant assay (ELISA) to determine the level of IFN-γ,IL-4 and IP-10 in BALF and lung TGF-β1 in vivo, and the level of IP-10 in culturemedium of cigarette smoke extract-stimulated RAW264.7 macrophage cell line invitro.Using immunohistochemical methods to detect the number of CXCR3 orβ-catenin positive cells.Using Western blot assay to detect the expression ofβ-cateninand cyclinD1 in in vivo animal models.Using reverse-transcriptase polymereasechain reaction (RT-PCR) to detect the expression of TCF-1 and LEF-1 mRNA in micelungs.
Results Administration of PTX prevented BALB/c mice chronically exposedto cigarette smoke (exposure duration: 4 months) from SIE and lead to pulmonaryfibrosis, accompanied by reversal of the proportion of IFN-γto IL-4 in BALF.PTXinhibited IP-10 release both in BALF in smoking mice (exposure duration: 1 week)and in cigarette smoke extract-stimulated RAW264.7 cells in vitro, and decreasedCXCR3~+ Th1 and Tc1 cell number in smoking mice lungs.Administration of PTXincreasedβ-catenin level in lung tissue and facilitated its transportation to the nucleus,boosted the expression of TCF-1 and TGF-β1, but has shown no significant impacton expression level of cyclinD1 and LEF-1.
Conclusions Administration of PTX prevent BALB/c mice chronically exposedto cigarette smoke (exposure duration: 4 months) from SIE and lead to puhnonaryfibrosis, which may be associated with its regulatory effect on Th1/Th2 cytokineprofile balance, inhibitory effect on IP-10-mediated chemotaxis of CXCR3+Th1 andTc1 cells to the lung, as well as activation of certain genes downstreamingWnt/β-catenin signaling pathway.
【目的】探讨PTX对慢性吸烟BALB／c小鼠肺组织病理学改变的影响及与IFN-γ／IL-4因子表达的关系；探讨PTX对干扰素诱导蛋白(IP-10)介导的CXCR3~+Th1和Tc1细胞向吸烟动物肺内趋化的影响；探讨PTX对慢性吸烟小鼠肺内Wnt／β-catenin信号通路表达的影响及与肺纤维化的关系。
【方法】慢性吸烟和PTX干预BALB／c小鼠，观察肺组织病理学改变。ELISA法检测慢性吸烟和PTX干预动物肺泡灌沈液IFN-γ、IL-4、IP-10表达和肺组织TGF-β1表达。ELISA法检测PTX对香烟烟雾提取物刺激体外培养RAW264.7细胞表达IP-10的影响。免疫组织化学法检测肺组织CXCR3阳性细胞。免疫组织化学染色和Western blot法检测β-catenin蛋白在动物肺组织内的表达。RT-PCR法检测TCF-1和LEF-1表达。Western blot法检测a-平滑肌肌动蛋白(a-SMA)表达变化。
【结果】PTX干预可导致慢性(4月)吸烟BALB／c小鼠发生肺纤维化，伴有IFN-β／IL-4因子比例逆转。PTX干预可抑制吸烟(1周)BALB／c小鼠肺内IFN-γ和IP-10表达，减少CXCR3~+Th1和Tc1细胞数量，抑制吸烟对RAW264.7细胞表达IFN-γ和IP-10的活化作用。PTX可活化β-catenin蛋白在肺组织的表达和向胞浆内转运，促进LEF-1基因和TGF-β1表达，但对cyclinD1蛋白表达和TCF-1基因表达水平无显著影响。
【结论】PTX可阻抑慢性吸烟BALB／c小鼠形成肺气肿，并在部分动物导致肺纤维化形成。该作用可能与调控Th1／Th2细胞因子平衡、抑制IP-10介导的CXCR3~+Th1和Tc1细胞向肺内趋化，以及激活Wnt／β-catenin信号通路有关。
Background Two of the cardinal points in smoke-induced emphysema (SIE), isexcessive activation of inflammatory cells and chemotaxis of immunoreactant Cellsinto the lung, while chemoreactants and certain signaling pathways are playing anessential role in the process of SIE.In previous research, we have discovered thatadministration of pentoxifylline (PTX) may prevent Guinea pigs from SIE, and that insome animals PTX even leads to a fibrotic phenotype.Wnt/β-catenin signalingpathway is a key regulatory pathway which determines growth, differentiation,proliferation and apoptosis in cells, activation of which has been identified to beassociated with human idiopathic pulmonary fibrosis-usual interstitial pneumonia(IPF/UIP) and epithelial-mesenchymal transition, the key events of pulmonaryfibrosis.However, it's not clear whether PTX could prevent SIE or lead to pulmonaryfibrosis in BALB/c mice, yet it's not clear whether and how PTX regulates theimmune mechanisms and Wnt/β-catenin signaling.
Objective To investigate the effect of PTX on pulmonary pathology inBALB/c mice and its correlations with expression of interferon-g (IFN-γ) and interleukin-4 (IL-4), on interferon-γ-inducible protein-10 (IP-10)-mediatedchemotaxis of CXCR3+Th1 and Tc1 cells, and on Wnt/β-catenin signaling。
Methods Using Hematoxylin and eosin staining to observe the pathologicalchanges in BALB/c mice chronically exposed to cigarette smoke and oral PTX.Usingenzyme-linked immunnoabsorbant assay (ELISA) to determine the level of IFN-γ,IL-4 and IP-10 in BALF and lung TGF-β1 in vivo, and the level of IP-10 in culturemedium of cigarette smoke extract-stimulated RAW264.7 macrophage cell line invitro.Using immunohistochemical methods to detect the number of CXCR3 orβ-catenin positive cells.Using Western blot assay to detect the expression ofβ-cateninand cyclinD1 in in vivo animal models.Using reverse-transcriptase polymereasechain reaction (RT-PCR) to detect the expression of TCF-1 and LEF-1 mRNA in micelungs.
Results Administration of PTX prevented BALB/c mice chronically exposedto cigarette smoke (exposure duration: 4 months) from SIE and lead to pulmonaryfibrosis, accompanied by reversal of the proportion of IFN-γto IL-4 in BALF.PTXinhibited IP-10 release both in BALF in smoking mice (exposure duration: 1 week)and in cigarette smoke extract-stimulated RAW264.7 cells in vitro, and decreasedCXCR3~+ Th1 and Tc1 cell number in smoking mice lungs.Administration of PTXincreasedβ-catenin level in lung tissue and facilitated its transportation to the nucleus,boosted the expression of TCF-1 and TGF-β1, but has shown no significant impacton expression level of cyclinD1 and LEF-1.
Conclusions Administration of PTX prevent BALB/c mice chronically exposedto cigarette smoke (exposure duration: 4 months) from SIE and lead to puhnonaryfibrosis, which may be associated with its regulatory effect on Th1/Th2 cytokineprofile balance, inhibitory effect on IP-10-mediated chemotaxis of CXCR3+Th1 andTc1 cells to the lung, as well as activation of certain genes downstreamingWnt/β-catenin signaling pathway.
引文
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