DcR3对Fas/FasL介导的大鼠肺泡上皮细胞（CCL-149）凋亡及肺纤维化动物模型的影响
摘要
间质性肺疾病（ILD）是以弥漫性肺实质、肺泡炎症和间质纤维化为病理基本病变，以活动性呼吸困难、X线胸片弥漫性浸润阴影、限制性通气障碍、弥散（DLCO）功能降低和低氧血症为临床表现的不同种类疾病群构成的临床-病理实体的总称。肺纤维化的发病率呈逐年上升的趋势，至今无有效的药物逆转肺纤维化的自然过程及其终末结局。
ILD确切的发病机制尚未完全阐明。假设ILD的演变过程可区分为三个阶段，即启动阶段、进展阶段和结局阶段。启动ILD的致病因子通常是毒素和（或）抗原，一旦暴露和接触了最初的致病因子，则产生一个复杂的炎症过程——肺泡炎，这是ILD发病的中心环节，炎性及免疫细胞的活化，不仅释放氧自由基等毒性物质，直接损伤I型肺泡上皮细胞和毛细血管内皮细胞，还释放蛋白酶等直接损伤间质、胶原组织和基底膜等。同时释放各种炎性介质，若炎症广泛和损伤严重，肺泡壁中成纤维细胞聚集和增殖，胶原组织增生、修复紊乱并沉积，肺泡壁增厚，瘢痕和纤维化形成，这种受损的肺泡壁将难以修复和恢复。
肺泡上皮细胞损伤后引起大量肺泡上皮细胞凋亡，而参与凋亡调节的Fas/FasL途径是导致细胞凋亡的因素，DcR3可以通过与FasL结合阻断这一途径而减轻凋亡，我们假设在间质性肺疾病早期给予DcR3，通过减轻肺泡上皮细胞凋亡从而阻止肺纤维化的进一步形成。在本研究的第一部分中，体外培养大鼠肺泡上皮细胞株（CCL-149），用FasL诱导细胞凋亡，同时用DcR3进行干预，通过MTT法及流式细胞术检测细胞凋亡情况，通过RT-PCR法及Western blot检测FasL及caspase3表达情况，结果显示：DcR3干预组肺泡上皮细胞的凋亡百分率低于FasL处理组，具有显著性差异（p＜0.05），DcR3干预组Fas及caspase3表达低于FasL处理组。说明DcR3在一定程度上抑制了大鼠肺泡上皮细胞的凋亡。
第二部分研究通过气管内灌注博来霉素复制大鼠肺纤维化模型，同时静脉注射DcR3进行干预，通过病理观察不同时期肺泡炎及肺纤维化程度的变化，ELISA法检测羟脯氨酸含量测定肺纤维化程度，采用Western blot方法及免疫组织化学法检测Fas、FasL及Caspase3等凋亡因子的表达，TUNEL法检测肺组织细胞凋亡情况，观察DcR3对大鼠肺纤维化模型的影响。病理结果显示：正常对照组：光镜观察可见大鼠肺结构清晰，各观察点均未出现明显改变，Masson染色未见绿色胶原沉积；肺泡炎的程度和肺纤维化程度在各个时间点无明显变化；博来霉素组：7天时肺泡结构清晰，多量中性粒细胞及巨噬细胞浸润，Masson染色可见极少量绿色胶原出现；至28天时炎性细胞减少，肺泡结构破坏，肺泡壁显著增厚，成纤维细胞增多，肺间质纤维化瘢痕形成；Masson染色可见肺泡间隔内有大量绿色胶原沉积。DcR3干预组：7天时以中性粒细胞浸润为主，较博来霉素组炎细胞浸润较轻，Masson染色未见绿色胶原沉积；至28天时部分标本表现局灶性改变，部分组织表现为肺泡间隔轻度增厚、少量成纤维细胞增生，部分可见肺组织成纤维细胞增多明显，肺泡结构破坏；Masson染色可见绿色胶原沉积及梭形的成纤维细胞。博来霉素组各时间点炎症程度高于对照组，与对照组比较均有显著性差异（p＜0.05）； DcR3干预组肺泡炎的程度低于博来霉素组，具有统计学差异（p＜0.05），且高于对照组具有显著性差异（p＜0.05）。对照组肺纤维化程度在各个时间点无明显变化；博来霉素组肺纤维化程度逐渐加重，各时间点与对照组比较均具有显著性差异（p＜0.05）；DcR3干预组肺纤维化程度也逐渐加重，与对照组比较差异有显著性（p＜0.05），28天时肺纤维程度低于博来霉素组，有显著性差异（p＜0.05）。ELISA法检测羟脯氨酸结果：博来霉素组羟脯氨酸含量高于对照组，DcR3干预组羟脯氨酸含量高于对照组但低于博来霉素组，具有统计学差异（p＜0.05）。Western blot法及免疫组织化学法检测Fas、FasL及caspase3表达情况显示：博来霉素组上述因子表达高于对照组，具有统计学意义（p＜0.05），DcR3组高于对照组而低于博来霉素组，且具有统计学意义（p＜0.05）。TUNEL法结果显示博来霉素组肺组织细胞凋亡指数高于正常对照组，有显著性差异（p＜0.05），DcR3干预组肺组织细胞凋亡指数低于博来霉素组，有显著性差异（p＜0.05），但高于正常对照组，有显著性差异（p＜0.05）。
结合以上实验结果：DcR3可以在体外抑制Fas/FasL诱导的大鼠肺泡上皮细胞（CCL-149）的凋亡，动物实验发现DcR3干预组肺泡炎程度和肺纤维化程度低于博来霉素组，且DcR3干预组Fas、FasL及caspase3表达低于博来霉素组，因此我们推测，在博莱霉素的肺纤维化动物模型中，早期给予DcR3可能通过抑制Fas/FasL介导的肺泡上皮细胞的凋亡而减轻肺纤维化的发展过程，该研究不仅完善了肺纤维的发病机制，也对指导临床治疗有重大的意义。
The interstitial lung diseases (ILDs) represent a large number of conditionsthat involve the parenchyma of the lung. This group of disorders is classifiedtogether because of similar clinical manifestations of exertional dyspnea,roentgenographic diffuse infiltration, restrictive pulmonary function，decreasedDLCO and hypoxemia, and pathologic manifestations of alveolitis and fibrosis.
It is not clarified clearly about the pathogenesis of ILD. Usually theoccurrence is divided into three phases, initiation stage, progression stage and endstage. Pathogenic factors are usually toxins and antigens. Exposure to thepathogenic factors can lead to alveolitis which is the most important part ofILD.The activation of inflammatory cells and immunocytes can release oxygenradicals and other toxins and injure typeⅠalveolar epithelial cells and capillaryendothelial cells. Alveolitis also can lead to injury of interstitium, collagen tissueand basement membrane by releasing proteinase.When alveolitis progress andlead to severe injury in the lungs, there may be fibroblasts proliferations, collagendeposit and formation of fibrosis.When the fibrosis produce, the injury ofalveolar wall can not be repaired.
The injury of alveolar epithelial cells can lead apoptosis of large number ofalveolar epithelial cells, and Fas/FasL signal pathway is an important reason forthe apoptosis. While DcR3can bind to FasL and block the Fas/FasL pathway,thenreduce the apoptosis. We suppose that the administration of DcR3to the ILDpatient in the early stage may reduce the apoptosis of alveolar epithelial cells andprevent the progression of pulmonary fibrosis.
In the first part of the study, the CCL-149cells were cultured in vitro. Threegroups were designed: control group, FasL group and DcR3group.The cellswere incubated with FasL to induce apoptosis in FasL group, and in DcR3group the cells were incubated with FasL and DcR3together. The cells were gated andanalyzed by MTT and flow cytometry for apoptosis. The expression of Fas andcaspase3were analyzed by RT-PCR and Western blot. MTT and flow cytometryresults showed: apoptosis percentage of DcR3group were lower than FasL groupand there was significant difference (p<0.05). RT-PCR and Western blot resultsshowed: the expression of Fas of DcR3group is lower than FasL group. Theresults suggest that DcR3can inhibit the apoptosis of CCL-149cells induced byFasL.
In the second part, we established pulmonary fibrosis model in rat byinstillation with bleomycin into the tracheal. The rats are divided into threegroups: control group, bleomycin group, and DcR3group.The rats in controlgroup and bleomycin group were injected intravenously with normal saline0.5mlevery other day and the rats in DcR3group were injected intravenously withDcR3protein(3.33μg/kg) every other day from the beginning of the model. Therats were sacrificed at the time of7d,21d and28d respectively. The right lungswere submerged in10%paraformaldehyde solution, paraffin-embedded, stainedsections in order to organize staining. The left lungs were saved for the detectionof Fas、FasL and caspase3by Western blot. The serum were collected for thedetection of hydroxyproline by ELLISA.
Histopathology results showed: control group: the structure of lungs arenormal at all the time of7d,14d and28d and Masson staining showed no greencollagen deposit. Bleomycin group: At7d,the structure of alveolar was clear andinfiltrated with large number of neutrophils and macrophages. At14d, alveolarseptum were thick and infiltrated with neutrophils,there were small amount offibroblasts in the interstitium.Masson staining showed small amount of greencollagen deposit. At28d, the inflammatory cells reduced and the structure ofalveolar were destroyed.The alveolar septum were significantly thickened,andthere were large amount of fibroblasts proliferation and fibrosis produced.Masson staining showed large amount of green collagen deposit.DcR3groups: the degrees the alveolitis and fibrosis were lower than bleomycin group andhigher than control group. Pathological assessment: the extent of alveolitis ofDcR3group manifested as a gradual reducing, the degree of inflammation werelower than the bleomycin group, there was significant difference (p<0.05); theextent of pulmonary fibrosis of DcR3group were lower than the bleomycingroup and there was significantly different (p<0.05).
The result of hydroxyproline content in serum by ELISA showed: thehydroxyproline content of DcR3group was lower than bleomycin group buthigher than control group, there were significantly different (p<0.05). Westernblot results showed： At28d,the expression of Fas,FasL and caspase3inbleomycin group were higher than control group, there was significantly different(p<0.05), the expression of Fas, FasL and caspase3in DcR3group were lowerthan bleomycin group, and there were significantly different (p<0.05). TheImmunohistochemistry results showed: the expression of Fas, FasL and caspase3in the lungs of DcR3group are lower than bleomycin group but higher thancontrol group, and there were significantly different (p<0.05). The TUNELresults showed:the cell apoptosis index of DcR3group are lower than bleomycingroup but higher than control group, and there were significantly different(p<0.05).
Combining the results of experiments, the following conclusions can bedrawn: DcR3can reduce the apoptosis of alveolar epithelial cells induced byFas/FasL pathway in CCL-149in vitro. In the pulmonary fibrosis animalmodel,the degree of alveolitis and the pulmonary fibrosis in DcR3group werelower than bleomycin group.Thus,in the pulmonary fibrosis animal modelinduced by bleomycin,the administration of DcR3may reduce the progression ofpulmonary fibrosis through inhibiting the apoptosis of alveolar epithelial cellsinduced by Fas/FasL signal pathway. The study improved the pathogenesis ofpulmonary fibrosis, and also has great significance to the clinical treatment.
ILD确切的发病机制尚未完全阐明。假设ILD的演变过程可区分为三个阶段，即启动阶段、进展阶段和结局阶段。启动ILD的致病因子通常是毒素和（或）抗原，一旦暴露和接触了最初的致病因子，则产生一个复杂的炎症过程——肺泡炎，这是ILD发病的中心环节，炎性及免疫细胞的活化，不仅释放氧自由基等毒性物质，直接损伤I型肺泡上皮细胞和毛细血管内皮细胞，还释放蛋白酶等直接损伤间质、胶原组织和基底膜等。同时释放各种炎性介质，若炎症广泛和损伤严重，肺泡壁中成纤维细胞聚集和增殖，胶原组织增生、修复紊乱并沉积，肺泡壁增厚，瘢痕和纤维化形成，这种受损的肺泡壁将难以修复和恢复。
肺泡上皮细胞损伤后引起大量肺泡上皮细胞凋亡，而参与凋亡调节的Fas/FasL途径是导致细胞凋亡的因素，DcR3可以通过与FasL结合阻断这一途径而减轻凋亡，我们假设在间质性肺疾病早期给予DcR3，通过减轻肺泡上皮细胞凋亡从而阻止肺纤维化的进一步形成。在本研究的第一部分中，体外培养大鼠肺泡上皮细胞株（CCL-149），用FasL诱导细胞凋亡，同时用DcR3进行干预，通过MTT法及流式细胞术检测细胞凋亡情况，通过RT-PCR法及Western blot检测FasL及caspase3表达情况，结果显示：DcR3干预组肺泡上皮细胞的凋亡百分率低于FasL处理组，具有显著性差异（p＜0.05），DcR3干预组Fas及caspase3表达低于FasL处理组。说明DcR3在一定程度上抑制了大鼠肺泡上皮细胞的凋亡。
第二部分研究通过气管内灌注博来霉素复制大鼠肺纤维化模型，同时静脉注射DcR3进行干预，通过病理观察不同时期肺泡炎及肺纤维化程度的变化，ELISA法检测羟脯氨酸含量测定肺纤维化程度，采用Western blot方法及免疫组织化学法检测Fas、FasL及Caspase3等凋亡因子的表达，TUNEL法检测肺组织细胞凋亡情况，观察DcR3对大鼠肺纤维化模型的影响。病理结果显示：正常对照组：光镜观察可见大鼠肺结构清晰，各观察点均未出现明显改变，Masson染色未见绿色胶原沉积；肺泡炎的程度和肺纤维化程度在各个时间点无明显变化；博来霉素组：7天时肺泡结构清晰，多量中性粒细胞及巨噬细胞浸润，Masson染色可见极少量绿色胶原出现；至28天时炎性细胞减少，肺泡结构破坏，肺泡壁显著增厚，成纤维细胞增多，肺间质纤维化瘢痕形成；Masson染色可见肺泡间隔内有大量绿色胶原沉积。DcR3干预组：7天时以中性粒细胞浸润为主，较博来霉素组炎细胞浸润较轻，Masson染色未见绿色胶原沉积；至28天时部分标本表现局灶性改变，部分组织表现为肺泡间隔轻度增厚、少量成纤维细胞增生，部分可见肺组织成纤维细胞增多明显，肺泡结构破坏；Masson染色可见绿色胶原沉积及梭形的成纤维细胞。博来霉素组各时间点炎症程度高于对照组，与对照组比较均有显著性差异（p＜0.05）； DcR3干预组肺泡炎的程度低于博来霉素组，具有统计学差异（p＜0.05），且高于对照组具有显著性差异（p＜0.05）。对照组肺纤维化程度在各个时间点无明显变化；博来霉素组肺纤维化程度逐渐加重，各时间点与对照组比较均具有显著性差异（p＜0.05）；DcR3干预组肺纤维化程度也逐渐加重，与对照组比较差异有显著性（p＜0.05），28天时肺纤维程度低于博来霉素组，有显著性差异（p＜0.05）。ELISA法检测羟脯氨酸结果：博来霉素组羟脯氨酸含量高于对照组，DcR3干预组羟脯氨酸含量高于对照组但低于博来霉素组，具有统计学差异（p＜0.05）。Western blot法及免疫组织化学法检测Fas、FasL及caspase3表达情况显示：博来霉素组上述因子表达高于对照组，具有统计学意义（p＜0.05），DcR3组高于对照组而低于博来霉素组，且具有统计学意义（p＜0.05）。TUNEL法结果显示博来霉素组肺组织细胞凋亡指数高于正常对照组，有显著性差异（p＜0.05），DcR3干预组肺组织细胞凋亡指数低于博来霉素组，有显著性差异（p＜0.05），但高于正常对照组，有显著性差异（p＜0.05）。
结合以上实验结果：DcR3可以在体外抑制Fas/FasL诱导的大鼠肺泡上皮细胞（CCL-149）的凋亡，动物实验发现DcR3干预组肺泡炎程度和肺纤维化程度低于博来霉素组，且DcR3干预组Fas、FasL及caspase3表达低于博来霉素组，因此我们推测，在博莱霉素的肺纤维化动物模型中，早期给予DcR3可能通过抑制Fas/FasL介导的肺泡上皮细胞的凋亡而减轻肺纤维化的发展过程，该研究不仅完善了肺纤维的发病机制，也对指导临床治疗有重大的意义。
The interstitial lung diseases (ILDs) represent a large number of conditionsthat involve the parenchyma of the lung. This group of disorders is classifiedtogether because of similar clinical manifestations of exertional dyspnea,roentgenographic diffuse infiltration, restrictive pulmonary function，decreasedDLCO and hypoxemia, and pathologic manifestations of alveolitis and fibrosis.
It is not clarified clearly about the pathogenesis of ILD. Usually theoccurrence is divided into three phases, initiation stage, progression stage and endstage. Pathogenic factors are usually toxins and antigens. Exposure to thepathogenic factors can lead to alveolitis which is the most important part ofILD.The activation of inflammatory cells and immunocytes can release oxygenradicals and other toxins and injure typeⅠalveolar epithelial cells and capillaryendothelial cells. Alveolitis also can lead to injury of interstitium, collagen tissueand basement membrane by releasing proteinase.When alveolitis progress andlead to severe injury in the lungs, there may be fibroblasts proliferations, collagendeposit and formation of fibrosis.When the fibrosis produce, the injury ofalveolar wall can not be repaired.
The injury of alveolar epithelial cells can lead apoptosis of large number ofalveolar epithelial cells, and Fas/FasL signal pathway is an important reason forthe apoptosis. While DcR3can bind to FasL and block the Fas/FasL pathway,thenreduce the apoptosis. We suppose that the administration of DcR3to the ILDpatient in the early stage may reduce the apoptosis of alveolar epithelial cells andprevent the progression of pulmonary fibrosis.
In the first part of the study, the CCL-149cells were cultured in vitro. Threegroups were designed: control group, FasL group and DcR3group.The cellswere incubated with FasL to induce apoptosis in FasL group, and in DcR3group the cells were incubated with FasL and DcR3together. The cells were gated andanalyzed by MTT and flow cytometry for apoptosis. The expression of Fas andcaspase3were analyzed by RT-PCR and Western blot. MTT and flow cytometryresults showed: apoptosis percentage of DcR3group were lower than FasL groupand there was significant difference (p<0.05). RT-PCR and Western blot resultsshowed: the expression of Fas of DcR3group is lower than FasL group. Theresults suggest that DcR3can inhibit the apoptosis of CCL-149cells induced byFasL.
In the second part, we established pulmonary fibrosis model in rat byinstillation with bleomycin into the tracheal. The rats are divided into threegroups: control group, bleomycin group, and DcR3group.The rats in controlgroup and bleomycin group were injected intravenously with normal saline0.5mlevery other day and the rats in DcR3group were injected intravenously withDcR3protein(3.33μg/kg) every other day from the beginning of the model. Therats were sacrificed at the time of7d,21d and28d respectively. The right lungswere submerged in10%paraformaldehyde solution, paraffin-embedded, stainedsections in order to organize staining. The left lungs were saved for the detectionof Fas、FasL and caspase3by Western blot. The serum were collected for thedetection of hydroxyproline by ELLISA.
Histopathology results showed: control group: the structure of lungs arenormal at all the time of7d,14d and28d and Masson staining showed no greencollagen deposit. Bleomycin group: At7d,the structure of alveolar was clear andinfiltrated with large number of neutrophils and macrophages. At14d, alveolarseptum were thick and infiltrated with neutrophils,there were small amount offibroblasts in the interstitium.Masson staining showed small amount of greencollagen deposit. At28d, the inflammatory cells reduced and the structure ofalveolar were destroyed.The alveolar septum were significantly thickened,andthere were large amount of fibroblasts proliferation and fibrosis produced.Masson staining showed large amount of green collagen deposit.DcR3groups: the degrees the alveolitis and fibrosis were lower than bleomycin group andhigher than control group. Pathological assessment: the extent of alveolitis ofDcR3group manifested as a gradual reducing, the degree of inflammation werelower than the bleomycin group, there was significant difference (p<0.05); theextent of pulmonary fibrosis of DcR3group were lower than the bleomycingroup and there was significantly different (p<0.05).
The result of hydroxyproline content in serum by ELISA showed: thehydroxyproline content of DcR3group was lower than bleomycin group buthigher than control group, there were significantly different (p<0.05). Westernblot results showed： At28d,the expression of Fas,FasL and caspase3inbleomycin group were higher than control group, there was significantly different(p<0.05), the expression of Fas, FasL and caspase3in DcR3group were lowerthan bleomycin group, and there were significantly different (p<0.05). TheImmunohistochemistry results showed: the expression of Fas, FasL and caspase3in the lungs of DcR3group are lower than bleomycin group but higher thancontrol group, and there were significantly different (p<0.05). The TUNELresults showed:the cell apoptosis index of DcR3group are lower than bleomycingroup but higher than control group, and there were significantly different(p<0.05).
Combining the results of experiments, the following conclusions can bedrawn: DcR3can reduce the apoptosis of alveolar epithelial cells induced byFas/FasL pathway in CCL-149in vitro. In the pulmonary fibrosis animalmodel,the degree of alveolitis and the pulmonary fibrosis in DcR3group werelower than bleomycin group.Thus,in the pulmonary fibrosis animal modelinduced by bleomycin,the administration of DcR3may reduce the progression ofpulmonary fibrosis through inhibiting the apoptosis of alveolar epithelial cellsinduced by Fas/FasL signal pathway. The study improved the pathogenesis ofpulmonary fibrosis, and also has great significance to the clinical treatment.
引文
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