慢性阻塞性肺疾病模型大鼠“肺病及肠”的实验观察
摘要
“肺合大肠”理论源自《内经》,是具有中医特色的脏腑表里相关理论,它不仅充分地体现了脏腑之间相互作用、相互影响的特性,也深刻地反映出中医学的整体观特点。“肺合大肠”理论肺肠相关的思想常被用于指导具体临床实践,一方面应用于慢性阻塞性肺疾病(COPD)、急性呼吸窘迫综合征(ARDS)、肺源性心脏病、肺性脑病、支气管哮喘、咳嗽等呼吸道相关疾病,另一方面则运用于消化系统相关疾病,如老年性便秘、顽固性消化性溃疡、慢性肠炎等。“肺病及肠”是“肺合大肠”理论具体表现形式之一,是对中医“肺合大肠”理论的实践认知与具体表达,通过对“肺病及肠”进行相关的观察与研究能够从一个角度印证“肺合大肠”理论,并为进一步揭示“肺合大肠”理论的科学内涵提供依据。
慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)是临床常见病、疑难病,临床资料表明患者除呼吸道症状外,还常伴有腹胀、便秘等胃肠道症状。
本课题在文献、理论研究基础上,从COPD角度对“肺病及肠”进行相关实验设计通过观察组织形态学改变、加味桔梗汤的干预作用及检测不同组别不同组织神经肽含量的变化,逐步分析阐明“肺病及肠”的相关特点。论文共分三部分：
第一部分文献综述。
对中医“肺合大肠”理论的研究概况、COPD的相关研究进展进行了系统地综述。
“肺合大肠”理论是中医药学具有代表性的特色理论之一,不仅具有极高的理论价值,而且还长期有效地用于指导中医辨证用药等临床实践,当前国内外众多学者从理论、临床、实验等方面对“肺合大肠”理论进行了大量研究,并取得了一定的进展。
而近年来,日趋严重的COPD高发病率问题已在全球引起关注。严重的进行性气流受限合并诸多肺外(消化道、心血管)并发症使患者生活质量受到严重影响,社会经济负担沉重。随着对COPD临床及实验研究的不断深入,对COPD发生发展的部分机制已渐清晰,即慢性炎症与气流受限是COPD的重要特征。
第二部分理论探讨。
对慢性阻塞性肺疾病中医病机的相关认识与观点进行梳理,并对其中医辨治思路展开分析。
COPD的中医病机可简要地归纳为“本虚标实,下虚上实”。本虚、下虚是指肺、脾、肾三脏亏虚。标实、上实则是指风、寒、湿等外邪及痰、瘀、虚等内邪与病理产物,这些内外诸邪成为肺失肃降,病情加重之诱因。
由于COPD中医病机复杂,常是多种病因合而为病,且病程绵长,易于反复,治疗时应抓住病机(本虚标实)兼顾其他,分清风寒、风热、寒痰、痰热、血瘀、脾虚、肾虚、肺虚等不同而治之,总令肺气得以宣畅为要；而中医药对COPD的辨治优势则可简要概括为急性发作期以减轻症状为主,稳定期以减缓病程进展为长两方面。尤以提高COPD患者稳定期机体免疫力、缩短病程及减少复发为中医药有别于西医治疗COPD的亮点。
以仲景《伤寒论》方证为线索,对《伤寒论》方辨治咳喘的规律进行分析与探讨。
《伤寒论》治咳诸方证治法上体现出张仲景治疗咳喘兼顾表里、寒热、攻补的指导思想；《伤寒论》认为咳喘治疗应视其病之所起而辨证论治,体现出仲景治咳必求于本的治疗原则；《伤寒论》治咳诸方证分列于太阳经、阳明经、太阴经、少阴经、厥阴经等篇中,显示出张仲景重视对咳喘不同表现,不同阶段的动态观察。
第三部分实验研究。
通过观察COPD模型大鼠组织形态学改变确认COPD中存在“肺病及肠”现象。从炎症细胞、细胞因子角度观察加味桔梗汤从肺治肠的干预作用,印证“肺病及肠”。检测不同组别不同组织神经激肽A (NKA).血管活性肠肽(VIP)含量变化,分析探讨加味桔梗汤对于COPD模型大鼠“肺病及肠”从肺论治的可能机制,并以此为基础进一步分析阐明“肺病及肠”NKA、VIP含量变化的相关特点,为更深入地揭示“肺病及肠”发生机制奠定基础。
实验一：COPD模型大鼠“肺病及肠”的病理改变及加味桔梗汤的干预作用
采用气管滴注脂多糖加熏香烟联合造模方法建立COPD大鼠模型。采用随机数字表法随机分为正常组、模型组、模型给药组、正常给药组,共4组。正常组、模型组灌胃蒸馏水,各给药组于第2－13天、15-28天以加味桔梗汤(桔梗、生甘草、紫苑、浙贝)灌胃。取大鼠肺、肠、心、肝、肾制作光镜标本,观察COPD模型大鼠组织形态学改变。观察结果：①光镜下可见模型组肺组织及支气管显著病理改变(间质增厚,肺泡结构紊乱,炎性细胞浸润,上皮细胞脱落),提示模型组肺泡结构破坏,肺组织受损；②模型给药组肺泡间质炎症减轻(肺泡壁血管充血及炎性细胞浸润改善),提示给予加味桔梗汤能有效改善肺部炎症,减少肺组织损伤；③模型组镜下可见肠组织黏膜层内淋巴细胞增多,腺体排列欠齐整、紧凑等,提示COPD模型大鼠同时存在肠的病理学改变；④模型给药组黏膜层内淋巴细胞明显减少为主要改善,提示加味桔梗汤对COPD模型大鼠的肠组织损伤有改善作用；⑤心、肝、肾组织结构完整,均未见明显异常,提示较之其他脏器,COPD对肠的影响更显著。
通过对不同组织病理形态学观察,可初步确认采用气管滴注脂多糖加熏香烟联合造模方法建立COPD大鼠模型中存在“肺病及肠”现象。
实验二：COPD模型大鼠“肺病及肠”的气道炎症与胃肠功能改变及加味桔梗汤的干预作用
采用气管滴注脂多糖加熏香烟联合造模方法建立COPD大鼠模型。模型给药组与正常给药组于第2-13天、15-28天以加味桔梗汤(桔梗、生甘草、紫苑、浙贝)灌胃进行治疗干预,正常组、模型组灌胃蒸馏水进行对照。
一方面,对实验动物进行肺泡灌洗,收集支气管肺泡灌洗液(BALF)并用ABC-ELISA法测定BALF中肿瘤坏死因子α(TNF-α)、白介素1β(IL-1β)含量及淋巴细胞计数,同时观察各组动物体重及肠推进率变化。观察结果：①模型组大鼠BALF中TNF-α、IL-1β含量及淋巴细胞计数均明显增高,提示COPD存在气道炎症与炎症细胞浸润发生；②模型给药组BALF中TNF-a含量及淋巴细胞计数均降低,IL-1β含量也表现出下降趋势,提示给予加味桔梗汤后,COPD气道炎症显著改善。
通过对炎症细胞与细胞因子检测,确认了加味桔梗汤对COPD(“肺病”)气道炎症的治疗作用。
另一方面,观察各组动物体重及肠推进率变化,结果显示：①模型组大鼠肠炭末推进率、体重增长明显降低,提示COPD能够对胃肠传输能力及营养状态产生抑制作用；②模型给药组大鼠肠炭末推进率、体重增长明显改善,提示加味桔梗汤通过对COPD的治疗能够改善胃肠传输能力及营养状态。
通过对肠推进率与体重变化的相关观察,确认了加味桔梗汤对COPD引起的胃肠传输能力及营养状态下降(“肺病及肠”)有改善作用。
对加味桔梗汤药效学指标检测结果综合分析可知,加味桔梗汤从肺论治不仅能有效控制COPD气道炎症,减少肺组织病理损伤,同时对于COPD引起的肠道传输功能障碍及营养状态低下(“肺病及肠”)等病理改变同样具有治疗、改善作用,即从肺论治,改善肺组织病理改变的同时,肠道病理改变亦同时减轻。
实验三：COPD模型大鼠“肺病及肠”的NKA、VIP含量变化及加味桔梗汤的干预作用
以气管滴注脂多糖加熏香烟联合造模方法建立COPD大鼠模型,取各组大鼠肺、肠、心、肝、脾、胃、脑、肾组织,用放免法检测肺、肠等组织中VIP、NKA含量。检测结果：①模型组大鼠肺、肠组织中NKA含量升高,VIP含量降低,其中以肺内NKA增高最具显著性,提示COPD能够引起肺、肠组织中NKA、VIP含量变化,NKA、VIP含量变化与“肺病及肠”有关；②模型给药组大鼠肺、肠组织中NKA含量降低,VIP含量升高,提示加味桔梗汤对COPD引起的肺、肠组织中NKA、VIP含量变化有调节作用；③肺组织中NKA、VIP含量与BALF中TNF-α、IL-1β含量及淋巴细胞计数相关性分析结果提示,加味桔梗汤对COPD气道炎症及肺组织病变的治疗改善作用可能与肺组织中NKA、VIP含量调节有关；④同时各组大鼠心、肝、脾、胃、脑、肾组织中NKA、VIP含量均无显著性差异,上升或下降趋势均不明显,提示COPD对NKA、VIP含量的影响以肺、肠组织间最为显著；⑤肺、肠组织中NKA、VIP含量相关性分析结果,可知肺、肠组织中NKA、VIP含量变化趋势表现出显著的同步性特点,即NKA、VIP含量在肺、肠组织间呈显著的正相关性,加味桔梗汤对COPD气道炎症(“肺病”)及其肠道传输功能障碍与营养状态低下(“肺病及肠”)的调节作用可能与调节肺、肠组织中NKA、VIP含量有关。
结论：
①采用气管滴注脂多糖加熏香烟联合造模方法建立的COPD大鼠模型,除有肺的病理改变外,还同时伴有肠组织的病理改变,且心、肝、肾组织均未见明显异常。因此,采用气管滴注脂多糖加熏香烟联合造模方法建立的COPD大鼠模型,肺组织病理改变的同时能引起肠道的特异性的改变(“肺病及肠”)。
②采用气管滴注脂多糖加熏香烟联合造模方法建立的COPD大鼠模型,通过给予加味桔梗汤进行药物干预,炎症细胞浸润及细胞因子过度释放均得到缓解,COPD引起的肠道传输功能障碍及营养状态低下(“肺病及肠”)也明显改善。因此,加味桔梗汤从肺论治改善肺组织病理改变的同时,肠道病理改变亦减轻。
③采用气管滴注脂多糖加熏香烟联合造模方法建立的COPD大鼠模型,加味桔梗汤治疗干预后大鼠肺肠组织中NKA、VIP含量变化显著,心、脑、脾、胃、肝、肾组织中NKA、VIP NKA、VIP含量变化不仅与气道炎症反应相关指标改变有关,还与肠组织中NKA、VIP含量变化趋势表现出显著的同步性特点(正相关性)。加味桔梗汤从肺治肠治疗“肺病及肠”的效应机制可能与调节肺肠组织中NKA、VIP的含量有关,其具体机制有待进一步深入研究。
Originated from "Huangdi Neijing", the Lung Being Relative to the Large Intestine Theory reflects the Holistic view of Chinese Medicine. On one hand, the Theory has been used to treat Respiratory diseases such as COPD, ARDS, Pulmonary heart disease, Bronchial asthma, cough, etc. On the other hand, it also has been used to treat digestive system-related diseases like Constipation, Peptic ulcer and Chronic enteritis. As a specific form of the Lung Being Relative to the Large Intestine Theory, "Enteropathy caused by lung disease" can confirm the Theory to some extent, and furthermore to provide some important evidences to reveal the meaning of the Theory.
Clinical data shows that other than respiratory symptoms, COPD usually accompanied by gastrointestinal symptoms such as abdominal distension and constipation. Treatments of COPD based on Chinese Medicine not only can relief symptoms during acute period, but also can reduce the incidence and mortality, and improve the quality of life as well. In spite of its significant effects on COPD, the mechanisms of the Chinese Medicine treatments have not been very clear yet.
Based on literature research, this paper designed three experiments on "Enteropathy caused by lung disease" in COPD. Through observing morphologic alterations and the effects of the modified Jiegeng Decoction on rats with COPD, and detecting Neuropeptide contents in different tissues of rats with COPD, analyzed and clarified the features of "Enteropathy caused by lung disease" step by step. The paper consists of three parts:
Part one is reviews. It reviewed systematically on the research survey of the Lung Being Relative to the Large Intestine Theory and advances in studies on COPD.
Part two is theoretical explorations. It straightened out the Mechanisms of COPD based on TCM, and analyzed the Strategy of TCM syndrome differentiation and treatment of COPD.
From TCM's point of view, the basic pathogenesis of COPD is essential debility and evil reality. Essential debility means lung, spleen and kidney deficiency. Evil reality means wind-evil, cold-evil, dampness, phlegm and stasis. So the treatment of COPD should adhere firmly to this basic mechanism and take into account other factors at the same time.
In "Shang Han Lun", the formulas which treating cough and asthma all reflect the discipline of taking into account of both exterior and interior, cold and heat, reinforcement and elimination, and show the principle of treating in terms of root cause as well. The formulas scattered in several sections in "Shang Han Lun" which reveals the observation of the process of cough and asthma.
Part three is experimental study. Observed the alternations of morphology in rats with COPD to confirm that there is a phenomenon of "Enteropathy caused by lung disease" in COPD, and validated the phenomenon through exploring the mechanism of the therapeutic effect of modified Jiegeng Decoction via inflammatory cell and cytokine. Observed the influence of facilitating lung on contents of NKA and VIP in lung tissues in rats with COPD, and investigated the mechanism.
Experiment one:COPD rat model was induced by cigarette smoking inhalation and intratracheal LPS exposure. Rats were divided into 4 groups, namely normal group, model group, model treating group, normal treating group. Normal group and model group were given saline, other groups were given modified Jiegeng Decoction from the 2nd day to 13th day and the 15th day to 28th day. Took lung, intestine, heart, liver and kidney tissues of rats, made specimen for optical microscope. Results showed:①The light-microscope observation show that in the model group, the structure of bronchoalveolus is destructive, detelectasis and the interval is broaden, coalesce. There were many inflammatory cells infiltration in alveolar wall. These pathological changes indicated the rats had COPD.②The range of pathological changes in model treating group reduced and the infiltration of inflammatory cell decreased obviously, indicated that modified Jiegeng Decoction can relief the degree of inflammation in lung tissue.③In the intestine tissues of model group, inflammatory cell infiltration in the epithelium, submucosa irregularly arranged, indicated the COPD model rats had pathological changes of intestine tissue.④The inflammatory cell infiltration in intestine tissues of model treating group decreased indicated modified Jiegeng Decoction can ease the lesions of intestine.⑤there was no significant histology damage in the tissues of heart, liver and kidney, indicated COPD injures intestine more seriously.
Experiment two:Measured the content of TNF-a, IL-1βwith the ABC-ELISA method and observed the body weights and the intestine propulsive motilities of the rats. Results showed:①Compare with normal group, the amount of lymphocytes and the content of TNF-a and IL-1βof model group increased significantly. It showed that the model group had the sign of inflammation.②The amount of lymphocytes and the content of TNF-a and IL-1βof model group decreased obviously, showed the inflammation in airway relieved.
On the other hand, the results of the body weight and the intestine propulsive motility showed①Compare with normal group, the body weight and the intestine propulsive motility of model group decreased significantly, indicated COPD can inhibits the gastrointestinal motility and impacts nutritional status.②The body weight and the intestine propulsive motility of model treating group increased obviously, indicated modified Jiegeng Decoction can improve the gastrointestinal motility and impacts nutritional status.
From the analysis of pharmacodynamic index test, modified Jiegeng Decoction not only controled the inflammation in airway, but also improved the gastrointestinal motility and impacts nutritional status. That is to say, treating COPD from lung can inhibit the pathological changes in lung tissues and at the same time ease the pathological changes in intestine tissue.
Experiment three:Took lung, intestine, heart, liver and kidney tissues of every group rats, measured the content of VIP and NKA in the tissues with radio-immunity methods. The results showed:③Compare with normal group, the amount of NKA in lung and intestine tissues of model group increased while the amount of VIP decreased, especially in lung tissues, indicated COPD can change the amount of NKA and VIP both in lung and intestine which is related with "Enteropathy caused by lung disease",②The amount of NKA in lung and intestine tissues of model treating group decreased while the amount of VIP increased, indicated modified Jiegeng Decoction can regulate the changes of NKA and VIP in lung and intestine which induced by COPD.③The results of the correlation analysis between the amount of NKA and VIP in lung tissue and the amount of TNF-a and IL-1βin BALF indicated the effect of modified Jiegeng Decoction may be related with its regulation of NKA and VIP in lung tissue.④The amount of NKA and VIP in other organ tissues did not change significantly, indicated the impact of COPD on the amount of NKA and VIP is most obvious in lung and intestine.⑤The results of the correlation analysis between the amount of NKA and VIP in lung and intestine showed, the changes in lung synchronized with the changes in intestine. The regulation of modified Jiegeng Decoction on the gastrointestinal motility and nutritional status may be related with its impact on the amounts of NKA and VIP in lung and intestine.
Conclusion:Rats with cigarette smoke and LPS-induced COPD have lesions of lung tissue accompanied by pathological changes of intestine tissue. Therefore, cigarette smoke and LPS-induced COPD rats have "Enteropathy caused by lung disease".
Treating COPD model rats with modified Jiegeng Decoction can reduce the inflammation in airway and improve the gastrointestinal motility and nutritional status. It indicates treating from lung can also relive the pathological changes of intestine.
The therapeutic effect of modified Jiegeng Decoction may be related with its regulation of the amounts of NKA and VIP in lung and intestine which need further research.
慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)是临床常见病、疑难病,临床资料表明患者除呼吸道症状外,还常伴有腹胀、便秘等胃肠道症状。
本课题在文献、理论研究基础上,从COPD角度对“肺病及肠”进行相关实验设计通过观察组织形态学改变、加味桔梗汤的干预作用及检测不同组别不同组织神经肽含量的变化,逐步分析阐明“肺病及肠”的相关特点。论文共分三部分：
第一部分文献综述。
对中医“肺合大肠”理论的研究概况、COPD的相关研究进展进行了系统地综述。
“肺合大肠”理论是中医药学具有代表性的特色理论之一,不仅具有极高的理论价值,而且还长期有效地用于指导中医辨证用药等临床实践,当前国内外众多学者从理论、临床、实验等方面对“肺合大肠”理论进行了大量研究,并取得了一定的进展。
而近年来,日趋严重的COPD高发病率问题已在全球引起关注。严重的进行性气流受限合并诸多肺外(消化道、心血管)并发症使患者生活质量受到严重影响,社会经济负担沉重。随着对COPD临床及实验研究的不断深入,对COPD发生发展的部分机制已渐清晰,即慢性炎症与气流受限是COPD的重要特征。
第二部分理论探讨。
对慢性阻塞性肺疾病中医病机的相关认识与观点进行梳理,并对其中医辨治思路展开分析。
COPD的中医病机可简要地归纳为“本虚标实,下虚上实”。本虚、下虚是指肺、脾、肾三脏亏虚。标实、上实则是指风、寒、湿等外邪及痰、瘀、虚等内邪与病理产物,这些内外诸邪成为肺失肃降,病情加重之诱因。
由于COPD中医病机复杂,常是多种病因合而为病,且病程绵长,易于反复,治疗时应抓住病机(本虚标实)兼顾其他,分清风寒、风热、寒痰、痰热、血瘀、脾虚、肾虚、肺虚等不同而治之,总令肺气得以宣畅为要；而中医药对COPD的辨治优势则可简要概括为急性发作期以减轻症状为主,稳定期以减缓病程进展为长两方面。尤以提高COPD患者稳定期机体免疫力、缩短病程及减少复发为中医药有别于西医治疗COPD的亮点。
以仲景《伤寒论》方证为线索,对《伤寒论》方辨治咳喘的规律进行分析与探讨。
《伤寒论》治咳诸方证治法上体现出张仲景治疗咳喘兼顾表里、寒热、攻补的指导思想；《伤寒论》认为咳喘治疗应视其病之所起而辨证论治,体现出仲景治咳必求于本的治疗原则；《伤寒论》治咳诸方证分列于太阳经、阳明经、太阴经、少阴经、厥阴经等篇中,显示出张仲景重视对咳喘不同表现,不同阶段的动态观察。
第三部分实验研究。
通过观察COPD模型大鼠组织形态学改变确认COPD中存在“肺病及肠”现象。从炎症细胞、细胞因子角度观察加味桔梗汤从肺治肠的干预作用,印证“肺病及肠”。检测不同组别不同组织神经激肽A (NKA).血管活性肠肽(VIP)含量变化,分析探讨加味桔梗汤对于COPD模型大鼠“肺病及肠”从肺论治的可能机制,并以此为基础进一步分析阐明“肺病及肠”NKA、VIP含量变化的相关特点,为更深入地揭示“肺病及肠”发生机制奠定基础。
实验一：COPD模型大鼠“肺病及肠”的病理改变及加味桔梗汤的干预作用
采用气管滴注脂多糖加熏香烟联合造模方法建立COPD大鼠模型。采用随机数字表法随机分为正常组、模型组、模型给药组、正常给药组,共4组。正常组、模型组灌胃蒸馏水,各给药组于第2－13天、15-28天以加味桔梗汤(桔梗、生甘草、紫苑、浙贝)灌胃。取大鼠肺、肠、心、肝、肾制作光镜标本,观察COPD模型大鼠组织形态学改变。观察结果：①光镜下可见模型组肺组织及支气管显著病理改变(间质增厚,肺泡结构紊乱,炎性细胞浸润,上皮细胞脱落),提示模型组肺泡结构破坏,肺组织受损；②模型给药组肺泡间质炎症减轻(肺泡壁血管充血及炎性细胞浸润改善),提示给予加味桔梗汤能有效改善肺部炎症,减少肺组织损伤；③模型组镜下可见肠组织黏膜层内淋巴细胞增多,腺体排列欠齐整、紧凑等,提示COPD模型大鼠同时存在肠的病理学改变；④模型给药组黏膜层内淋巴细胞明显减少为主要改善,提示加味桔梗汤对COPD模型大鼠的肠组织损伤有改善作用；⑤心、肝、肾组织结构完整,均未见明显异常,提示较之其他脏器,COPD对肠的影响更显著。
通过对不同组织病理形态学观察,可初步确认采用气管滴注脂多糖加熏香烟联合造模方法建立COPD大鼠模型中存在“肺病及肠”现象。
实验二：COPD模型大鼠“肺病及肠”的气道炎症与胃肠功能改变及加味桔梗汤的干预作用
采用气管滴注脂多糖加熏香烟联合造模方法建立COPD大鼠模型。模型给药组与正常给药组于第2-13天、15-28天以加味桔梗汤(桔梗、生甘草、紫苑、浙贝)灌胃进行治疗干预,正常组、模型组灌胃蒸馏水进行对照。
一方面,对实验动物进行肺泡灌洗,收集支气管肺泡灌洗液(BALF)并用ABC-ELISA法测定BALF中肿瘤坏死因子α(TNF-α)、白介素1β(IL-1β)含量及淋巴细胞计数,同时观察各组动物体重及肠推进率变化。观察结果：①模型组大鼠BALF中TNF-α、IL-1β含量及淋巴细胞计数均明显增高,提示COPD存在气道炎症与炎症细胞浸润发生；②模型给药组BALF中TNF-a含量及淋巴细胞计数均降低,IL-1β含量也表现出下降趋势,提示给予加味桔梗汤后,COPD气道炎症显著改善。
通过对炎症细胞与细胞因子检测,确认了加味桔梗汤对COPD(“肺病”)气道炎症的治疗作用。
另一方面,观察各组动物体重及肠推进率变化,结果显示：①模型组大鼠肠炭末推进率、体重增长明显降低,提示COPD能够对胃肠传输能力及营养状态产生抑制作用；②模型给药组大鼠肠炭末推进率、体重增长明显改善,提示加味桔梗汤通过对COPD的治疗能够改善胃肠传输能力及营养状态。
通过对肠推进率与体重变化的相关观察,确认了加味桔梗汤对COPD引起的胃肠传输能力及营养状态下降(“肺病及肠”)有改善作用。
对加味桔梗汤药效学指标检测结果综合分析可知,加味桔梗汤从肺论治不仅能有效控制COPD气道炎症,减少肺组织病理损伤,同时对于COPD引起的肠道传输功能障碍及营养状态低下(“肺病及肠”)等病理改变同样具有治疗、改善作用,即从肺论治,改善肺组织病理改变的同时,肠道病理改变亦同时减轻。
实验三：COPD模型大鼠“肺病及肠”的NKA、VIP含量变化及加味桔梗汤的干预作用
以气管滴注脂多糖加熏香烟联合造模方法建立COPD大鼠模型,取各组大鼠肺、肠、心、肝、脾、胃、脑、肾组织,用放免法检测肺、肠等组织中VIP、NKA含量。检测结果：①模型组大鼠肺、肠组织中NKA含量升高,VIP含量降低,其中以肺内NKA增高最具显著性,提示COPD能够引起肺、肠组织中NKA、VIP含量变化,NKA、VIP含量变化与“肺病及肠”有关；②模型给药组大鼠肺、肠组织中NKA含量降低,VIP含量升高,提示加味桔梗汤对COPD引起的肺、肠组织中NKA、VIP含量变化有调节作用；③肺组织中NKA、VIP含量与BALF中TNF-α、IL-1β含量及淋巴细胞计数相关性分析结果提示,加味桔梗汤对COPD气道炎症及肺组织病变的治疗改善作用可能与肺组织中NKA、VIP含量调节有关；④同时各组大鼠心、肝、脾、胃、脑、肾组织中NKA、VIP含量均无显著性差异,上升或下降趋势均不明显,提示COPD对NKA、VIP含量的影响以肺、肠组织间最为显著；⑤肺、肠组织中NKA、VIP含量相关性分析结果,可知肺、肠组织中NKA、VIP含量变化趋势表现出显著的同步性特点,即NKA、VIP含量在肺、肠组织间呈显著的正相关性,加味桔梗汤对COPD气道炎症(“肺病”)及其肠道传输功能障碍与营养状态低下(“肺病及肠”)的调节作用可能与调节肺、肠组织中NKA、VIP含量有关。
结论：
①采用气管滴注脂多糖加熏香烟联合造模方法建立的COPD大鼠模型,除有肺的病理改变外,还同时伴有肠组织的病理改变,且心、肝、肾组织均未见明显异常。因此,采用气管滴注脂多糖加熏香烟联合造模方法建立的COPD大鼠模型,肺组织病理改变的同时能引起肠道的特异性的改变(“肺病及肠”)。
②采用气管滴注脂多糖加熏香烟联合造模方法建立的COPD大鼠模型,通过给予加味桔梗汤进行药物干预,炎症细胞浸润及细胞因子过度释放均得到缓解,COPD引起的肠道传输功能障碍及营养状态低下(“肺病及肠”)也明显改善。因此,加味桔梗汤从肺论治改善肺组织病理改变的同时,肠道病理改变亦减轻。
③采用气管滴注脂多糖加熏香烟联合造模方法建立的COPD大鼠模型,加味桔梗汤治疗干预后大鼠肺肠组织中NKA、VIP含量变化显著,心、脑、脾、胃、肝、肾组织中NKA、VIP NKA、VIP含量变化不仅与气道炎症反应相关指标改变有关,还与肠组织中NKA、VIP含量变化趋势表现出显著的同步性特点(正相关性)。加味桔梗汤从肺治肠治疗“肺病及肠”的效应机制可能与调节肺肠组织中NKA、VIP的含量有关,其具体机制有待进一步深入研究。
Originated from "Huangdi Neijing", the Lung Being Relative to the Large Intestine Theory reflects the Holistic view of Chinese Medicine. On one hand, the Theory has been used to treat Respiratory diseases such as COPD, ARDS, Pulmonary heart disease, Bronchial asthma, cough, etc. On the other hand, it also has been used to treat digestive system-related diseases like Constipation, Peptic ulcer and Chronic enteritis. As a specific form of the Lung Being Relative to the Large Intestine Theory, "Enteropathy caused by lung disease" can confirm the Theory to some extent, and furthermore to provide some important evidences to reveal the meaning of the Theory.
Clinical data shows that other than respiratory symptoms, COPD usually accompanied by gastrointestinal symptoms such as abdominal distension and constipation. Treatments of COPD based on Chinese Medicine not only can relief symptoms during acute period, but also can reduce the incidence and mortality, and improve the quality of life as well. In spite of its significant effects on COPD, the mechanisms of the Chinese Medicine treatments have not been very clear yet.
Based on literature research, this paper designed three experiments on "Enteropathy caused by lung disease" in COPD. Through observing morphologic alterations and the effects of the modified Jiegeng Decoction on rats with COPD, and detecting Neuropeptide contents in different tissues of rats with COPD, analyzed and clarified the features of "Enteropathy caused by lung disease" step by step. The paper consists of three parts:
Part one is reviews. It reviewed systematically on the research survey of the Lung Being Relative to the Large Intestine Theory and advances in studies on COPD.
Part two is theoretical explorations. It straightened out the Mechanisms of COPD based on TCM, and analyzed the Strategy of TCM syndrome differentiation and treatment of COPD.
From TCM's point of view, the basic pathogenesis of COPD is essential debility and evil reality. Essential debility means lung, spleen and kidney deficiency. Evil reality means wind-evil, cold-evil, dampness, phlegm and stasis. So the treatment of COPD should adhere firmly to this basic mechanism and take into account other factors at the same time.
In "Shang Han Lun", the formulas which treating cough and asthma all reflect the discipline of taking into account of both exterior and interior, cold and heat, reinforcement and elimination, and show the principle of treating in terms of root cause as well. The formulas scattered in several sections in "Shang Han Lun" which reveals the observation of the process of cough and asthma.
Part three is experimental study. Observed the alternations of morphology in rats with COPD to confirm that there is a phenomenon of "Enteropathy caused by lung disease" in COPD, and validated the phenomenon through exploring the mechanism of the therapeutic effect of modified Jiegeng Decoction via inflammatory cell and cytokine. Observed the influence of facilitating lung on contents of NKA and VIP in lung tissues in rats with COPD, and investigated the mechanism.
Experiment one:COPD rat model was induced by cigarette smoking inhalation and intratracheal LPS exposure. Rats were divided into 4 groups, namely normal group, model group, model treating group, normal treating group. Normal group and model group were given saline, other groups were given modified Jiegeng Decoction from the 2nd day to 13th day and the 15th day to 28th day. Took lung, intestine, heart, liver and kidney tissues of rats, made specimen for optical microscope. Results showed:①The light-microscope observation show that in the model group, the structure of bronchoalveolus is destructive, detelectasis and the interval is broaden, coalesce. There were many inflammatory cells infiltration in alveolar wall. These pathological changes indicated the rats had COPD.②The range of pathological changes in model treating group reduced and the infiltration of inflammatory cell decreased obviously, indicated that modified Jiegeng Decoction can relief the degree of inflammation in lung tissue.③In the intestine tissues of model group, inflammatory cell infiltration in the epithelium, submucosa irregularly arranged, indicated the COPD model rats had pathological changes of intestine tissue.④The inflammatory cell infiltration in intestine tissues of model treating group decreased indicated modified Jiegeng Decoction can ease the lesions of intestine.⑤there was no significant histology damage in the tissues of heart, liver and kidney, indicated COPD injures intestine more seriously.
Experiment two:Measured the content of TNF-a, IL-1βwith the ABC-ELISA method and observed the body weights and the intestine propulsive motilities of the rats. Results showed:①Compare with normal group, the amount of lymphocytes and the content of TNF-a and IL-1βof model group increased significantly. It showed that the model group had the sign of inflammation.②The amount of lymphocytes and the content of TNF-a and IL-1βof model group decreased obviously, showed the inflammation in airway relieved.
On the other hand, the results of the body weight and the intestine propulsive motility showed①Compare with normal group, the body weight and the intestine propulsive motility of model group decreased significantly, indicated COPD can inhibits the gastrointestinal motility and impacts nutritional status.②The body weight and the intestine propulsive motility of model treating group increased obviously, indicated modified Jiegeng Decoction can improve the gastrointestinal motility and impacts nutritional status.
From the analysis of pharmacodynamic index test, modified Jiegeng Decoction not only controled the inflammation in airway, but also improved the gastrointestinal motility and impacts nutritional status. That is to say, treating COPD from lung can inhibit the pathological changes in lung tissues and at the same time ease the pathological changes in intestine tissue.
Experiment three:Took lung, intestine, heart, liver and kidney tissues of every group rats, measured the content of VIP and NKA in the tissues with radio-immunity methods. The results showed:③Compare with normal group, the amount of NKA in lung and intestine tissues of model group increased while the amount of VIP decreased, especially in lung tissues, indicated COPD can change the amount of NKA and VIP both in lung and intestine which is related with "Enteropathy caused by lung disease",②The amount of NKA in lung and intestine tissues of model treating group decreased while the amount of VIP increased, indicated modified Jiegeng Decoction can regulate the changes of NKA and VIP in lung and intestine which induced by COPD.③The results of the correlation analysis between the amount of NKA and VIP in lung tissue and the amount of TNF-a and IL-1βin BALF indicated the effect of modified Jiegeng Decoction may be related with its regulation of NKA and VIP in lung tissue.④The amount of NKA and VIP in other organ tissues did not change significantly, indicated the impact of COPD on the amount of NKA and VIP is most obvious in lung and intestine.⑤The results of the correlation analysis between the amount of NKA and VIP in lung and intestine showed, the changes in lung synchronized with the changes in intestine. The regulation of modified Jiegeng Decoction on the gastrointestinal motility and nutritional status may be related with its impact on the amounts of NKA and VIP in lung and intestine.
Conclusion:Rats with cigarette smoke and LPS-induced COPD have lesions of lung tissue accompanied by pathological changes of intestine tissue. Therefore, cigarette smoke and LPS-induced COPD rats have "Enteropathy caused by lung disease".
Treating COPD model rats with modified Jiegeng Decoction can reduce the inflammation in airway and improve the gastrointestinal motility and nutritional status. It indicates treating from lung can also relive the pathological changes of intestine.
The therapeutic effect of modified Jiegeng Decoction may be related with its regulation of the amounts of NKA and VIP in lung and intestine which need further research.
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