红景天对博莱霉素诱导的大鼠肺损伤干预作用实验研究
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摘要
目的：根据红景天中医药理特性和现代医学研究结果，以及SARS期间对急性肺损
伤的临床治疗情况，本课题采用博莱霉素(BLM)经支气管灌肺诱导大鼠肺损伤模
型，观察肺损伤第3、 7、 28天各个时期的功能状态、病理特点和肿瘤坏死因子-
α(TNF-α)、粒单细胞-集落刺激因子(GM-CSF)、巨噬细胞趋化蛋白-1(MCP-1)
变化规律，研究中药红景天对肺损伤不同时期炎症和纤维化过程的干预作用和可
能机理。
方法：将大鼠分为正常对照组、BLM组、BLM+红景天组和BLM+甲强龙组，实验组
用BLM 5mg／kg经支气管灌肺造成大鼠肺损伤；运用计算机体层摄影(CT)、血气
分析等临床方法观察大鼠肺组织影像和功能状态；用肺系数和肺通透指数显示肺
炎性水肿和渗出情况；用HE染色、VG染色和电子显微镜研究各个时期大鼠的病
理特点；用免疫组织化学观察GM-CSF、α-SMA肺组织中的表达；用酶联免疫吸附
实验检测大鼠血浆TNF-α、GM-CSF、MCP-1含量；用氯胺T法测定第28天肺组织
胶原蛋白含量。
结果：CT检查显示BLM损伤第3天双肺出现模糊云雾状阴影，严重者呈大片状阴
影，边界不清，以肺门为中心放散走行，逐步变淡，第28天肺门旁血管、支气管
周围和小叶间隔出现结节状或蜂窝状改变和网状致密影，部分条索状高密度影沿
支气管走行，自肺门向肺中、上肺野放射，肺间质扭曲变形，伴肺部和支气管过
度充气征；红景天治疗组影像改变第3天明显轻于模型组，第28天改变大致与模
型组相似，但密度稍轻于模型组。各组肺指数和通透指数在BLM损伤各期普遍增
高，以第3和第7天为重，红景天治疗组有所降低，氧分压也明显高于模型组。
病理和电子显微镜检查提示BLM损伤后第3天和第7天肺组织以急性肺泡炎
和间质性肺炎为主，表现为弥漫性炎性细胞浸润，肺广泛出血和急性水肿；电镜
下可见Ⅰ型细胞变性、崩解和脱落；Ⅱ型细胞增生、肿胀，肺泡内板层小体明显
增多，血管内皮细胞肿胀，红景天组病理改变明显轻于模型组。第28天以肺间质
改变为主，气管壁增厚，平滑肌明显增生，淋巴细胞呈节结状改变，肺泡隔增厚
增宽，成纤维细胞增多；电镜下可见纤维细胞增生，胶原纤维明显增多，血管内
中文摘要
皮系统和肺泡上皮系统结构紊乱，红景天组病理改变与模型组接近。
免疫组化显示正常肺组织中肺泡巨噬细胞不表达或微弱表达GM一csF，BLM损伤
后表达增强，红景天与甲强龙组治疗后第7天GM一CSF阳性反应比模型组减低，第
28天三组之间无显著差异，Q一SMA从BLM损伤第7天后表达增强，第28天最强，
红景天对a一SMA无明显抑制效果。ELISA结果显示，BLM肺损伤第3和第7天各
组血清TNF一a、MCP一1、GM一CSF浓度明显升高，红景天治疗组血浆TNF一a、MCP一1、
GM一CS低于模型组，在第28天三组血浆TNF一Q、MCP一1、GM一CSF的含量无显著差
别。肺损伤第28天肺胶原蛋白含量测定，模型、甲强龙和红景天三组胶原含量均
升高，无显著差别。
结论:1.BLM引起的大鼠肺损伤是炎性反应和纤维增生共同组成的病理发展过程，
早期损伤以炎性渗出和出血为主，与SARS目前临床报道的病理改变相似;后期以
慢性炎症和纤维组织增生为主。
2.肺损伤早期，红景天可能通过干扰TNF一a、MCP一、GM一CSF的合成抑制炎症
反应引起的急性肺组织水肿和出血。在肺损伤各个时期，红景天对血管内皮细胞
及毛细血管有明显的保护和扩张作用，有效改善肺组织微循环。
3.在本实验中，红景天对肺损伤过程中纤维细胞增生、胶原合成抑制作用不
明显，待于将来进一步研究证实。
Purpose: According to Traditional Chinese Medicine theory and the effect of RRL on SARS in prevalent period, to study the effect of RRL on rat lung injury induced by BLM on 3 day. 7 day and 28 day in terms of the lung function, lung pathology and TNF- a , GM-CSF> MCP-1 in rat serum, To analyze the treatment mechanism of RRL on inflammatory and fibrosis in lung injury.
Method: The lung injury modal is made by intratracheal bleomycin (5mg/kg) and the rats are divided into control group, BLM group, BLM+RRL group and BLM+MPD group. Compute Tomograph and blood gas analyzer are employed to indicate lung function and image changes. The lung coefficient and lung perfusion index are applied to demonstrate the inflammatory edema and perfusion degree of lung. H.E. staining, V.G. staining and transmission electron microscopy (TEM) are used to illustrate lung pathology feature. The immunohistochemistre stain for GM-CSF. a -SMA in lung. TNF- a , GM-CSF. MCP-1 in serum are checked with enzyme linked immunoabsorb assay. The collagen content in lung is analyzed by hydroxyproline measurement. Result: CT illustrates the pieces of cloudlike shadow on 3day in BLM group. Some of them are bigger than others and the boundary is not clear, on other hand, the density come to be thinner from the center of lung gradually, on 28day,the CT show the high-density knot or netlike shadow distributed from
lung center to border region, meanwhile, lung interstitial becomes deformed companied by over expended bronchus. The image changes of RRL+BLM group are lighter than BLM group on 3day and 7day,but similar on 28day except a little less density.
Although the lung coefficient and lung perfusion index are increase at three different points in BLM group, RRL+BLM group and MPD+BLM group, especially on 3 and 7day. RRL+BLM group is lower than BLM group, but PaO2 higher on 3and and 7day.
On 3day and 7day after BLM administration, the pathology study illustrates acute pulmonary alveoli and acute interstitial inflammation, showing extensive infiltration of white cells and widespread edema and hemorrhage. Meanwhile, TEM manifests type I pulmonary epithelium transforming, broken and detachment; but type II cell in
proliferation and swollen. The alveoli contain many lamina-body and endothelium is damaged. The RRL+BLM group much lighter than BLM group. The lung interstitial is more abnormal obviously on 28day under light microscopy, including thickening of bronchi wall, proliferation of smooth muscle cell, lymphocyte accumulation around, widening of alveolar partition and increase of fibroblast. TEM demonstrates proliferation of fibroblast, accumulation of collagen in lung, and disorder of the structural systems of microcirculation and alveoli in BLM group. The characteristics of RRL+BLM group are lighter than BLM group.
Immunohistochmical staining shows the GM-CSF isn't expressed or weakly expressed in lung of control group. Controversially, it is over expressed in three groups on 3day and 7day after BLM administration, although the positive degree of RRL+BLM and MPD+BLM groups is lower than BLM group. But they are not distinct among three groups on 28day. The ELISA evidences that TNF- a . MCP-1. GM-CSF in serum of three groups are raised on 3 and 7day after BLM administration. The level of RRL+BLM lower than BLM group, but they are not different apparently on 28day. The content of collagen of three groups are more than control and there are not evident distinct among themselves on 28day. Conclusion:
l.The lung injury induced by BLM includes inflammatory reaction and fibrosis process in whole course. The injury in early stage mainly shows acute inflammatory leakage and hemorrhage, which same as SARS in clinic in early stage. Otherwise, the lung injury mainly produces chronic inflammation and fibrosis in late stage. 2.Rhodiola rosea L(RRL) have the ability to suppress edema, leakage and hemorrhage caused by inflammation through disturbing synthesis of TNF-a , MCP-K GM-CSF in early stage. In addition, RRL is capable of protection endothelium from BLM damage
伤的临床治疗情况，本课题采用博莱霉素(BLM)经支气管灌肺诱导大鼠肺损伤模
型，观察肺损伤第3、 7、 28天各个时期的功能状态、病理特点和肿瘤坏死因子-
α(TNF-α)、粒单细胞-集落刺激因子(GM-CSF)、巨噬细胞趋化蛋白-1(MCP-1)
变化规律，研究中药红景天对肺损伤不同时期炎症和纤维化过程的干预作用和可
能机理。
方法：将大鼠分为正常对照组、BLM组、BLM+红景天组和BLM+甲强龙组，实验组
用BLM 5mg／kg经支气管灌肺造成大鼠肺损伤；运用计算机体层摄影(CT)、血气
分析等临床方法观察大鼠肺组织影像和功能状态；用肺系数和肺通透指数显示肺
炎性水肿和渗出情况；用HE染色、VG染色和电子显微镜研究各个时期大鼠的病
理特点；用免疫组织化学观察GM-CSF、α-SMA肺组织中的表达；用酶联免疫吸附
实验检测大鼠血浆TNF-α、GM-CSF、MCP-1含量；用氯胺T法测定第28天肺组织
胶原蛋白含量。
结果：CT检查显示BLM损伤第3天双肺出现模糊云雾状阴影，严重者呈大片状阴
影，边界不清，以肺门为中心放散走行，逐步变淡，第28天肺门旁血管、支气管
周围和小叶间隔出现结节状或蜂窝状改变和网状致密影，部分条索状高密度影沿
支气管走行，自肺门向肺中、上肺野放射，肺间质扭曲变形，伴肺部和支气管过
度充气征；红景天治疗组影像改变第3天明显轻于模型组，第28天改变大致与模
型组相似，但密度稍轻于模型组。各组肺指数和通透指数在BLM损伤各期普遍增
高，以第3和第7天为重，红景天治疗组有所降低，氧分压也明显高于模型组。
病理和电子显微镜检查提示BLM损伤后第3天和第7天肺组织以急性肺泡炎
和间质性肺炎为主，表现为弥漫性炎性细胞浸润，肺广泛出血和急性水肿；电镜
下可见Ⅰ型细胞变性、崩解和脱落；Ⅱ型细胞增生、肿胀，肺泡内板层小体明显
增多，血管内皮细胞肿胀，红景天组病理改变明显轻于模型组。第28天以肺间质
改变为主，气管壁增厚，平滑肌明显增生，淋巴细胞呈节结状改变，肺泡隔增厚
增宽，成纤维细胞增多；电镜下可见纤维细胞增生，胶原纤维明显增多，血管内
中文摘要
皮系统和肺泡上皮系统结构紊乱，红景天组病理改变与模型组接近。
免疫组化显示正常肺组织中肺泡巨噬细胞不表达或微弱表达GM一csF，BLM损伤
后表达增强，红景天与甲强龙组治疗后第7天GM一CSF阳性反应比模型组减低，第
28天三组之间无显著差异，Q一SMA从BLM损伤第7天后表达增强，第28天最强，
红景天对a一SMA无明显抑制效果。ELISA结果显示，BLM肺损伤第3和第7天各
组血清TNF一a、MCP一1、GM一CSF浓度明显升高，红景天治疗组血浆TNF一a、MCP一1、
GM一CS低于模型组，在第28天三组血浆TNF一Q、MCP一1、GM一CSF的含量无显著差
别。肺损伤第28天肺胶原蛋白含量测定，模型、甲强龙和红景天三组胶原含量均
升高，无显著差别。
结论:1.BLM引起的大鼠肺损伤是炎性反应和纤维增生共同组成的病理发展过程，
早期损伤以炎性渗出和出血为主，与SARS目前临床报道的病理改变相似;后期以
慢性炎症和纤维组织增生为主。
2.肺损伤早期，红景天可能通过干扰TNF一a、MCP一、GM一CSF的合成抑制炎症
反应引起的急性肺组织水肿和出血。在肺损伤各个时期，红景天对血管内皮细胞
及毛细血管有明显的保护和扩张作用，有效改善肺组织微循环。
3.在本实验中，红景天对肺损伤过程中纤维细胞增生、胶原合成抑制作用不
明显，待于将来进一步研究证实。
Purpose: According to Traditional Chinese Medicine theory and the effect of RRL on SARS in prevalent period, to study the effect of RRL on rat lung injury induced by BLM on 3 day. 7 day and 28 day in terms of the lung function, lung pathology and TNF- a , GM-CSF> MCP-1 in rat serum, To analyze the treatment mechanism of RRL on inflammatory and fibrosis in lung injury.
Method: The lung injury modal is made by intratracheal bleomycin (5mg/kg) and the rats are divided into control group, BLM group, BLM+RRL group and BLM+MPD group. Compute Tomograph and blood gas analyzer are employed to indicate lung function and image changes. The lung coefficient and lung perfusion index are applied to demonstrate the inflammatory edema and perfusion degree of lung. H.E. staining, V.G. staining and transmission electron microscopy (TEM) are used to illustrate lung pathology feature. The immunohistochemistre stain for GM-CSF. a -SMA in lung. TNF- a , GM-CSF. MCP-1 in serum are checked with enzyme linked immunoabsorb assay. The collagen content in lung is analyzed by hydroxyproline measurement. Result: CT illustrates the pieces of cloudlike shadow on 3day in BLM group. Some of them are bigger than others and the boundary is not clear, on other hand, the density come to be thinner from the center of lung gradually, on 28day,the CT show the high-density knot or netlike shadow distributed from
lung center to border region, meanwhile, lung interstitial becomes deformed companied by over expended bronchus. The image changes of RRL+BLM group are lighter than BLM group on 3day and 7day,but similar on 28day except a little less density.
Although the lung coefficient and lung perfusion index are increase at three different points in BLM group, RRL+BLM group and MPD+BLM group, especially on 3 and 7day. RRL+BLM group is lower than BLM group, but PaO2 higher on 3and and 7day.
On 3day and 7day after BLM administration, the pathology study illustrates acute pulmonary alveoli and acute interstitial inflammation, showing extensive infiltration of white cells and widespread edema and hemorrhage. Meanwhile, TEM manifests type I pulmonary epithelium transforming, broken and detachment; but type II cell in
proliferation and swollen. The alveoli contain many lamina-body and endothelium is damaged. The RRL+BLM group much lighter than BLM group. The lung interstitial is more abnormal obviously on 28day under light microscopy, including thickening of bronchi wall, proliferation of smooth muscle cell, lymphocyte accumulation around, widening of alveolar partition and increase of fibroblast. TEM demonstrates proliferation of fibroblast, accumulation of collagen in lung, and disorder of the structural systems of microcirculation and alveoli in BLM group. The characteristics of RRL+BLM group are lighter than BLM group.
Immunohistochmical staining shows the GM-CSF isn't expressed or weakly expressed in lung of control group. Controversially, it is over expressed in three groups on 3day and 7day after BLM administration, although the positive degree of RRL+BLM and MPD+BLM groups is lower than BLM group. But they are not distinct among three groups on 28day. The ELISA evidences that TNF- a . MCP-1. GM-CSF in serum of three groups are raised on 3 and 7day after BLM administration. The level of RRL+BLM lower than BLM group, but they are not different apparently on 28day. The content of collagen of three groups are more than control and there are not evident distinct among themselves on 28day. Conclusion:
l.The lung injury induced by BLM includes inflammatory reaction and fibrosis process in whole course. The injury in early stage mainly shows acute inflammatory leakage and hemorrhage, which same as SARS in clinic in early stage. Otherwise, the lung injury mainly produces chronic inflammation and fibrosis in late stage. 2.Rhodiola rosea L(RRL) have the ability to suppress edema, leakage and hemorrhage caused by inflammation through disturbing synthesis of TNF-a , MCP-K GM-CSF in early stage. In addition, RRL is capable of protection endothelium from BLM damage
引文
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3潘力，郭英，暗志仁，等．中华物理医学杂志．1996，18(3) ：94
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