加味小苦辛汤治疗儿童肺纤维化临床经验总结及相关实验研究
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摘要
目的
总结临床运用加味小苦辛汤治疗儿童肺纤维化的经验；观察加味小苦辛汤对博莱霉素诱导的小鼠肺纤维化的影响,探讨肺纤维化的发病机制及加味小苦辛汤治疗儿童肺纤维化的作用机理。
方法
72只雌性C57BL/6小鼠随机分为正常对照组、模型组、西药组、加味小苦辛汤高、中、低剂量组,每组12只。模型组、西药组和中药各组以博莱霉素(40mg/kg)200μl×5次腹腔注射建立肺纤维化小鼠模型,正常组以生理盐水代替。各组小鼠于造模次日起灌胃,中药高、中、低剂量组分别给予中药加味小苦辛汤颗粒剂4.6g/kg、2.3g/kg.1.15g/kg；西药组用强的松5mg/kg；模型组与正常对照组予0.5%CMC10ml/kg,日1次。于连续给药物第14、28天分批随机处死小鼠,称取全肺湿重后,取右肺组织置于4%甲醛溶液中固定,常规脱水、石蜡包埋,连续组织切片,进行苏木精-伊红染色(HE染色)、三色染色(Masson染色)及免疫组化染色。观察各组病理切片肺组织形态学改变与TGF-β1、ICAM-1、NF-κβ的表达,并通过图像分析比较各组小鼠肺组织TGF-β1TGF-β1、 ICAM-1、NF-κβ的积分光密度和平均光密度值。
结果
1.对小鼠肺质量系数的影响：模型组肺系数在治疗后14和28天均显著高于空白组,有显著的统计学意义(P<0.01)；西药组与空白组相比,升高有统计学意义(P<0.05)；中药高剂量组于第14天和28天时均低于模型组,有统计学意义(P<0.05)；第28天时中药中、低剂量组与正常组无显著差异(P>0.05),中药高剂量组较西药组降低,差异具有统计学意义(P<0.05)。
2.对肺组织形态学的影响：①HE染色可见：正常组无肺泡炎及肺纤维化改变,肺泡结构完整,肺泡腔内无明显渗出。模型组第14天时,细支气管和血管周围有炎性细胞聚集,肺泡隔增宽,肺泡腔内明显渗出；第28天时,纤维化程度明显,有大片实变区,部分肺泡壁破坏,肺泡腔塌陷,肺泡壁增厚,肺泡隔纤维化显著。②Masson染色可见：14天时模型组肺泡炎明显,纤维化程度较重,肺泡腔内充满渗出物和脱落的各种炎性细胞,肺泡间隔可见明显纤维增生灶,28天时肺泡壁及间隔,支气管与小血管周围大量纤维增生。通过HE和Masson染色观察可见,西药组和中药高、中、低剂量组肺泡炎和纤维化程度均较模型组减轻明显,其中中药高剂量组尤为明显。
3.对TGF-β1表达的影响：14和28天的模型组与正常对照组比较,细胞积分光密度、平均光密度均显著增加(P<0.01)；而中药高、中、低三组在细胞积分光密度、平均光密度两方面均较模型组显著降低(P<0.01)；其中中药高剂量组与西药组相比,第14天积分光密度的差别不显著(P>0.05),第28天则较西药组降低(P<0.05)。在平均光密度方面,中药高剂量组与西药组两组之间差别不显著(P>0.05)。而中药高剂量组、西药组与正常对照组在细胞积分光密度、平均光密度两方面相比较,差别不显著(P>0.05)。
4.对ICAM-1表达的影响：积分光密度方面,14和28天的模型组与正常对照组比较增加显著(P<0.01)；而中药高、中、低三组在细胞积分光密度、平均光密度两方面均较模型组显著降低(P<0.01)；其中中药高剂量组与西药组相比,第14天与28天积分光密度的差别显著(P<0.01),第28天中药低剂量组与西药组平均光密度差别亦显著(P<0.01)。平均光密度方面,14天时各组与正常对照组比较均差异显著(P<0.01),28天时中药高剂量组与正常对照组相比无明显差异(P>0.05)：中药各组与模型组比较,降低较为显著(P<0.01)；中药高剂量组与西药组两组之间差别显著(P<0.01)。
5,对NF-κB表达的影响：14和28天各组与正常对照组比较,细胞积分光密度、平均光密度均显著增加(P<0.01),与模型组相比,中药各组与西药组细胞积分光密度、平均光密度降低显著(P<0.01);与西药组相比,14天中药各组积分光密度降低显著(P<0.01),28天中药高剂量组积分光密度(P<0.05)与平均光密度降低明显(P<0.01),中药中剂量组积分光密度降低明显(P<0.01)。
结论：
1.儿童肺纤维化归属于中医“肺痹”的范畴,本病的病性虚实夹杂,病机复杂,总以肺气虚损为本,血瘀、痰热痹阻肺络为标。治疗宜宗“郁非辛不开,火非苦不降”之旨,以辛开苦降、调畅气机之法,达到清肺化痰、止咳平喘、活瘀通络,运用加味小苦辛汤加减化裁辨证治疗儿童肺纤维化,取得了较好的临床效果。
2.采用腹腔注射博莱霉素(40mg/kg)200μl×5次的方法成功复制了肺纤维化小鼠模型,病理改变符合早期肺泡炎为主、晚期肺纤维化为主的发展过程。
3.中药加味小苦辛汤具有改善肺纤维化小鼠一般状态,降低肺质量系数,使其肺泡炎和肺纤维化程度明显减轻的作用。
4.博莱霉素诱导的肺纤维化小鼠肺组织中TGF-β、ICAM-1、NF-κβ的表达显著增加,显示TGF-β、ICAM-1、NF-κβ参与了肺纤维化发生发展进程,并可能是其中的重要环节。
5.中药加味小苦辛汤可能是通过下调肺组织中TGF-β、ICAM-1、NF-κβ表达而发挥抗纤维化的作用的。
Objectives
To summarize the experience of the clinical treatment on children with pulmonary fibrosis by the Modified Xiaokuxin Soup, and to observe the effect of treatment on mice with BLM-induecd pulmonary fibrosis by the Modified Xiaokuxin Soup.To investigate the pathogenesis of pulmonary fibrosis and mechanism of the treatment on pulmonary fibrosis in children by the Modified Xiaokuxin Soup.
Methods
72C57BL/6female mice were randomly divided into control group, model group, prednisone group and high,moderate and low Modified Xiaokuxin Soup groups, n=12. Groups of model group, Chinese medicine group and western medicine group with bleomycin(40mg/kg)200μl intraperitoneal injection5times were modeled into pulmonary fibrosis in mice, and the control group with normal saline instead. Mice in each group were gavaged from the day after molding, the three doses groups of traditional Chinese medicine were respectively given the Modified Xiaokuxin Soup granules,4.6g/kg,2.3g/kg,1.15g/kg; the western medicine group were given prednisone5mg/kg; the model group and control group were given to0.5%CMC10ml/kg once a day. On the14th and28th day after the consecutive gavage,mice were killed in batches. Then take full wet lung weight, and take the right lung tissues were placed in4%formaldehyde solution for fixation, conventional dehydrat ion, embedded in paraffin to be consecutive tissue sections, whicd were then conducted Suwood alcohol-eosin (HE staining) trichrome stain(Masson stain) and immunohistochemical staining. Morphological changes of the biopsy lung tissue and expression of TGF-β1, ICAM-1, NF-κβ in each group were observed. And the integrated optical densit(IOD) and mean optical density (MOD) value of TGF-β1, ICAM-1, NF-κβ in lung tissue of mice in each group were compared by image analysis.
Results
1. The impact of the lung mass coefficient:Lung mass coefficient in the model group on14th and28th days were significantly higher than the control group after treatment, there was a significant statistical significance (P<0.01); the western medicine group compared with the control group were statistically s ignifican (P<0.05); Chinese medicine high dose group on14th and28th days were lower than the model group,which was statistically significan(P<0.05); there is no significant differencebetween the low-dose of Chinese medicine group and the control group on28th day(P>0.05),and the Chinese medicine high dose group was lower than western medicine group, the difference was statistically significant (P<0.05).
2. The impact on Lung tissue morphology:①HE staining:in the control group, there was not changes in pulmonary alveolitis and fibrosis,and the alveolar structure was integrity, the leakage in alveolar cavity was not significant. In the model group,on the14th day, inflammatory cell gathered together around the bronchioles and perivascular, the alveolar septa was widened,leakage of the alveolar cavity was significant; while on the28th day, there are large areas of consolidation fibrosis area,part of the alveolar wall destruction, collapse of the alveolar space,alveolar wall thickening, alveolar septal fibrosis significant.②Masson staining:On the14th day, in the model group, alveolitis was significant and fibrosis was severe. The alveolar space was filled with exudate and the shedding of a variety of inflammatory cells, there was visible apparent fiber hyperplasia lesions in the alveolar septa. On the28th day, around the alveolar wall, interval bronchus and small blood vessels, a large number of fibers were proliferated. In summary, in three of the Chinese medicine and Western medicine group, the alveolitis and fibrosis degree reduced compared with the model group, among that Chinese medicine high dose group was particularly evident.
3. The impact on TGF-β1expression:on the14th and28th days, in the model group and control group, IOD and MOD of the cells were significantly increased (P<0.01); IOD and MOD of the cells of the three dose of Chinese medicine group was significantly lower compared with the model group (P<0.01). Chinese medicine high dose group compared with the western medicine group,on the14th day,the difference of IOD was not significant (P>0.05),while on the28th day was lower than western medicine group (P<0.05). There was no difference between the Chinese medicine high dose group and the western medicine group in MOD(P>0.05). Chinese medicine high dose group, western medicine group and the control group, the difference in IOD and MOD of the cells was not significant (P>0.05).
4. The impact on ICAM-1expression:The IOD of the cells in the model group was significantly increased than the control group (P<0.01); while the three dose of the Chinese medicine groups were significantly reduced compared with the model group in IOD and MOD of the cells (P<0.01); there was significant difference between the high dose of Chinese medicine group and the western medicine group on the14"'and28th days (P<0.01),which was the same as the MOD between the low dose of Chinese medicine group and the western medicine group on the28th day. The differences were significant in each group compared with the control group in MOD on the14th day (P<0.01), while there was no difference between the high dose of Chinese medicine group and the control group on the28th day (P>0.05); the three dose of the Chinese medicine groups were significantly reduced compared with the model group (P<0.01);and the difference was significant in the high dose of Chinese medicine group compared with the western medicine group (P<0.01).
5. The impact on NF-κB expression:The IOD and MOD of the cells in each group increased significantly than the control group on the14th and28th days (P<0.01). Compared to the model group, IOD and MOD of the three dose of Chinese medicine group reduced significantly compared with the model group in the IOD and MOD of the cells (P<0.01). IOD in each dose of Chinese medicine group was decreased significantly than the western medicine group on the14th day (P<0.01), and in the high dose of Chinese medicine group IOD and MOD was decreased significantly (P<0.01), with the middle dose of Chinese medicine group most obvious (P<0.01).
Conclusions:
1. We at tribute pulmonary f ibrosis in chi ldren to " lung Bi" category in Chinese Medicine. The actual situation of the disease is a mixture of complex pathogenesis, with a total deficiency oriented to lung, blood stasis and phlegm blockage of the lung as a standard network. The treatment under the principle that "non-Xin Yu is not open, non-bitter the fire did not fall", uses acrid bitter drop and adjusting qi of the law, to clear the lungs phlegm, cough and asthma and live stas is meridians, with the modified Xiaokuxin Soup added and subtracted, giving dialectical treatment of children with pulmonary fibrosis, achieving a certain effect.
2. In the way of intraperi toneal injection of bleomycin (40mg/kg),200μ1,5times, we had successfully copied pulmonary fibrosis in a mouse model, whose pathological changes was in line with the development of the early alveolitis and advanced pulmonary fibrosis.
3. The modified Xiaokuxin Soup could improve the pulmonary fibrosis in mice, and can reduce lung mass coefficient.It significantly reduced the alveolitis and pulmonary fibrosis.
4. The expression of TGF-β1, ICAM-1,NF-κβ in pulmonary fibrosis lung tissue of mice induced by Bleomycin increase significantly, showed that TGF-β1, ICAM-1and NF-κβ involved in the development of pulmonary fibrosis process, and in which may be an important link.
5. The modified Xiaokuxin Soup may be down lung tissue of TGF-β1, ICAM-1, NF-κβ expression and play the role of anti-fibrosis.
总结临床运用加味小苦辛汤治疗儿童肺纤维化的经验；观察加味小苦辛汤对博莱霉素诱导的小鼠肺纤维化的影响,探讨肺纤维化的发病机制及加味小苦辛汤治疗儿童肺纤维化的作用机理。
方法
72只雌性C57BL/6小鼠随机分为正常对照组、模型组、西药组、加味小苦辛汤高、中、低剂量组,每组12只。模型组、西药组和中药各组以博莱霉素(40mg/kg)200μl×5次腹腔注射建立肺纤维化小鼠模型,正常组以生理盐水代替。各组小鼠于造模次日起灌胃,中药高、中、低剂量组分别给予中药加味小苦辛汤颗粒剂4.6g/kg、2.3g/kg.1.15g/kg；西药组用强的松5mg/kg；模型组与正常对照组予0.5%CMC10ml/kg,日1次。于连续给药物第14、28天分批随机处死小鼠,称取全肺湿重后,取右肺组织置于4%甲醛溶液中固定,常规脱水、石蜡包埋,连续组织切片,进行苏木精-伊红染色(HE染色)、三色染色(Masson染色)及免疫组化染色。观察各组病理切片肺组织形态学改变与TGF-β1、ICAM-1、NF-κβ的表达,并通过图像分析比较各组小鼠肺组织TGF-β1TGF-β1、 ICAM-1、NF-κβ的积分光密度和平均光密度值。
结果
1.对小鼠肺质量系数的影响：模型组肺系数在治疗后14和28天均显著高于空白组,有显著的统计学意义(P<0.01)；西药组与空白组相比,升高有统计学意义(P<0.05)；中药高剂量组于第14天和28天时均低于模型组,有统计学意义(P<0.05)；第28天时中药中、低剂量组与正常组无显著差异(P>0.05),中药高剂量组较西药组降低,差异具有统计学意义(P<0.05)。
2.对肺组织形态学的影响：①HE染色可见：正常组无肺泡炎及肺纤维化改变,肺泡结构完整,肺泡腔内无明显渗出。模型组第14天时,细支气管和血管周围有炎性细胞聚集,肺泡隔增宽,肺泡腔内明显渗出；第28天时,纤维化程度明显,有大片实变区,部分肺泡壁破坏,肺泡腔塌陷,肺泡壁增厚,肺泡隔纤维化显著。②Masson染色可见：14天时模型组肺泡炎明显,纤维化程度较重,肺泡腔内充满渗出物和脱落的各种炎性细胞,肺泡间隔可见明显纤维增生灶,28天时肺泡壁及间隔,支气管与小血管周围大量纤维增生。通过HE和Masson染色观察可见,西药组和中药高、中、低剂量组肺泡炎和纤维化程度均较模型组减轻明显,其中中药高剂量组尤为明显。
3.对TGF-β1表达的影响：14和28天的模型组与正常对照组比较,细胞积分光密度、平均光密度均显著增加(P<0.01)；而中药高、中、低三组在细胞积分光密度、平均光密度两方面均较模型组显著降低(P<0.01)；其中中药高剂量组与西药组相比,第14天积分光密度的差别不显著(P>0.05),第28天则较西药组降低(P<0.05)。在平均光密度方面,中药高剂量组与西药组两组之间差别不显著(P>0.05)。而中药高剂量组、西药组与正常对照组在细胞积分光密度、平均光密度两方面相比较,差别不显著(P>0.05)。
4.对ICAM-1表达的影响：积分光密度方面,14和28天的模型组与正常对照组比较增加显著(P<0.01)；而中药高、中、低三组在细胞积分光密度、平均光密度两方面均较模型组显著降低(P<0.01)；其中中药高剂量组与西药组相比,第14天与28天积分光密度的差别显著(P<0.01),第28天中药低剂量组与西药组平均光密度差别亦显著(P<0.01)。平均光密度方面,14天时各组与正常对照组比较均差异显著(P<0.01),28天时中药高剂量组与正常对照组相比无明显差异(P>0.05)：中药各组与模型组比较,降低较为显著(P<0.01)；中药高剂量组与西药组两组之间差别显著(P<0.01)。
5,对NF-κB表达的影响：14和28天各组与正常对照组比较,细胞积分光密度、平均光密度均显著增加(P<0.01),与模型组相比,中药各组与西药组细胞积分光密度、平均光密度降低显著(P<0.01);与西药组相比,14天中药各组积分光密度降低显著(P<0.01),28天中药高剂量组积分光密度(P<0.05)与平均光密度降低明显(P<0.01),中药中剂量组积分光密度降低明显(P<0.01)。
结论：
1.儿童肺纤维化归属于中医“肺痹”的范畴,本病的病性虚实夹杂,病机复杂,总以肺气虚损为本,血瘀、痰热痹阻肺络为标。治疗宜宗“郁非辛不开,火非苦不降”之旨,以辛开苦降、调畅气机之法,达到清肺化痰、止咳平喘、活瘀通络,运用加味小苦辛汤加减化裁辨证治疗儿童肺纤维化,取得了较好的临床效果。
2.采用腹腔注射博莱霉素(40mg/kg)200μl×5次的方法成功复制了肺纤维化小鼠模型,病理改变符合早期肺泡炎为主、晚期肺纤维化为主的发展过程。
3.中药加味小苦辛汤具有改善肺纤维化小鼠一般状态,降低肺质量系数,使其肺泡炎和肺纤维化程度明显减轻的作用。
4.博莱霉素诱导的肺纤维化小鼠肺组织中TGF-β、ICAM-1、NF-κβ的表达显著增加,显示TGF-β、ICAM-1、NF-κβ参与了肺纤维化发生发展进程,并可能是其中的重要环节。
5.中药加味小苦辛汤可能是通过下调肺组织中TGF-β、ICAM-1、NF-κβ表达而发挥抗纤维化的作用的。
Objectives
To summarize the experience of the clinical treatment on children with pulmonary fibrosis by the Modified Xiaokuxin Soup, and to observe the effect of treatment on mice with BLM-induecd pulmonary fibrosis by the Modified Xiaokuxin Soup.To investigate the pathogenesis of pulmonary fibrosis and mechanism of the treatment on pulmonary fibrosis in children by the Modified Xiaokuxin Soup.
Methods
72C57BL/6female mice were randomly divided into control group, model group, prednisone group and high,moderate and low Modified Xiaokuxin Soup groups, n=12. Groups of model group, Chinese medicine group and western medicine group with bleomycin(40mg/kg)200μl intraperitoneal injection5times were modeled into pulmonary fibrosis in mice, and the control group with normal saline instead. Mice in each group were gavaged from the day after molding, the three doses groups of traditional Chinese medicine were respectively given the Modified Xiaokuxin Soup granules,4.6g/kg,2.3g/kg,1.15g/kg; the western medicine group were given prednisone5mg/kg; the model group and control group were given to0.5%CMC10ml/kg once a day. On the14th and28th day after the consecutive gavage,mice were killed in batches. Then take full wet lung weight, and take the right lung tissues were placed in4%formaldehyde solution for fixation, conventional dehydrat ion, embedded in paraffin to be consecutive tissue sections, whicd were then conducted Suwood alcohol-eosin (HE staining) trichrome stain(Masson stain) and immunohistochemical staining. Morphological changes of the biopsy lung tissue and expression of TGF-β1, ICAM-1, NF-κβ in each group were observed. And the integrated optical densit(IOD) and mean optical density (MOD) value of TGF-β1, ICAM-1, NF-κβ in lung tissue of mice in each group were compared by image analysis.
Results
1. The impact of the lung mass coefficient:Lung mass coefficient in the model group on14th and28th days were significantly higher than the control group after treatment, there was a significant statistical significance (P<0.01); the western medicine group compared with the control group were statistically s ignifican (P<0.05); Chinese medicine high dose group on14th and28th days were lower than the model group,which was statistically significan(P<0.05); there is no significant differencebetween the low-dose of Chinese medicine group and the control group on28th day(P>0.05),and the Chinese medicine high dose group was lower than western medicine group, the difference was statistically significant (P<0.05).
2. The impact on Lung tissue morphology:①HE staining:in the control group, there was not changes in pulmonary alveolitis and fibrosis,and the alveolar structure was integrity, the leakage in alveolar cavity was not significant. In the model group,on the14th day, inflammatory cell gathered together around the bronchioles and perivascular, the alveolar septa was widened,leakage of the alveolar cavity was significant; while on the28th day, there are large areas of consolidation fibrosis area,part of the alveolar wall destruction, collapse of the alveolar space,alveolar wall thickening, alveolar septal fibrosis significant.②Masson staining:On the14th day, in the model group, alveolitis was significant and fibrosis was severe. The alveolar space was filled with exudate and the shedding of a variety of inflammatory cells, there was visible apparent fiber hyperplasia lesions in the alveolar septa. On the28th day, around the alveolar wall, interval bronchus and small blood vessels, a large number of fibers were proliferated. In summary, in three of the Chinese medicine and Western medicine group, the alveolitis and fibrosis degree reduced compared with the model group, among that Chinese medicine high dose group was particularly evident.
3. The impact on TGF-β1expression:on the14th and28th days, in the model group and control group, IOD and MOD of the cells were significantly increased (P<0.01); IOD and MOD of the cells of the three dose of Chinese medicine group was significantly lower compared with the model group (P<0.01). Chinese medicine high dose group compared with the western medicine group,on the14th day,the difference of IOD was not significant (P>0.05),while on the28th day was lower than western medicine group (P<0.05). There was no difference between the Chinese medicine high dose group and the western medicine group in MOD(P>0.05). Chinese medicine high dose group, western medicine group and the control group, the difference in IOD and MOD of the cells was not significant (P>0.05).
4. The impact on ICAM-1expression:The IOD of the cells in the model group was significantly increased than the control group (P<0.01); while the three dose of the Chinese medicine groups were significantly reduced compared with the model group in IOD and MOD of the cells (P<0.01); there was significant difference between the high dose of Chinese medicine group and the western medicine group on the14"'and28th days (P<0.01),which was the same as the MOD between the low dose of Chinese medicine group and the western medicine group on the28th day. The differences were significant in each group compared with the control group in MOD on the14th day (P<0.01), while there was no difference between the high dose of Chinese medicine group and the control group on the28th day (P>0.05); the three dose of the Chinese medicine groups were significantly reduced compared with the model group (P<0.01);and the difference was significant in the high dose of Chinese medicine group compared with the western medicine group (P<0.01).
5. The impact on NF-κB expression:The IOD and MOD of the cells in each group increased significantly than the control group on the14th and28th days (P<0.01). Compared to the model group, IOD and MOD of the three dose of Chinese medicine group reduced significantly compared with the model group in the IOD and MOD of the cells (P<0.01). IOD in each dose of Chinese medicine group was decreased significantly than the western medicine group on the14th day (P<0.01), and in the high dose of Chinese medicine group IOD and MOD was decreased significantly (P<0.01), with the middle dose of Chinese medicine group most obvious (P<0.01).
Conclusions:
1. We at tribute pulmonary f ibrosis in chi ldren to " lung Bi" category in Chinese Medicine. The actual situation of the disease is a mixture of complex pathogenesis, with a total deficiency oriented to lung, blood stasis and phlegm blockage of the lung as a standard network. The treatment under the principle that "non-Xin Yu is not open, non-bitter the fire did not fall", uses acrid bitter drop and adjusting qi of the law, to clear the lungs phlegm, cough and asthma and live stas is meridians, with the modified Xiaokuxin Soup added and subtracted, giving dialectical treatment of children with pulmonary fibrosis, achieving a certain effect.
2. In the way of intraperi toneal injection of bleomycin (40mg/kg),200μ1,5times, we had successfully copied pulmonary fibrosis in a mouse model, whose pathological changes was in line with the development of the early alveolitis and advanced pulmonary fibrosis.
3. The modified Xiaokuxin Soup could improve the pulmonary fibrosis in mice, and can reduce lung mass coefficient.It significantly reduced the alveolitis and pulmonary fibrosis.
4. The expression of TGF-β1, ICAM-1,NF-κβ in pulmonary fibrosis lung tissue of mice induced by Bleomycin increase significantly, showed that TGF-β1, ICAM-1and NF-κβ involved in the development of pulmonary fibrosis process, and in which may be an important link.
5. The modified Xiaokuxin Soup may be down lung tissue of TGF-β1, ICAM-1, NF-κβ expression and play the role of anti-fibrosis.
引文
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