外寒伤肺的理论和实验研究
摘要
寒邪是六淫之中常见的致病因素。寒邪由外而入者,称之为外寒。外寒易伤肺致病,《黄帝内经》中有“形寒寒饮则伤肺”、“肺恶寒”等经典理论。检索国内近20年的相关文献,关于寒证的研究较多,而从病因学的角度系统研究寒邪及其致病机理的较少,且研究不够深入。本课题拟在中医学病因病机理论的指导下,在对寒邪进行理论回顾基础上,模拟温度、时间等作用因素,制作外寒伤肺的动物模型,以肺脏作为研究的靶器官,观察六淫寒邪对小鼠肺脏通调水道、卫外等机能的影响,并通过检测肺部AQP-1、BAFF、NF-κB表达的改变,探讨寒邪伤肺的可能分子机制,为六淫寒邪病因病机理论提供客观的科学实验数据,并为临床辨证论治提供新的思路和量化检测指标。本课题具有理论创新和一定的临床指导价值。
1.理论研究
寒是六气之一,乃冬季之主气,是大自然正常的气候变化,正常的寒气并不致病,若气候变化异常,寒气过重,伤人正气,致人疾病,这种“不正之寒气”中医学上称之为寒邪(淫),寒邪并不仅仅是一个单纯的异常气候因素,应该还包括物理、化学因素、气象因素、生物致病因子等,且与机体的体质、反应性甚或某些基因的表达密切相关。
肺位于胸腔,左右各一,为脏腑之华盖,百脉之朝会,主气司呼吸,具有宣发肃降之生理特性。通过宣发肃降,通调水道,对体内水液的输布、运行和排泄起着疏通和调节作用；通过宣发卫气于体表,实现卫外御邪的功能。
《黄帝内经》记载有：“肺恶寒”、“形寒寒饮则伤肺”、“重寒伤肺”,肺恶寒与肺的生理特性密切相关。肺脏通过鼻窍与外界直接相通,且肺脏清虚娇嫩,在中医学上被称之为“娇脏”,不耐寒袭,肺脏主身之皮毛,皮毛受寒,亦可内合于肺。
外寒伤肺的基本病机为肺阳受损。肺阳是肺气中具有温煦、推动、宣发等作用的部分。寒为阴邪,易伤阳气。寒邪客于肺,可使肺阳受损,肺失宣降,肺行水功能障碍,肺内水液停骤为饮；卫气不能输布于体表,卫外功能障碍,导致卫外不固。
2.实验研究
2.1实验动物及分组
SPF级昆明种小鼠50只,体重17±1g,雌雄各半。常规饲养7天后随机分为7组：①常温对照组,②4℃7天组,③4℃14天组,④0℃7天组,⑤0℃14天组,⑥0℃7天药物治疗组,⑦4℃7天药物治疗组。
2.2实验药物
甘草干姜汤加麻黄,组成：甘草30g、干姜30g、麻黄20g。将上述三种中药混合经水煎煮、过滤、浓缩,配制成每毫升含生药0.2g的水煎剂,装瓶后置于4℃冰箱密闭保存备用
2.3指标检测
2.3.1一般情况观察
观察小鼠的神态、活动量、口唇耳色泽,皮毛情况以及食量、体重的改变情况。
2.3.2小鼠肺组织结构观察
采用苏木素伊红(HE)染色法,光镜观察。
2.3.3肺湿干重比值(w/D)计算
w/D=肺湿重/烘干后重量。
2.3.4肺组织AQP-1表达的测定
采用Western blot法检测。
2.3.5血清IgG和呼吸道液IgG的检测
采用ELISA试剂盒检测。
2.3.6肺组织BAFF表达的检测
采用实时定量荧光PCR检测。
2.3.7肺组织NF-κB表达的检测
采用Western blot法检测。
2.4统计学处理
数据采用x±s表示,以SPSS16.0统计软件进行统计分析,采用采用方差分析和t检验进行统计学处理,P<0.05为差异有统计学意义
3.结果
4℃7天组、4℃14天组,0℃7天组、0℃14天组小鼠造模期间口唇、耳朵、尾巴颜色逐渐变苍白,活动量减少,体重增幅减小,部分小鼠体重逐渐减轻,消瘦明显,食量减少。肺组织病理切片显示4℃7天组、0℃7天组小鼠肺组织水肿充血,肺泡腔内有大量水液潴留,并可见炎症细胞浸润,以上结果符合寒邪伤肺的证候学特点,且肺部病变明显,说明成功复制了外寒伤肺动物模型。
称量小鼠肺脏的干湿重量,发现与正常对照组相比,4℃7天组、0℃7天组小鼠肺组织湿干重比值升高(P<0.05)。采用Western blot法检测肺组织AQP-1,发现与正常对照组相比,4℃7天组、0℃7天组小鼠肺组织AQP-1的表达水平下降,提示外寒可能通过下调AQP-1的表达影响肺的通调水道功能。
ELISA去检测外寒小鼠IgG-S和IgG-R的浓度发现,与正常组相比,4℃7天组、4℃14天组,0℃7天组、0℃14天组小鼠IgG-S和IgG-R的浓度明显升高,BAFF的表达量上调,同时NF-κB的p65亚基蛋白表达量也出现增加。结合小鼠肺部病理组织切片结果,我们推测,外寒破坏小鼠肺脏的卫外功能,侵入机体,损伤肺脏,触发机体的获得性免疫,使抗体的分泌增加,其作用机制是通过上调BAFF的表达激活NF-κB信号通路。采用甘草干姜汤加麻黄治疗后,4℃7天药物治疗组和0℃7天药物治疗组小鼠肺部病理改变明显减轻,AQP-1的表达增加。
The cold-evil, one of the six evils, is the common pathogenic factor of diseases. Which from outside was named exogenous cold-evil. Exogenous cold-evil can impair lung easily. There are many famous ideas in " Huangdi Neijing", such as "Cold body and cold drink injure lung ","lung aversion to cold". The research of Cold syndrome is sufficient, But the cold-evil theory and empirical research was obviously insufficient for20years. Through guided by the etiological factor and pathogenesis theory of traditional chinese medicine and reviewed the documents, the topic is established the animal model of exogenous cold-evil injure lung and examine the antibody, AQP-1, BAFF and NF-κB expression of lung which reflect the governing regulation of water passages and defending function. The topic provides the evidences to explain the machinisms of exogenous cold-evil, enrich the theories of six evils and give new index of the treatment based on syndrome differentiation for exogenous cold-evil. The research have the innovation in the theory and give guidance to the clinics for exogenous cold-evil.
1. Theory research
Cold is one of the six influences of the natural environment and is a normal climatic variation of nature. it is the primary climatic factors in winter. when the climatic variations are too unusual, the occurrence of the natural cold is so excessive that people can not adapt to it, such cold will affect the human body and cause diseases. The cold under such circumstances is then called "cold-evil". Cold-evil in the traditional chinese medicine not only includes to temperature in environment, but also relates to meteorological factors, biological factors, chemical factors, body constitution and responsivity, etc.
Lung locates in thoracic cavity, so each one, which is the organ's canopy and connecting all vessels. The lung governs qi, performs respiration, governs disseminating, cleansing and descending, and regulates the waterways. Lung can diffuse defend qi on the skin and hair to achieve the function of resisting the evils outside.
There are many theories in " Huangdi Neijing", such as "Cold body and cold drink injure lung ","lung aversion to cold". Aversion to cold is closely related physiological characteristics of the lung. Lungs connected directly through the nasal passage with the outside, and delicate which called "fragile organ" in the traditional chinese medicine. The lung governs the skin and hair, when the skin and hair catch cold, it can also involve the lung.
The basic pathogenesis of exogenous cold-evil injury lung is lung yang damage. Lung yang is warm, promoting, diffusing part of lung qi. Cold evil is yin pathogen and apt to attack yang. Exogenous cold-evil attacks lung and damages the lung yang, which leads failure of lung qi in dispersion and regulates the waterways, defend qi can not diffuse on the skin and hair and failure to resisting the evils outside.
2. Experiment study
2.1Animals and grouping
50specific pathogen free Kunming mice,17±g, male and female in half, have been conventionally breeded in the laboratory for7days, then randomly divided into7groups:normal control group,4℃7days group,4℃14days group,0℃7days group,0℃14days group,0℃7days herbs group,4℃7days herbs group.
2.2Herbs
Gancao ganjiang decoction add mahuang, formulation:gancao30g, ganjiang30g, mahuang20g. Mixing the three kinds of herbs and decocting, filtering, concentrating, containing0.2g drug of each milliliter decoction, bottling and placed4℃sealed conservation.
2.3Index detection
1) General state of health in mice, such as demeanor, activity, color and luster of fur and dietary, were observed.
2) Lung tissue structure were observed with hematoxylin eosin(HE) staining method.
3) Account the ratio of lung W/D.
4) AQP-1protein expression in lung were measured by Western blot.
5) Serum IgG and respiratory tract IgG were detected by ELISA kit.
6) ExPression of BAFF mRNA in lung were detected by realtime quantitative fluorescence PCR.
7) NF-κB p65protein expression in lung were measured by Western blot.
2.4Statistical analysis
All data were analyzed by SPSS16.0statistical soft ware. Experimental data were showed with mean±standard deviation. T test and ANOVA was used to compared the differences. P<0.05level was used to indicate statistically significant difference.
3. Results
The mouse of4℃7days,4℃14days,0℃7days group and0℃14days group became pale, less active, and reduced weight gain, part of mouse's weight and food intake gradually reduced. Lung pathological section revealed that the mouse lung tissue of4℃and0℃7days group became edema, congestion, alveolar space had plenty of water fluid retention, and visible infiltration of inflammatory cells. The results were consistent with the evidence of exogenous cold-evil injury lung, and lung lesions were obvious. The animal model of exogenous cold-evil injury lung was success.
Weighing the mice wet and dry lung and account the W/D ratio. We found the W/D ratio of4℃and0℃7days group increased (P<0.05) and the expression of AQP-1descended compared with the normal control group, we speculated that the exogenous cold-evil can interfere lung water transport and the mechanism may be down-regulating expression of AQP-1protein.
Compared with the normal group, IgG-S and IgG-R concentra-tions of4℃7days group,4℃14days group,0℃7days group and0℃14days group were significantly increased, the BAFF mRNA expression and NF-κB p65subunit expression also raised. Combination the mice lung histopathology results, we speculated that the exogenous cold-evil destroyed the mice lung defense function, damaged the lung, which triggered the body's acquired immunity and made the secretion of antibodies increasing. Its mechanism may be through up-regulating expression of BAFF and activate NF-κB signaling pathway.The mouse pulmonary pathological of4℃and0℃for7days which herbs treated significantly recovered, and the expression of AQP-1increased.
1.理论研究
寒是六气之一,乃冬季之主气,是大自然正常的气候变化,正常的寒气并不致病,若气候变化异常,寒气过重,伤人正气,致人疾病,这种“不正之寒气”中医学上称之为寒邪(淫),寒邪并不仅仅是一个单纯的异常气候因素,应该还包括物理、化学因素、气象因素、生物致病因子等,且与机体的体质、反应性甚或某些基因的表达密切相关。
肺位于胸腔,左右各一,为脏腑之华盖,百脉之朝会,主气司呼吸,具有宣发肃降之生理特性。通过宣发肃降,通调水道,对体内水液的输布、运行和排泄起着疏通和调节作用；通过宣发卫气于体表,实现卫外御邪的功能。
《黄帝内经》记载有：“肺恶寒”、“形寒寒饮则伤肺”、“重寒伤肺”,肺恶寒与肺的生理特性密切相关。肺脏通过鼻窍与外界直接相通,且肺脏清虚娇嫩,在中医学上被称之为“娇脏”,不耐寒袭,肺脏主身之皮毛,皮毛受寒,亦可内合于肺。
外寒伤肺的基本病机为肺阳受损。肺阳是肺气中具有温煦、推动、宣发等作用的部分。寒为阴邪,易伤阳气。寒邪客于肺,可使肺阳受损,肺失宣降,肺行水功能障碍,肺内水液停骤为饮；卫气不能输布于体表,卫外功能障碍,导致卫外不固。
2.实验研究
2.1实验动物及分组
SPF级昆明种小鼠50只,体重17±1g,雌雄各半。常规饲养7天后随机分为7组：①常温对照组,②4℃7天组,③4℃14天组,④0℃7天组,⑤0℃14天组,⑥0℃7天药物治疗组,⑦4℃7天药物治疗组。
2.2实验药物
甘草干姜汤加麻黄,组成：甘草30g、干姜30g、麻黄20g。将上述三种中药混合经水煎煮、过滤、浓缩,配制成每毫升含生药0.2g的水煎剂,装瓶后置于4℃冰箱密闭保存备用
2.3指标检测
2.3.1一般情况观察
观察小鼠的神态、活动量、口唇耳色泽,皮毛情况以及食量、体重的改变情况。
2.3.2小鼠肺组织结构观察
采用苏木素伊红(HE)染色法,光镜观察。
2.3.3肺湿干重比值(w/D)计算
w/D=肺湿重/烘干后重量。
2.3.4肺组织AQP-1表达的测定
采用Western blot法检测。
2.3.5血清IgG和呼吸道液IgG的检测
采用ELISA试剂盒检测。
2.3.6肺组织BAFF表达的检测
采用实时定量荧光PCR检测。
2.3.7肺组织NF-κB表达的检测
采用Western blot法检测。
2.4统计学处理
数据采用x±s表示,以SPSS16.0统计软件进行统计分析,采用采用方差分析和t检验进行统计学处理,P<0.05为差异有统计学意义
3.结果
4℃7天组、4℃14天组,0℃7天组、0℃14天组小鼠造模期间口唇、耳朵、尾巴颜色逐渐变苍白,活动量减少,体重增幅减小,部分小鼠体重逐渐减轻,消瘦明显,食量减少。肺组织病理切片显示4℃7天组、0℃7天组小鼠肺组织水肿充血,肺泡腔内有大量水液潴留,并可见炎症细胞浸润,以上结果符合寒邪伤肺的证候学特点,且肺部病变明显,说明成功复制了外寒伤肺动物模型。
称量小鼠肺脏的干湿重量,发现与正常对照组相比,4℃7天组、0℃7天组小鼠肺组织湿干重比值升高(P<0.05)。采用Western blot法检测肺组织AQP-1,发现与正常对照组相比,4℃7天组、0℃7天组小鼠肺组织AQP-1的表达水平下降,提示外寒可能通过下调AQP-1的表达影响肺的通调水道功能。
ELISA去检测外寒小鼠IgG-S和IgG-R的浓度发现,与正常组相比,4℃7天组、4℃14天组,0℃7天组、0℃14天组小鼠IgG-S和IgG-R的浓度明显升高,BAFF的表达量上调,同时NF-κB的p65亚基蛋白表达量也出现增加。结合小鼠肺部病理组织切片结果,我们推测,外寒破坏小鼠肺脏的卫外功能,侵入机体,损伤肺脏,触发机体的获得性免疫,使抗体的分泌增加,其作用机制是通过上调BAFF的表达激活NF-κB信号通路。采用甘草干姜汤加麻黄治疗后,4℃7天药物治疗组和0℃7天药物治疗组小鼠肺部病理改变明显减轻,AQP-1的表达增加。
The cold-evil, one of the six evils, is the common pathogenic factor of diseases. Which from outside was named exogenous cold-evil. Exogenous cold-evil can impair lung easily. There are many famous ideas in " Huangdi Neijing", such as "Cold body and cold drink injure lung ","lung aversion to cold". The research of Cold syndrome is sufficient, But the cold-evil theory and empirical research was obviously insufficient for20years. Through guided by the etiological factor and pathogenesis theory of traditional chinese medicine and reviewed the documents, the topic is established the animal model of exogenous cold-evil injure lung and examine the antibody, AQP-1, BAFF and NF-κB expression of lung which reflect the governing regulation of water passages and defending function. The topic provides the evidences to explain the machinisms of exogenous cold-evil, enrich the theories of six evils and give new index of the treatment based on syndrome differentiation for exogenous cold-evil. The research have the innovation in the theory and give guidance to the clinics for exogenous cold-evil.
1. Theory research
Cold is one of the six influences of the natural environment and is a normal climatic variation of nature. it is the primary climatic factors in winter. when the climatic variations are too unusual, the occurrence of the natural cold is so excessive that people can not adapt to it, such cold will affect the human body and cause diseases. The cold under such circumstances is then called "cold-evil". Cold-evil in the traditional chinese medicine not only includes to temperature in environment, but also relates to meteorological factors, biological factors, chemical factors, body constitution and responsivity, etc.
Lung locates in thoracic cavity, so each one, which is the organ's canopy and connecting all vessels. The lung governs qi, performs respiration, governs disseminating, cleansing and descending, and regulates the waterways. Lung can diffuse defend qi on the skin and hair to achieve the function of resisting the evils outside.
There are many theories in " Huangdi Neijing", such as "Cold body and cold drink injure lung ","lung aversion to cold". Aversion to cold is closely related physiological characteristics of the lung. Lungs connected directly through the nasal passage with the outside, and delicate which called "fragile organ" in the traditional chinese medicine. The lung governs the skin and hair, when the skin and hair catch cold, it can also involve the lung.
The basic pathogenesis of exogenous cold-evil injury lung is lung yang damage. Lung yang is warm, promoting, diffusing part of lung qi. Cold evil is yin pathogen and apt to attack yang. Exogenous cold-evil attacks lung and damages the lung yang, which leads failure of lung qi in dispersion and regulates the waterways, defend qi can not diffuse on the skin and hair and failure to resisting the evils outside.
2. Experiment study
2.1Animals and grouping
50specific pathogen free Kunming mice,17±g, male and female in half, have been conventionally breeded in the laboratory for7days, then randomly divided into7groups:normal control group,4℃7days group,4℃14days group,0℃7days group,0℃14days group,0℃7days herbs group,4℃7days herbs group.
2.2Herbs
Gancao ganjiang decoction add mahuang, formulation:gancao30g, ganjiang30g, mahuang20g. Mixing the three kinds of herbs and decocting, filtering, concentrating, containing0.2g drug of each milliliter decoction, bottling and placed4℃sealed conservation.
2.3Index detection
1) General state of health in mice, such as demeanor, activity, color and luster of fur and dietary, were observed.
2) Lung tissue structure were observed with hematoxylin eosin(HE) staining method.
3) Account the ratio of lung W/D.
4) AQP-1protein expression in lung were measured by Western blot.
5) Serum IgG and respiratory tract IgG were detected by ELISA kit.
6) ExPression of BAFF mRNA in lung were detected by realtime quantitative fluorescence PCR.
7) NF-κB p65protein expression in lung were measured by Western blot.
2.4Statistical analysis
All data were analyzed by SPSS16.0statistical soft ware. Experimental data were showed with mean±standard deviation. T test and ANOVA was used to compared the differences. P<0.05level was used to indicate statistically significant difference.
3. Results
The mouse of4℃7days,4℃14days,0℃7days group and0℃14days group became pale, less active, and reduced weight gain, part of mouse's weight and food intake gradually reduced. Lung pathological section revealed that the mouse lung tissue of4℃and0℃7days group became edema, congestion, alveolar space had plenty of water fluid retention, and visible infiltration of inflammatory cells. The results were consistent with the evidence of exogenous cold-evil injury lung, and lung lesions were obvious. The animal model of exogenous cold-evil injury lung was success.
Weighing the mice wet and dry lung and account the W/D ratio. We found the W/D ratio of4℃and0℃7days group increased (P<0.05) and the expression of AQP-1descended compared with the normal control group, we speculated that the exogenous cold-evil can interfere lung water transport and the mechanism may be down-regulating expression of AQP-1protein.
Compared with the normal group, IgG-S and IgG-R concentra-tions of4℃7days group,4℃14days group,0℃7days group and0℃14days group were significantly increased, the BAFF mRNA expression and NF-κB p65subunit expression also raised. Combination the mice lung histopathology results, we speculated that the exogenous cold-evil destroyed the mice lung defense function, damaged the lung, which triggered the body's acquired immunity and made the secretion of antibodies increasing. Its mechanism may be through up-regulating expression of BAFF and activate NF-κB signaling pathway.The mouse pulmonary pathological of4℃and0℃for7days which herbs treated significantly recovered, and the expression of AQP-1increased.
引文
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