天然免疫系统中Toll-like-receptor家族内TLR-9分子在鼻息肉发病机制中的探讨
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摘要
目的:观察人下鼻甲黏膜及鼻-鼻窦炎/鼻息肉黏膜组织及其黏膜上皮细胞的形态学及改变,检测嗜酸性粒细胞阳离子蛋白ECP在其组织中的表达,以期探讨鼻-鼻窦炎/鼻息肉黏膜及其上皮细胞的病理学特征,以及ECP作为鼻-鼻窦炎/鼻息肉黏膜及其上皮细胞的观测指标的意义所在,初步探讨慢性鼻窦炎与鼻息肉的同源性问题。
方法:选择华中科技大学附属协和医院2006年3月~2006年12月入院行内窥镜手术患者,慢性鼻鼻窦炎不伴息肉组5例;慢性鼻鼻窦炎伴息肉组5例;以上标本均取自构突尾端上颌窦开口处黏膜;下鼻甲粘膜对照组5例,取自行鼻中隔偏曲手术、鼻外伤等无鼻窦炎及变应性疾病史的下鼻甲组织。
每个标本分两份,一份行细胞培养,采用原代差异性细胞培养方法获得黏膜上皮细胞,以备后续研究之用及观察其细胞结构;另一份行组织学观测:将其分成两份,一份放入4%的戊二醛溶液中固定,常规电镜制片,观察组织的形态学变化;另一份放入10%甲醛溶液中固定,石蜡包埋行ECP原位杂交检测,采用图像分析仪分析切片的灰度值,应用统计软件SPPS11.0软件包,方差分析各组之间的差异,进行两两间的差异比较。
结果:1.细胞培养结果:人原代培养的鼻黏膜上皮细胞中可观察到四种细胞:纤毛柱状细胞、杯状细胞、无纤毛柱状细胞、基底细胞;原代鼻黏膜上皮细胞培养经抗人上皮细胞抗原流式细胞术检测,显示密度区域集中,培养人鼻黏膜原代细胞中上皮细胞占90.1%;
2.形态学结果:H-E染色见鼻息肉黏膜组织中嗜酸性粒细胞侵润;电镜下见下鼻甲组织中上皮层连续,基底层排列整齐,下鼻甲黏膜的柱状上皮细胞的细胞膜表面微绒毛整齐,核居中,有核仁,而鼻息肉黏膜组织中上皮层不连续,组织结构紊乱,基底膜增厚、水肿、空泡,鼻息肉胞膜上皮细胞的细胞核不明显,胞膜皱褶,表面纤毛倒伏,胞浆内有空泡;
3.下鼻甲组的组织中未见明显的ECP阳性表达,而单纯鼻窦炎组的组织中及鼻息肉组的组织中有ECP阳性表达,ECP位于黏膜及黏膜下,血管周,统计学结果表明下鼻甲组与单纯鼻窦炎组、鼻息肉组有差异性显示,但鼻息肉组与单纯鼻窦炎组无差异性显示。
结论:1.采用本文方法原代培养鼻黏膜上皮细胞所得上皮细胞的纯度高;
2.鼻-鼻窦炎及鼻息肉组织及上皮细胞中有形态学的改变,表现在嗜酸性粒细胞增多,电镜下上皮层不连续、组织结构紊乱、基底层增厚,细胞表面纤毛减少、倒伏、胞膜皱褶、胞核不明显、胞浆内有空泡。
3. ECP单纯鼻窦炎组及鼻息肉组织中均高表达,鼻甲组与单纯鼻窦炎组、鼻息肉组有差异性显示,但鼻息肉组与单纯鼻窦炎组无差异性显示两者无差异性,提示ECP参与了鼻-鼻窦炎、鼻息肉的发生、发展,初步明确鼻-鼻窦炎、鼻息肉存在同源性的潜在可能;为本文后续的研究将其作为判断指标提供依据。
目的:检测天然免疫系统家簇中Toll-like-receptor - 9在人下鼻甲、鼻窦炎、鼻息肉黏膜上皮细胞中的存在及表达,观察其变化特点,以期探讨其在鼻息肉发病中的作用及其功能、意义。
方法:选择华中科技大学附属协和医院2006年3月~2006年12月入院行内窥镜手术的患者,其中慢性鼻鼻窦炎伴息肉组5例;标本均取自构突尾端上颌窦开口处黏膜;下鼻甲粘膜对照组5例,取自行鼻中隔偏曲手术、鼻外伤等无鼻窦炎及变应性疾病史的下鼻甲组织。
将消化法行原代细胞培养所获得的鼻黏膜上皮细胞采用流式细胞术行双抗(抗人TLR-9、抗人上皮细胞抗原--角蛋白)标记,以纯化上皮细胞和检测上皮细胞中TLR-9的含量;
同时采用western-blot免疫印迹法检测所培养的下鼻甲、鼻窦炎/鼻息肉组织黏膜上皮细胞中的TL R-9蛋白的表达,改变。
采用图像分析仪分析条带的灰度值,应用统计软件SPPS11.0软件包,统计分析组间的差异比较。
结果:1.流式细胞术显示鼻窦炎/鼻息肉组和下鼻甲组的黏膜上皮细胞中均有TLR-9的表达,其中下鼻甲组49~60%,鼻息肉组11~20%,病变组TLR-9表达低于下鼻甲组40%,有差异性;
2. western-blot免疫印迹法显示鼻息肉组条带灰度低于下鼻甲组,经统计两者有差异性(p<0.01)。
结论:1.TLR-9存在于正常和鼻息肉的黏膜上皮中,但鼻息肉组水平下降,两者有差异性;
2.推测其机制可能为病原微生物作用鼻腔鼻窦黏膜上皮细胞后,其非甲基化DNA结合粘膜上皮细胞上的TLR-9产生免疫因子,出现较多的嗜酸性粒细胞浸润和黏膜的高反应性,进一步论证见第三部分实验。
目的:利用TLR-9外源性配体——CpGDNA作用原代培养的人鼻窦炎/鼻息肉黏膜上皮细胞后,观测细胞中TLR-9与ECP变化,分析两者的相关性,以期探讨自然免疫系统中TLR家簇中TLR-9在鼻窦炎/鼻息肉发病中的作用及机制。
方法:将原代培养的人鼻窦炎鼻息肉黏膜上皮细胞培养瓶中的培养基换成不含任何因子的DMEM/F12培养基,在co2细胞培养箱中培养24小时,次日用0μg/mL、5μg/mL的CpGDNA刺激细胞,作用6小时后,采用western-blot免疫印迹方法检测各标本中TLR-9、ECP的蛋白含量,绘制曲线图,分析两者的相关性。
结果:1.CpGDNA刺激人黏膜上皮细胞后,TLR9蛋白表现为高表达,ECP蛋白表现为低表达;
2.CpGDNA刺激人黏膜上皮细胞后,TLR9与ECP两者的相关性还未明确,须大样本的统计。
结论:1.CpGDNA对人鼻黏膜上皮细胞中的TLR9有上调的作用,引起TLR9上调的中间环节尚需深入探讨;
2.CpGDNA作用人鼻窦炎/鼻息肉鼻黏膜上皮细胞后的ECP表达降低,提示CpGDNA作用人鼻鼻窦炎/鼻息肉黏膜上皮细胞上的受体后,上调TLR9,降低诱导免疫反应。
Purposes:. To understand the ultrastructure feature of human nasal polyps, sinusitis and inferior turbinate tissues and cells , and the expression of osinophil cationic protein (ECP) in these tissues.
Methods: 5 cases of CRSwNP,5cases of CRS and 5 cases of in-ferior turbinate mucosa undergoing sinus surgery were gathered from Xiehe hospital afflilting Huazhong Techenical University ,to detect the expression of ECP by site hybridization,celeberate the primary human nasal mucosa epithelial cells cultures ,and find the morphology of these tissues and cells through the light and/or electric microscopy examina-tions.
Results:1. under rhe light and/or electric microscopye the eosinop-hilic cells have highter in CRSwNP group ,degranulating and cytolytic or legs.
2.the level of ECP in CRSwNP group and in CRS group were higher than in inferipor turbinate group,they have difference among them,but in CRSwNP group and in CRS group ,there were no difference between them.
3.The methods of primary cell culture of human nasal mucosa were proved to gain pured epithelial cells(90.1%).
Conclusion: The finding showed that the ultrastructures have chan-ged and ECP expressed higher in CRSwNP and in CRS.
Purpose: By determininge the presence and function of TLR-9 protein in primary epithelial cell cultures of chronic rhinosinusitis with nasal polyps(CRSwNP),and try to explain the effection of innate immune recognition playing in the pathogenesis of CRSwNP.
Methods: Fetching 5 inferior turbinate and 5 CRSwNP mucosa undergoing sinus surgery were established their primary epithelial cell cultures,flow cytometry was used to confirm purity of the cell and to assess expression of TLR-9 protein,western-blot was used to measure the TLR-9 protein.
Results: Data showed that TLR-9 protein were showed both in inferior turbinate and CRSwNPgroup primary epithelial cells,but the level of expression in CRSwNP group was lower.
Conclusion: The finding of TLR-9 protein is both expressed in normal and diseased sinonasal epithelial cells and the expression is decreased in CRSwNP suggest that impaired innate immune responses to pathogens via TLR-9 on sinonasal epithelial cells, eosinophilic infiltrate,mucosal higher reactions .
Objective : To investigate the regulatory effects of Toll like receptor ( TLR9) ligands unmethylated CpGmotifs(CpGDNA) which effect human sinonnasal mucosa epithelial cells and observed the expressions of TLR9 and ECP protin in the epithelial cells by primary culture.,and try to find that the innate immune system via TLR9 play ports in the human nasal polyps mechanism.
Methods : Putting 0μg/mL、5μg/mL CpG DNA in the cell culture plates with human nasal mucosa epithelial cells ,after 6 hours,Western-blot method was used to examine the effects of CpG DNA on expressions of protin for TLR9 and ECP ,and compaired the relationship of them.
Rusults : 1.CpGDNA was up- regulated the expression of TLR9 ;
2. The level of TLR9 was higher and the level of ECP was lower after situmul-ation by the ligand of CpGDNA,
3. The relationship between the TLR9 and ECP was still uncer-tainly,it need more spieces and data to indentified.
Conclusion :These findings may suggest that innate immune responses to pathogens via TLR9 represent a mechanism in chronic inflammatory sinus disease,and CpGDNA was up- regulated the expression of TLR9.
方法:选择华中科技大学附属协和医院2006年3月~2006年12月入院行内窥镜手术患者,慢性鼻鼻窦炎不伴息肉组5例;慢性鼻鼻窦炎伴息肉组5例;以上标本均取自构突尾端上颌窦开口处黏膜;下鼻甲粘膜对照组5例,取自行鼻中隔偏曲手术、鼻外伤等无鼻窦炎及变应性疾病史的下鼻甲组织。
每个标本分两份,一份行细胞培养,采用原代差异性细胞培养方法获得黏膜上皮细胞,以备后续研究之用及观察其细胞结构;另一份行组织学观测:将其分成两份,一份放入4%的戊二醛溶液中固定,常规电镜制片,观察组织的形态学变化;另一份放入10%甲醛溶液中固定,石蜡包埋行ECP原位杂交检测,采用图像分析仪分析切片的灰度值,应用统计软件SPPS11.0软件包,方差分析各组之间的差异,进行两两间的差异比较。
结果:1.细胞培养结果:人原代培养的鼻黏膜上皮细胞中可观察到四种细胞:纤毛柱状细胞、杯状细胞、无纤毛柱状细胞、基底细胞;原代鼻黏膜上皮细胞培养经抗人上皮细胞抗原流式细胞术检测,显示密度区域集中,培养人鼻黏膜原代细胞中上皮细胞占90.1%;
2.形态学结果:H-E染色见鼻息肉黏膜组织中嗜酸性粒细胞侵润;电镜下见下鼻甲组织中上皮层连续,基底层排列整齐,下鼻甲黏膜的柱状上皮细胞的细胞膜表面微绒毛整齐,核居中,有核仁,而鼻息肉黏膜组织中上皮层不连续,组织结构紊乱,基底膜增厚、水肿、空泡,鼻息肉胞膜上皮细胞的细胞核不明显,胞膜皱褶,表面纤毛倒伏,胞浆内有空泡;
3.下鼻甲组的组织中未见明显的ECP阳性表达,而单纯鼻窦炎组的组织中及鼻息肉组的组织中有ECP阳性表达,ECP位于黏膜及黏膜下,血管周,统计学结果表明下鼻甲组与单纯鼻窦炎组、鼻息肉组有差异性显示,但鼻息肉组与单纯鼻窦炎组无差异性显示。
结论:1.采用本文方法原代培养鼻黏膜上皮细胞所得上皮细胞的纯度高;
2.鼻-鼻窦炎及鼻息肉组织及上皮细胞中有形态学的改变,表现在嗜酸性粒细胞增多,电镜下上皮层不连续、组织结构紊乱、基底层增厚,细胞表面纤毛减少、倒伏、胞膜皱褶、胞核不明显、胞浆内有空泡。
3. ECP单纯鼻窦炎组及鼻息肉组织中均高表达,鼻甲组与单纯鼻窦炎组、鼻息肉组有差异性显示,但鼻息肉组与单纯鼻窦炎组无差异性显示两者无差异性,提示ECP参与了鼻-鼻窦炎、鼻息肉的发生、发展,初步明确鼻-鼻窦炎、鼻息肉存在同源性的潜在可能;为本文后续的研究将其作为判断指标提供依据。
目的:检测天然免疫系统家簇中Toll-like-receptor - 9在人下鼻甲、鼻窦炎、鼻息肉黏膜上皮细胞中的存在及表达,观察其变化特点,以期探讨其在鼻息肉发病中的作用及其功能、意义。
方法:选择华中科技大学附属协和医院2006年3月~2006年12月入院行内窥镜手术的患者,其中慢性鼻鼻窦炎伴息肉组5例;标本均取自构突尾端上颌窦开口处黏膜;下鼻甲粘膜对照组5例,取自行鼻中隔偏曲手术、鼻外伤等无鼻窦炎及变应性疾病史的下鼻甲组织。
将消化法行原代细胞培养所获得的鼻黏膜上皮细胞采用流式细胞术行双抗(抗人TLR-9、抗人上皮细胞抗原--角蛋白)标记,以纯化上皮细胞和检测上皮细胞中TLR-9的含量;
同时采用western-blot免疫印迹法检测所培养的下鼻甲、鼻窦炎/鼻息肉组织黏膜上皮细胞中的TL R-9蛋白的表达,改变。
采用图像分析仪分析条带的灰度值,应用统计软件SPPS11.0软件包,统计分析组间的差异比较。
结果:1.流式细胞术显示鼻窦炎/鼻息肉组和下鼻甲组的黏膜上皮细胞中均有TLR-9的表达,其中下鼻甲组49~60%,鼻息肉组11~20%,病变组TLR-9表达低于下鼻甲组40%,有差异性;
2. western-blot免疫印迹法显示鼻息肉组条带灰度低于下鼻甲组,经统计两者有差异性(p<0.01)。
结论:1.TLR-9存在于正常和鼻息肉的黏膜上皮中,但鼻息肉组水平下降,两者有差异性;
2.推测其机制可能为病原微生物作用鼻腔鼻窦黏膜上皮细胞后,其非甲基化DNA结合粘膜上皮细胞上的TLR-9产生免疫因子,出现较多的嗜酸性粒细胞浸润和黏膜的高反应性,进一步论证见第三部分实验。
目的:利用TLR-9外源性配体——CpGDNA作用原代培养的人鼻窦炎/鼻息肉黏膜上皮细胞后,观测细胞中TLR-9与ECP变化,分析两者的相关性,以期探讨自然免疫系统中TLR家簇中TLR-9在鼻窦炎/鼻息肉发病中的作用及机制。
方法:将原代培养的人鼻窦炎鼻息肉黏膜上皮细胞培养瓶中的培养基换成不含任何因子的DMEM/F12培养基,在co2细胞培养箱中培养24小时,次日用0μg/mL、5μg/mL的CpGDNA刺激细胞,作用6小时后,采用western-blot免疫印迹方法检测各标本中TLR-9、ECP的蛋白含量,绘制曲线图,分析两者的相关性。
结果:1.CpGDNA刺激人黏膜上皮细胞后,TLR9蛋白表现为高表达,ECP蛋白表现为低表达;
2.CpGDNA刺激人黏膜上皮细胞后,TLR9与ECP两者的相关性还未明确,须大样本的统计。
结论:1.CpGDNA对人鼻黏膜上皮细胞中的TLR9有上调的作用,引起TLR9上调的中间环节尚需深入探讨;
2.CpGDNA作用人鼻窦炎/鼻息肉鼻黏膜上皮细胞后的ECP表达降低,提示CpGDNA作用人鼻鼻窦炎/鼻息肉黏膜上皮细胞上的受体后,上调TLR9,降低诱导免疫反应。
Purposes:. To understand the ultrastructure feature of human nasal polyps, sinusitis and inferior turbinate tissues and cells , and the expression of osinophil cationic protein (ECP) in these tissues.
Methods: 5 cases of CRSwNP,5cases of CRS and 5 cases of in-ferior turbinate mucosa undergoing sinus surgery were gathered from Xiehe hospital afflilting Huazhong Techenical University ,to detect the expression of ECP by site hybridization,celeberate the primary human nasal mucosa epithelial cells cultures ,and find the morphology of these tissues and cells through the light and/or electric microscopy examina-tions.
Results:1. under rhe light and/or electric microscopye the eosinop-hilic cells have highter in CRSwNP group ,degranulating and cytolytic or legs.
2.the level of ECP in CRSwNP group and in CRS group were higher than in inferipor turbinate group,they have difference among them,but in CRSwNP group and in CRS group ,there were no difference between them.
3.The methods of primary cell culture of human nasal mucosa were proved to gain pured epithelial cells(90.1%).
Conclusion: The finding showed that the ultrastructures have chan-ged and ECP expressed higher in CRSwNP and in CRS.
Purpose: By determininge the presence and function of TLR-9 protein in primary epithelial cell cultures of chronic rhinosinusitis with nasal polyps(CRSwNP),and try to explain the effection of innate immune recognition playing in the pathogenesis of CRSwNP.
Methods: Fetching 5 inferior turbinate and 5 CRSwNP mucosa undergoing sinus surgery were established their primary epithelial cell cultures,flow cytometry was used to confirm purity of the cell and to assess expression of TLR-9 protein,western-blot was used to measure the TLR-9 protein.
Results: Data showed that TLR-9 protein were showed both in inferior turbinate and CRSwNPgroup primary epithelial cells,but the level of expression in CRSwNP group was lower.
Conclusion: The finding of TLR-9 protein is both expressed in normal and diseased sinonasal epithelial cells and the expression is decreased in CRSwNP suggest that impaired innate immune responses to pathogens via TLR-9 on sinonasal epithelial cells, eosinophilic infiltrate,mucosal higher reactions .
Objective : To investigate the regulatory effects of Toll like receptor ( TLR9) ligands unmethylated CpGmotifs(CpGDNA) which effect human sinonnasal mucosa epithelial cells and observed the expressions of TLR9 and ECP protin in the epithelial cells by primary culture.,and try to find that the innate immune system via TLR9 play ports in the human nasal polyps mechanism.
Methods : Putting 0μg/mL、5μg/mL CpG DNA in the cell culture plates with human nasal mucosa epithelial cells ,after 6 hours,Western-blot method was used to examine the effects of CpG DNA on expressions of protin for TLR9 and ECP ,and compaired the relationship of them.
Rusults : 1.CpGDNA was up- regulated the expression of TLR9 ;
2. The level of TLR9 was higher and the level of ECP was lower after situmul-ation by the ligand of CpGDNA,
3. The relationship between the TLR9 and ECP was still uncer-tainly,it need more spieces and data to indentified.
Conclusion :These findings may suggest that innate immune responses to pathogens via TLR9 represent a mechanism in chronic inflammatory sinus disease,and CpGDNA was up- regulated the expression of TLR9.
引文
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