肺失肃降的病理生理研究及其临床指导意义探讨
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摘要
1选题思路和研究目的
新世纪，在中医药全面现代化的进程中，中医基础理论的研究明显滞后于临床和中药方面的研究，很大程度上影响了其对临床工作的指导作用和中医现代化的整体进程。
中医名词术语的不规范及概念的模糊性和内涵的不确定性是中医基础理论中较突出的问题。如何更好地运用现代的语言表述、逻辑思维以及现代科技手段去研究它们的内涵和认识这些术语的本质?并在此基础上促进中医基础理论的发展，更好地对中医临床发挥指导作用?这就是本课题立题的最初设想。以肺而言，肺气宣发与肃降一直以来都是中医藏象学研究的一个薄弱环节。导师结合多年的教学、科研及临床经验，带领我们从这一角度深入开展“肺气宣发与肃降的病理生理研究及其临床指导意义的探讨”工作。多年来，先后开展了“肺主皮毛的理论探讨”、“卫气的病理生理研究”、“肺与大肠相表里”、“魄门亦为五藏使”和“肺气宣发和肃降的病理生理研究”等。同时，反思前些年中医在抗击“非典”中的经验，更使我们确信，深入研究有关肺气的宣发肃降理论，对指导临床工作具有重要的现实意义。基于以上原因，本课题在项目前期工作的基础上，更集中、更深入研究肺失肃降的理论及其与急性肺损伤的相关性，阐明它们共同的病理基础；从《内经》藏象学有关肺气的理论认识急性肺损伤(ALI)的发病机理及其防治方法，并进一步提示运用中医基础理论与发掘历代治疗经验对防治急性呼吸道感染严重并发症、降低其死亡率与后遗症的临床意义。
2研究方法
2．1理论挖掘和文献整理
通过对有关肺主“肃降”理论的文献整理和分析，结合现代中医理论研究参考，明确肺主“肃降”的概念、内涵及功能特点，并结合临床实践的观察，阐明肺失肃降形成的病理机制；通过相关中西医学文献整理、对比和分析研究，认识肺失肃降与急性肺损伤的相关性，并从中医理论和经验出发，阐述祛痰逐水法防治急性肺损伤的立法依据及临床指导意义。
2．2实验研究方法
选用复制LPS诱导的ALI大鼠模型，观察实验动物的超微病理组织病理变化、血气分析、肺湿／干比值及血清炎症因子TNF-α和抗炎因子IL-4以及肺泡灌洗液中PMN细胞分类计数等，探讨仲景祛痰逐水方药对ALI的影响。
2．2．1实验性急性肺损伤大鼠模型的建立
内毒素是革兰氏阴性细菌细胞壁的脂多糖成份，通过静脉注入或气管内吸入内毒素可以很好地模拟感染后的ALI。我们要研究的是急性上呼吸道感染后并发的ALI，发病过程和病理变化都与之较符合，因此我们选用大肠杆菌脂多糖诱导的ALI模型。按照文献方法，用尾静脉注射大肠杆菌脂多糖(LPS)复制大鼠急性肺损伤模型，致伤后，模型组大鼠动脉血氧分压(PaO_2)呈下降趋势；病理观察肺脏体积明显增大，表面可见大小不等的暗红色斑片状病灶；光镜下观察，肺组织内有大量炎细胞浸润，可见肺间质及肺泡水肿，肺出血明显，造模成功。
2．2．2检测指标的确定及检测方法
①一般状况观察：包括各组大鼠实验处置前后的外观、活动、进食、饮水、大小便、毛色、呼吸的频率和幅度、呼吸道分泌物、体重等。
②血气分析：动物麻醉后，即刻腹主动脉采血，用全自动血气分析仪检测。
③肺组织湿／干比：处死动物后取右肺上叶准确称取湿重，干燥24h后，再称取干重，计算肺湿干／比。
④肺组织病理学变化观察：肺组织石蜡包埋切片，HE染色，用于光镜下观察。
⑤肺组织超微结构变化观察：戊二醛、锇酸双固定，透射电镜观察肺组织超微结构变化。
⑥肺泡灌洗液PMN计数：肺泡灌洗液采用甲紫染色计数白细胞总数，姬姆萨—瑞氏染色计数细胞分类。
⑦大鼠血清中肿瘤坏死因子α(TNF-α)的测定：用放射免疫分析法(RIA)测定大鼠血清肿瘤坏死因子α。
⑧大鼠血清白细胞介素4(IL-4)的测定：用放射免疫分析法(RIA)测定大鼠血清白细胞介素4。
3研究结果
3．1理论提示：
通过文献整理，在对肺主“肃降”的内涵及肺失“肃降”的临床表现进行了分析、讨论后，关于肺失肃降，我们有了以下认识：
①．肺失肃降是阻塞性、限制性肺系疾病(如哮喘、SARS、肺炎、急性肺损伤等)发生的病理基础。这是因为生理情况下，肺主肃降是肺气活动有效性的根本特征，也是肺一切生理活动的基础。
②．结合文献资料与临床观察，急性肺损伤表现的症状、体征与中医肺失肃降的证候基本符合。由此初步认为，急性肺损伤的病理改变与肺失肃降相关。虽然脏腑病机中形成肺失肃降的途径很广，既有慢性肺、脾、肾虚损，也有急性的外感实邪传里，但显然后者与急性肺损伤更为相符。
③．从中医病机分析，“痰”是肺失肃降的关键，在病变过程中起着极重要作用。痰既是呼吸系统疾病的最一般、最基本和最重要的病理产物，又是影响肺气功能活动重要的继发性病因。故无论因病生痰，还是因痰致病，痰是原始病因与继发性病理产物的复合体，是威胁肺气活动的重要病邪。所以，从中医视角观察，急性肺损伤的肺实变、玻璃样变等病理改变及其进一步发展形成的急性呼吸窘迫综合征与“痰”的关系最密切。急性肺损伤时因过度炎症反应产生的渗出物、水肿液等停聚于肺组织间隙，就形成了中医的“痰”。因此，我们认为肺失肃降是ALI发生的病理基础，痰实结聚胸膈是ALI的病机关键。
④．重温《伤寒论》中外感寒邪，化热入里之痰热结胸，以及寒实结胸、水结胸等辨证论治理论及其经典方药，启发我们认识到除痰利肺气是中医救治ALI的关键，这是中医药治疗呼吸道阻塞的窘迫证候的特色和优势；同时，在历史积累的宝贵经验和方法中，挖掘出祛痰逐水法用于治疗ALI。
3．2实验研究结果
实验结果显示：
①．造模后大鼠明显表现毛色无光泽，竖毛、易惊、进食减少；大便干，灌服中药后大便稀，便次增多；呼吸在注射脂多糖后半小时加快，呼吸道有少量粉红色分泌物从鼻中流出。但在造模第二天后，造模组及各中药干预组大鼠呼吸频率减慢。
②．血气分析模型组大鼠动脉血氧分压(PaO_2)与中药干预组及空白对照组比较明显降低(P＜0.01)，空白对照组和各中药干预组氧分压间无显著差异，均在正常范围。
③．肺组织湿／干比值(w／d)肺组织湿／干比造模后明显升高，模型组高于各中药干预组及空白对照组，模型组、中药干预组及空白对照组间比较有显著性差异(P＜0.05)。
④．各组大鼠肺组织病理学改变，模型组大鼠肺间质毛细血管扩张充血明显，间质大量炎细胞浸润，部分肺泡内充盈渗出物，透明膜形成；中药干预各组大鼠肺组织病理改变程度较模型组轻。空白对照组光镜下肺泡内无渗出，间质有少量炎细胞浸润，无间质毛细血管扩张充血和增宽。
⑤．超微病理改变：透射电镜下，模型组肺泡Ⅰ型细胞肿胀，并有核破裂，肺泡Ⅱ型细胞板层小体空泡改变，细胞肿胀。同时基底膜明显增厚、毛细血管壁变薄并扩张充血明显。中药干预各组电镜下肺泡细胞改变不显著，但基底膜仍增厚并见毛细血管充血。空白对照组则肺泡细胞、基底膜及毛细血管均未见异常改变。
⑥．大鼠肺泡灌洗液(BALF)白细胞计数及多形核白细胞(PMN)分类计数白细胞计数中药干预组明显低于模型组，P＜0.05，有显著性差异；中药干预组与空白组比较，P＞0.05，无显著性差异；模型组高于空白组，P＜0.05，有显著性差异。PMN分类计数结果显示：各组间比较，模型组明显高于各组，P＜0.05，有显著性差异。
⑦．大鼠血清中肿瘤坏死因子(TNF)，模型组中明显升高，模型组高于中药干预组及空白对照组，并中药干预组高于空白对照组，有显著性差异(P＜0.05)。
⑧．大鼠血清中血清白介素4(IL-4)，模型组中明显升高，模型组高于中药干预组及空白对照组，并中药干预组高于空白对照组，有显著性差异(P＜0.05)。
4结论
①．通过文献整理、临床观察及实验模拟，我们认为急性肺损伤／急性呼吸窘迫综合征与中医肺失肃降的密切相关性。肺失肃降是ALI发生的病理基础，痰实结聚胸膈是ALI形成的关键环节。
②．祛痰逐水法方药，对急性肺损伤组织有保护作用，能使急性肺损伤组织病理损害程度减轻、组织水肿缓解等。祛痰逐水法方药能明显减少促炎因子—肿瘤坏死因子，并使肺组织中炎细胞的聚集减轻，也说明祛痰逐水方药能通过减少促炎因子肿瘤坏死因子和减少PMN在肺组织中的聚集，从而减轻病情，保护肺组织。同时，祛痰逐水方药既能抑制过度炎症反应，也能预防抗炎反应过度，所以其作用机制还可能是调节促炎—抗炎间的平衡。而究竟对抗炎因子作用为主还是以对炎症因子作用为主，本实验未能涉及。但未来关于中医药对急性肺损伤的作用可从此方面入手。
③．临床治疗如肺气肿、慢性肺心病、大叶性肺炎及急性肺损伤的肺实变等阻塞性、限制性肺系疾病，不仅可用肃肺降气的方法，更可把治痰作为重要的治疗思路和治疗途径。临床上对于各类病因引起的上呼吸道感染的严重并发症，以肺失肃降为主要病理表现者，如急性肺损伤，更可结合病情，在急性期，根据中医辨证论治，把握时机，果断攻邪，及时适度用祛痰逐水、破结、通导大便等攻逐方法，使痰饮邪气从下而出，并上逆肺气得降。这也是维护肺气的重要方法，体现了自张仲景以来，中医治疗呼吸系统疾病的基本经验。
④．中西医学是两个不同的医学体系，中医藏象学中的“肺”，不能简单等同于现代医学中的肺，因此临床中中医治疗肺系疾病，也必定以整体观和辨证论治为出发点，辨清外感与内伤，分清虚实、寒热，而非简单的只针对细菌、病毒，一味地用清热解毒药来抗炎、抗病毒。
5创新性
①．理论上系统阐述肺失肃降的概念和病机，突出强调痰饮是肺失肃降的病理关键，为祛痰逐水法治疗在临床中的应用(如治疗急性肺损伤)提供理论依据；
②．论证了肺失肃降与ALI／ARDS的相关性，为从动物实验研究肺失肃降的病机开阔了思路，也为运用中医药历史上积累的宝贵经验，防治ALI／ARDS寻找到切入点。
③．首次从峻下和温下两种祛痰逐水法，从免疫组化、病理组织形态和超微结构，探讨中医药对ALI／ARDS的治疗作用和机制，为指导中医药参与治疗肺系危急重症做好基础研究，更好地发挥中医药的特色与优势。
1. The Reasons and objective of the research
In the new century, during the process of all-round modernization of traditionalChinese medicine, research on the basic theories of traditional Chinese medicine fallsbehind that of clinic and Chinese herbs obviously, and this severely affect its guidanceon clinic and the process of whole modernization of traditional Chinese medicine.
Irregularity of terminologies, murkiness of concepts and incertitude ofmeanings are the outstanding problems in the basic theories of traditionalChinese medicine. How to research the meanings and essence of these conceptsby using modern scientific and technological ways and to accelerate thedevelopment of basic theories of traditional Chinese medicine is the primaryassumption of this research. Research on the ascending and descending functionsof the lung qi has always been a weak aspect of Zangxiang theories of traditionalChinese medicine. Our tutor lead us to carry out the path-physiological researchon the lung qi and its effect on guiding clinical work of traditional Chinesemedicine from this aspect combing his teaching, researching and clinicalexperience. We have been carrying out the following researches for many years,such as discussion on the lung dominates the skin and hair, research on thedescending and ascending functions of the lung qi. Meanwhile, think about theexperience of traditional Chinese medicine on dealing with SARS in the earlieryears make us believe that it has realistic effect to research deeply on the theories of the descending and ascending functions of the lung qi to guide clinical work.Based on these reasons and the earlier work, we plan to research the theories ofthe lung which loses its ascending and descending functions and to clarify itspathological basis, probe the method of recognizing the process of ALI andmechanism to treat and prevent it by using the theories of the lung qi in theCanon of Medicine, furthermore, clue the clinical meaning of using basictheories of traditional Chinese medicine and dredging clinical experience ofdifferent times to prevent and treat with severe complication of acute respiratoryinfection and to bring down its death rate and latter diseases.
2. Research method
2.1 Research method of theories
On the basis of arranging and analyzing the literature of the descending andclearing functions of the lung, combing the text of Basic theories of TCM atpresent, we identified the concept, meaning and functional characteristics of thedescending and clearing functions of the lung and clarified the mechanism of thelung which loses its descending and clearing functions combing the clinicalexperience. Meanwhile, on the basis of arranging and researching on the relatedTCM and western medicine literatures, we set up the TCM and western medicinemechanism of ALI, and according to the theories of differentiating the syndromeand treatment, we clarified the basis of the method of exorcizing the phlegm andwater and its clinical guiding meaning.
2.2 Experimental research method
We try to choose to copy the ALI mice models induced by LPS to observe thesuper-micro pathological change of organization, lung weight moisture, BloodGas Analyze and TNF-a, IL-4, PMN cell count in the BALF, thus to discuss theeffect of Zhang zhongjing's formula of exorcizing phlegm and water on ALI.
2.2.1 To make the mice model of ALI
Endotoxin is the LPS of the cell wall of Gram Negative Bacilli, vein injectionand trachea aspiration are the good ways to simulate ALL What we researched is ALIcaused by acute upper respiratory infection, the process of the disease and thepathological change coincide with it, so we chose ALI model induced bylipopolysaccharide LPS. According to literature method, we used tail vein injectionmethod to inject lipopolysaccharide LPS to copy ALI mice model, after injured, PaO_2of the model team began to descend, the volume of lung obviously expanded, big andsmall dark red plaques could be seen on the surface of the lung. Observed through optical Microscope, amounts of inflammatory cells exposure could be seen, also,dropsy could be seen in the alveolar and pulmonary, lung hemorrhage was obvious,and this proved that the model was successful.
2.1.2 Determination of Examination target and examination method
1) General condition observation: including big mice' outward appearance, theactivity, food eating, the drinking, the feces and urine, hair, the breath frequency andscope, the respiratory tract secretion, the body weight of each group before and afterthe model-making.
2) Blood gas analysis: After the animal has been anaesthetized, instantly picks theblood from abdomen aorta and examines with the entire automatic blood vigoranalyzer.
3). Calculation of lung wet/dry weight ratios: Weight moisture of the lung: afterthe animal was killed, choose the upper part of the right lung, weighs it, and thendry it for 24 hours, then weighs it again and calculate the wet/dry weight ratios ofthe lung.
4) Observation of the pathological change of the lung organization: use paraffinsection method to entrap the lung organization, dye with HE method, and observewith optical microscope.
5) Super-micro structure change observation: use Glutaral and Osmic acid to stablethe organization and use TEM to observe the super-micro change of the lungorganization.
6) Counting of BALF PMN: use Jurgens Staining Method to count the amount ofwhite ceils and Giemsa Staining Method to count the cells.
7) Determination of TNF-a: RIA method to determine TNF-a.
8) Determination of IL-4: RIA method to determine IL-4.
3. Results:
3.1 Theory research results:
Combine with the literature material and after analyzing and discussing onthe essence of the descending and clearing functions of the lung and the clinicalsymptoms of the lung which loses its descending and clearing functions, wemake the following conclusions on it:
1). Dysfunction of the descending and clearing functions of the lung is thepathological basis of immanent obstruction and restriction lung diseases. This isbecause the descending and clearing functions of the lung is the basiccharacteristics of the activities of the lung qi under the physiological condition and also the basis of all the physiological activities of the lung.
2). According to the clinical manifestation of ALI, We realize the correlationbetween dysfunction of the descending and clearing functions of the lung anddevelopment of ALI.
3). Phlegm is the key mechanism of the lung when it loses its descending andclearing functions and it acts an important role in the process when the lung losesits descending and clearing functions. Phlegm is the basic and most importantpathological change of the respiratory system diseases. It is not only thepathological product of the body, but also one of the most important factors tocause diseases. According to the etiology and mechanism theories of TCM, nomatter what diseases produce phlegm, or the phlegm cause diseases, phlegm isthe combination of the primary etiology and secondary pathological product, andbecomes an important factor to cause diseases.
4). ALI/ARDS coincides with the symptoms of "Jiexiong" of TCM, the mainpathological characteristics of ALI/ARDS is the formation of pulmonary edema andtransparent membrane which contains abundant protein in the alveolar exudationcaused by the high permeability of the lung micro-vessel and combine with thepulmonary fibrosis. All these exudates and sub-eschar tissue fluid stay in the gaps ofthe lung organization and form the phlegm of TCM. So, we think that the pathologicalbasis of ALI is because the lung loses its descending and clearing functions, and thephlegm stays in the chest is the key mechanism. Therefore, to exorcizing the phlegmand make the movement of lung qi normal is the key method to deal with ALI, this isthe combination of TCM theories and clinical experience and is the importantexperience to deal with ARDS. So, we decide to choose the method of exorcizing thephlegm and water to deal with the ALI mice induced by endotoxin.
3.2 Experimental research results:
1). After the model has been made, the mice appeared the followingcharacteristics: the hair erect and lose gloss, easy to be frightened, dietingdecrease, dry stools, after taking Chinese herbs, the stools becomes loose andstool frequency increases, breath frequency increases after injecting LPS, pinkexcrete fluid from the nose, but the second day after the model was made, thebreath frequency of the mice in each team decreased.
Lung moisture became higher obviously after the model was made, model team ishigher than that of treating team, and treating team is higher than that of blankteam, there are obvious differences between each team.(p＜0.05)。
2). Blood gas analysis: PaO_2 of the model team is obviously lower than that ofother teams (p＜0.01), no differences exist between the treating team and blank team,both of them are in the normal range.
3). Weight moisture of the lung: after the animal was killed, choose the upperpart of the right lung, weighs it, and then dry it for 24 hours, then weighs it andcalculate the moisture of the lung.
4). Pathological changes of the lung organization of each team: the micro-vessel of thelung of the mice in the model team expanded obviously and obvious congestionformed, amounts of inflammatory cells infiltrated in the pulmonary, parts of thealveolar were filled with exudation, transparent membranes formed, changes of thepathological characteristics in each treating teams are lighter than that of the modelteam, alveolar in the blank team has no exudation observed with optic microscope,little of inflammatory cells infiltrated in the pulmonary, no micro-vessel congestedand expanded in the pulmonary.
5). Super-micro structure change observation: observed with TEM, we found thatⅠcells of the alveolar in the model team was intumescent, the core of some of the cellsbroken,Ⅱcells of the alveolar appeared LB caving, and ceils intumescence,meanwhile, basilar membrane thickened, micro-vessel became weak and congested.The Changes of alveolar cells in each Treating teams was not obvious, but basilarmembrane thickened, micro-vessel became weak and congested. No changesappeared in the alveolar, basilar membrane and micro-vessel in the blank team.
6). Counting of BALF white cells and PMN: counting of white cells is obviouslylower in the treating teams than that of the model team(p＜0.05), compared withblank team, no obvious difference (p＞0.05), counting of white cells is obviouslyhigher in the model team than that of the blank team(p＜0.05). PMN cells countingresult is that the model team is obviously higher than that of other teams(p＜0.05).
7). Determination of TNF-a: TNF in the model team is higher than that of treatingteam, and treating team higher than that of blank team (p＜0.05).
8). Determination of IL-4:IL-4 in the model team is higher than that of treatingteam, and treating team higher than that of blank team (p＜0.05).
4. Conclusions
1). ALI/ARDS correlated with dysfunction of the descending and clearingfunctions of the lung. Impairment of clearing and descending function of the lung isthe pathological basis of ALI, and the phlegm stays in the chest is the key mechanism.
2). Formulas of exorcizing the phlegm and water can protect the lungorganization of ALI, and can relieve the pathological injury of the lung and theedema. It can obviously relieve TNF-a and the gathering of inflammatory ceils inthe lung organization, which proved that it can relieve the symptoms of ALl by lowerthe TNF-a and PMN. Meanwhile, it can restrict and protect the over-inflammatoryreaction, so, its effect mechanism probably exists in make the balance of adjustinginflammation and anti-inflammation. But, if it is effective to anti-inflammation factorsor inflammation factors has not been researched. But further research could beconsidered in the future.
3). To deal with diseases such as pulmonary emphysema, chronic pneumocardialdisease, Lobar Pneumonia and acute lung injury in TCM clinics, we can not only usethe method of descending and clearing the lung qi, but also the method of treat withphlegm. In the TCM clinics, when deal with the related diseases caused by upperrespiratory infection, such as acute lung injury, which has the main pathologicalcharacteristics of loses its descending and clearing function, we can choose themethod of exorcizing phlegm and water and recover the stools, thus to make thephlegm excreted and protect the lung qi. This method represents the basic experienceof TCM to deal with respiratory system diseases since Zhang zhongjing's time.
4). TCM and western medicine are the two different systems, the lung in theZangxiang theories of TCM can not be simply equaled to that of western medicine. So,in TCM clinics, when deal with lung system disease, we must focus on the integrationviews and the method of differentiating and treating syndromes according to Zangfutheories of TCM, which need to differentiate the exterior and interior, deficiency andexcess, cold and heat, but not just deal with bacteria or virus and just use the methodof dealing with inflammation and virus.
5. Creativity
1). Systematically clarified the key pathological mechanism of the lung when it losesits descending and clearing functions and specially mentioned the relationshipbetween the phlegm and it, thus, supply theoretical basis for using the method ofexorcizing phlegm and water to treat with ALI.
2). From the research, we expand the idea of how to carry out the study ondysfunction of the descending and clearing functions of the lung, and find a newentry point that some classical empirical Chinese medical formula will be used to treatALI/ARDS.
3). Using strong exorcizing and warm exorcizing method for the first time and discussed the effect and mechanism of TCM to deal with ALI and ARDS from thesphere of RIA, pathology and micro-structure, thus did important basic research forTCM to participate in dealing with acute severe respiratory system diseases andsupplied material for the coming clinical job.
新世纪，在中医药全面现代化的进程中，中医基础理论的研究明显滞后于临床和中药方面的研究，很大程度上影响了其对临床工作的指导作用和中医现代化的整体进程。
中医名词术语的不规范及概念的模糊性和内涵的不确定性是中医基础理论中较突出的问题。如何更好地运用现代的语言表述、逻辑思维以及现代科技手段去研究它们的内涵和认识这些术语的本质?并在此基础上促进中医基础理论的发展，更好地对中医临床发挥指导作用?这就是本课题立题的最初设想。以肺而言，肺气宣发与肃降一直以来都是中医藏象学研究的一个薄弱环节。导师结合多年的教学、科研及临床经验，带领我们从这一角度深入开展“肺气宣发与肃降的病理生理研究及其临床指导意义的探讨”工作。多年来，先后开展了“肺主皮毛的理论探讨”、“卫气的病理生理研究”、“肺与大肠相表里”、“魄门亦为五藏使”和“肺气宣发和肃降的病理生理研究”等。同时，反思前些年中医在抗击“非典”中的经验，更使我们确信，深入研究有关肺气的宣发肃降理论，对指导临床工作具有重要的现实意义。基于以上原因，本课题在项目前期工作的基础上，更集中、更深入研究肺失肃降的理论及其与急性肺损伤的相关性，阐明它们共同的病理基础；从《内经》藏象学有关肺气的理论认识急性肺损伤(ALI)的发病机理及其防治方法，并进一步提示运用中医基础理论与发掘历代治疗经验对防治急性呼吸道感染严重并发症、降低其死亡率与后遗症的临床意义。
2研究方法
2．1理论挖掘和文献整理
通过对有关肺主“肃降”理论的文献整理和分析，结合现代中医理论研究参考，明确肺主“肃降”的概念、内涵及功能特点，并结合临床实践的观察，阐明肺失肃降形成的病理机制；通过相关中西医学文献整理、对比和分析研究，认识肺失肃降与急性肺损伤的相关性，并从中医理论和经验出发，阐述祛痰逐水法防治急性肺损伤的立法依据及临床指导意义。
2．2实验研究方法
选用复制LPS诱导的ALI大鼠模型，观察实验动物的超微病理组织病理变化、血气分析、肺湿／干比值及血清炎症因子TNF-α和抗炎因子IL-4以及肺泡灌洗液中PMN细胞分类计数等，探讨仲景祛痰逐水方药对ALI的影响。
2．2．1实验性急性肺损伤大鼠模型的建立
内毒素是革兰氏阴性细菌细胞壁的脂多糖成份，通过静脉注入或气管内吸入内毒素可以很好地模拟感染后的ALI。我们要研究的是急性上呼吸道感染后并发的ALI，发病过程和病理变化都与之较符合，因此我们选用大肠杆菌脂多糖诱导的ALI模型。按照文献方法，用尾静脉注射大肠杆菌脂多糖(LPS)复制大鼠急性肺损伤模型，致伤后，模型组大鼠动脉血氧分压(PaO_2)呈下降趋势；病理观察肺脏体积明显增大，表面可见大小不等的暗红色斑片状病灶；光镜下观察，肺组织内有大量炎细胞浸润，可见肺间质及肺泡水肿，肺出血明显，造模成功。
2．2．2检测指标的确定及检测方法
①一般状况观察：包括各组大鼠实验处置前后的外观、活动、进食、饮水、大小便、毛色、呼吸的频率和幅度、呼吸道分泌物、体重等。
②血气分析：动物麻醉后，即刻腹主动脉采血，用全自动血气分析仪检测。
③肺组织湿／干比：处死动物后取右肺上叶准确称取湿重，干燥24h后，再称取干重，计算肺湿干／比。
④肺组织病理学变化观察：肺组织石蜡包埋切片，HE染色，用于光镜下观察。
⑤肺组织超微结构变化观察：戊二醛、锇酸双固定，透射电镜观察肺组织超微结构变化。
⑥肺泡灌洗液PMN计数：肺泡灌洗液采用甲紫染色计数白细胞总数，姬姆萨—瑞氏染色计数细胞分类。
⑦大鼠血清中肿瘤坏死因子α(TNF-α)的测定：用放射免疫分析法(RIA)测定大鼠血清肿瘤坏死因子α。
⑧大鼠血清白细胞介素4(IL-4)的测定：用放射免疫分析法(RIA)测定大鼠血清白细胞介素4。
3研究结果
3．1理论提示：
通过文献整理，在对肺主“肃降”的内涵及肺失“肃降”的临床表现进行了分析、讨论后，关于肺失肃降，我们有了以下认识：
①．肺失肃降是阻塞性、限制性肺系疾病(如哮喘、SARS、肺炎、急性肺损伤等)发生的病理基础。这是因为生理情况下，肺主肃降是肺气活动有效性的根本特征，也是肺一切生理活动的基础。
②．结合文献资料与临床观察，急性肺损伤表现的症状、体征与中医肺失肃降的证候基本符合。由此初步认为，急性肺损伤的病理改变与肺失肃降相关。虽然脏腑病机中形成肺失肃降的途径很广，既有慢性肺、脾、肾虚损，也有急性的外感实邪传里，但显然后者与急性肺损伤更为相符。
③．从中医病机分析，“痰”是肺失肃降的关键，在病变过程中起着极重要作用。痰既是呼吸系统疾病的最一般、最基本和最重要的病理产物，又是影响肺气功能活动重要的继发性病因。故无论因病生痰，还是因痰致病，痰是原始病因与继发性病理产物的复合体，是威胁肺气活动的重要病邪。所以，从中医视角观察，急性肺损伤的肺实变、玻璃样变等病理改变及其进一步发展形成的急性呼吸窘迫综合征与“痰”的关系最密切。急性肺损伤时因过度炎症反应产生的渗出物、水肿液等停聚于肺组织间隙，就形成了中医的“痰”。因此，我们认为肺失肃降是ALI发生的病理基础，痰实结聚胸膈是ALI的病机关键。
④．重温《伤寒论》中外感寒邪，化热入里之痰热结胸，以及寒实结胸、水结胸等辨证论治理论及其经典方药，启发我们认识到除痰利肺气是中医救治ALI的关键，这是中医药治疗呼吸道阻塞的窘迫证候的特色和优势；同时，在历史积累的宝贵经验和方法中，挖掘出祛痰逐水法用于治疗ALI。
3．2实验研究结果
实验结果显示：
①．造模后大鼠明显表现毛色无光泽，竖毛、易惊、进食减少；大便干，灌服中药后大便稀，便次增多；呼吸在注射脂多糖后半小时加快，呼吸道有少量粉红色分泌物从鼻中流出。但在造模第二天后，造模组及各中药干预组大鼠呼吸频率减慢。
②．血气分析模型组大鼠动脉血氧分压(PaO_2)与中药干预组及空白对照组比较明显降低(P＜0.01)，空白对照组和各中药干预组氧分压间无显著差异，均在正常范围。
③．肺组织湿／干比值(w／d)肺组织湿／干比造模后明显升高，模型组高于各中药干预组及空白对照组，模型组、中药干预组及空白对照组间比较有显著性差异(P＜0.05)。
④．各组大鼠肺组织病理学改变，模型组大鼠肺间质毛细血管扩张充血明显，间质大量炎细胞浸润，部分肺泡内充盈渗出物，透明膜形成；中药干预各组大鼠肺组织病理改变程度较模型组轻。空白对照组光镜下肺泡内无渗出，间质有少量炎细胞浸润，无间质毛细血管扩张充血和增宽。
⑤．超微病理改变：透射电镜下，模型组肺泡Ⅰ型细胞肿胀，并有核破裂，肺泡Ⅱ型细胞板层小体空泡改变，细胞肿胀。同时基底膜明显增厚、毛细血管壁变薄并扩张充血明显。中药干预各组电镜下肺泡细胞改变不显著，但基底膜仍增厚并见毛细血管充血。空白对照组则肺泡细胞、基底膜及毛细血管均未见异常改变。
⑥．大鼠肺泡灌洗液(BALF)白细胞计数及多形核白细胞(PMN)分类计数白细胞计数中药干预组明显低于模型组，P＜0.05，有显著性差异；中药干预组与空白组比较，P＞0.05，无显著性差异；模型组高于空白组，P＜0.05，有显著性差异。PMN分类计数结果显示：各组间比较，模型组明显高于各组，P＜0.05，有显著性差异。
⑦．大鼠血清中肿瘤坏死因子(TNF)，模型组中明显升高，模型组高于中药干预组及空白对照组，并中药干预组高于空白对照组，有显著性差异(P＜0.05)。
⑧．大鼠血清中血清白介素4(IL-4)，模型组中明显升高，模型组高于中药干预组及空白对照组，并中药干预组高于空白对照组，有显著性差异(P＜0.05)。
4结论
①．通过文献整理、临床观察及实验模拟，我们认为急性肺损伤／急性呼吸窘迫综合征与中医肺失肃降的密切相关性。肺失肃降是ALI发生的病理基础，痰实结聚胸膈是ALI形成的关键环节。
②．祛痰逐水法方药，对急性肺损伤组织有保护作用，能使急性肺损伤组织病理损害程度减轻、组织水肿缓解等。祛痰逐水法方药能明显减少促炎因子—肿瘤坏死因子，并使肺组织中炎细胞的聚集减轻，也说明祛痰逐水方药能通过减少促炎因子肿瘤坏死因子和减少PMN在肺组织中的聚集，从而减轻病情，保护肺组织。同时，祛痰逐水方药既能抑制过度炎症反应，也能预防抗炎反应过度，所以其作用机制还可能是调节促炎—抗炎间的平衡。而究竟对抗炎因子作用为主还是以对炎症因子作用为主，本实验未能涉及。但未来关于中医药对急性肺损伤的作用可从此方面入手。
③．临床治疗如肺气肿、慢性肺心病、大叶性肺炎及急性肺损伤的肺实变等阻塞性、限制性肺系疾病，不仅可用肃肺降气的方法，更可把治痰作为重要的治疗思路和治疗途径。临床上对于各类病因引起的上呼吸道感染的严重并发症，以肺失肃降为主要病理表现者，如急性肺损伤，更可结合病情，在急性期，根据中医辨证论治，把握时机，果断攻邪，及时适度用祛痰逐水、破结、通导大便等攻逐方法，使痰饮邪气从下而出，并上逆肺气得降。这也是维护肺气的重要方法，体现了自张仲景以来，中医治疗呼吸系统疾病的基本经验。
④．中西医学是两个不同的医学体系，中医藏象学中的“肺”，不能简单等同于现代医学中的肺，因此临床中中医治疗肺系疾病，也必定以整体观和辨证论治为出发点，辨清外感与内伤，分清虚实、寒热，而非简单的只针对细菌、病毒，一味地用清热解毒药来抗炎、抗病毒。
5创新性
①．理论上系统阐述肺失肃降的概念和病机，突出强调痰饮是肺失肃降的病理关键，为祛痰逐水法治疗在临床中的应用(如治疗急性肺损伤)提供理论依据；
②．论证了肺失肃降与ALI／ARDS的相关性，为从动物实验研究肺失肃降的病机开阔了思路，也为运用中医药历史上积累的宝贵经验，防治ALI／ARDS寻找到切入点。
③．首次从峻下和温下两种祛痰逐水法，从免疫组化、病理组织形态和超微结构，探讨中医药对ALI／ARDS的治疗作用和机制，为指导中医药参与治疗肺系危急重症做好基础研究，更好地发挥中医药的特色与优势。
1. The Reasons and objective of the research
In the new century, during the process of all-round modernization of traditionalChinese medicine, research on the basic theories of traditional Chinese medicine fallsbehind that of clinic and Chinese herbs obviously, and this severely affect its guidanceon clinic and the process of whole modernization of traditional Chinese medicine.
Irregularity of terminologies, murkiness of concepts and incertitude ofmeanings are the outstanding problems in the basic theories of traditionalChinese medicine. How to research the meanings and essence of these conceptsby using modern scientific and technological ways and to accelerate thedevelopment of basic theories of traditional Chinese medicine is the primaryassumption of this research. Research on the ascending and descending functionsof the lung qi has always been a weak aspect of Zangxiang theories of traditionalChinese medicine. Our tutor lead us to carry out the path-physiological researchon the lung qi and its effect on guiding clinical work of traditional Chinesemedicine from this aspect combing his teaching, researching and clinicalexperience. We have been carrying out the following researches for many years,such as discussion on the lung dominates the skin and hair, research on thedescending and ascending functions of the lung qi. Meanwhile, think about theexperience of traditional Chinese medicine on dealing with SARS in the earlieryears make us believe that it has realistic effect to research deeply on the theories of the descending and ascending functions of the lung qi to guide clinical work.Based on these reasons and the earlier work, we plan to research the theories ofthe lung which loses its ascending and descending functions and to clarify itspathological basis, probe the method of recognizing the process of ALI andmechanism to treat and prevent it by using the theories of the lung qi in theCanon of Medicine, furthermore, clue the clinical meaning of using basictheories of traditional Chinese medicine and dredging clinical experience ofdifferent times to prevent and treat with severe complication of acute respiratoryinfection and to bring down its death rate and latter diseases.
2. Research method
2.1 Research method of theories
On the basis of arranging and analyzing the literature of the descending andclearing functions of the lung, combing the text of Basic theories of TCM atpresent, we identified the concept, meaning and functional characteristics of thedescending and clearing functions of the lung and clarified the mechanism of thelung which loses its descending and clearing functions combing the clinicalexperience. Meanwhile, on the basis of arranging and researching on the relatedTCM and western medicine literatures, we set up the TCM and western medicinemechanism of ALI, and according to the theories of differentiating the syndromeand treatment, we clarified the basis of the method of exorcizing the phlegm andwater and its clinical guiding meaning.
2.2 Experimental research method
We try to choose to copy the ALI mice models induced by LPS to observe thesuper-micro pathological change of organization, lung weight moisture, BloodGas Analyze and TNF-a, IL-4, PMN cell count in the BALF, thus to discuss theeffect of Zhang zhongjing's formula of exorcizing phlegm and water on ALI.
2.2.1 To make the mice model of ALI
Endotoxin is the LPS of the cell wall of Gram Negative Bacilli, vein injectionand trachea aspiration are the good ways to simulate ALL What we researched is ALIcaused by acute upper respiratory infection, the process of the disease and thepathological change coincide with it, so we chose ALI model induced bylipopolysaccharide LPS. According to literature method, we used tail vein injectionmethod to inject lipopolysaccharide LPS to copy ALI mice model, after injured, PaO_2of the model team began to descend, the volume of lung obviously expanded, big andsmall dark red plaques could be seen on the surface of the lung. Observed through optical Microscope, amounts of inflammatory cells exposure could be seen, also,dropsy could be seen in the alveolar and pulmonary, lung hemorrhage was obvious,and this proved that the model was successful.
2.1.2 Determination of Examination target and examination method
1) General condition observation: including big mice' outward appearance, theactivity, food eating, the drinking, the feces and urine, hair, the breath frequency andscope, the respiratory tract secretion, the body weight of each group before and afterthe model-making.
2) Blood gas analysis: After the animal has been anaesthetized, instantly picks theblood from abdomen aorta and examines with the entire automatic blood vigoranalyzer.
3). Calculation of lung wet/dry weight ratios: Weight moisture of the lung: afterthe animal was killed, choose the upper part of the right lung, weighs it, and thendry it for 24 hours, then weighs it again and calculate the wet/dry weight ratios ofthe lung.
4) Observation of the pathological change of the lung organization: use paraffinsection method to entrap the lung organization, dye with HE method, and observewith optical microscope.
5) Super-micro structure change observation: use Glutaral and Osmic acid to stablethe organization and use TEM to observe the super-micro change of the lungorganization.
6) Counting of BALF PMN: use Jurgens Staining Method to count the amount ofwhite ceils and Giemsa Staining Method to count the cells.
7) Determination of TNF-a: RIA method to determine TNF-a.
8) Determination of IL-4: RIA method to determine IL-4.
3. Results:
3.1 Theory research results:
Combine with the literature material and after analyzing and discussing onthe essence of the descending and clearing functions of the lung and the clinicalsymptoms of the lung which loses its descending and clearing functions, wemake the following conclusions on it:
1). Dysfunction of the descending and clearing functions of the lung is thepathological basis of immanent obstruction and restriction lung diseases. This isbecause the descending and clearing functions of the lung is the basiccharacteristics of the activities of the lung qi under the physiological condition and also the basis of all the physiological activities of the lung.
2). According to the clinical manifestation of ALI, We realize the correlationbetween dysfunction of the descending and clearing functions of the lung anddevelopment of ALI.
3). Phlegm is the key mechanism of the lung when it loses its descending andclearing functions and it acts an important role in the process when the lung losesits descending and clearing functions. Phlegm is the basic and most importantpathological change of the respiratory system diseases. It is not only thepathological product of the body, but also one of the most important factors tocause diseases. According to the etiology and mechanism theories of TCM, nomatter what diseases produce phlegm, or the phlegm cause diseases, phlegm isthe combination of the primary etiology and secondary pathological product, andbecomes an important factor to cause diseases.
4). ALI/ARDS coincides with the symptoms of "Jiexiong" of TCM, the mainpathological characteristics of ALI/ARDS is the formation of pulmonary edema andtransparent membrane which contains abundant protein in the alveolar exudationcaused by the high permeability of the lung micro-vessel and combine with thepulmonary fibrosis. All these exudates and sub-eschar tissue fluid stay in the gaps ofthe lung organization and form the phlegm of TCM. So, we think that the pathologicalbasis of ALI is because the lung loses its descending and clearing functions, and thephlegm stays in the chest is the key mechanism. Therefore, to exorcizing the phlegmand make the movement of lung qi normal is the key method to deal with ALI, this isthe combination of TCM theories and clinical experience and is the importantexperience to deal with ARDS. So, we decide to choose the method of exorcizing thephlegm and water to deal with the ALI mice induced by endotoxin.
3.2 Experimental research results:
1). After the model has been made, the mice appeared the followingcharacteristics: the hair erect and lose gloss, easy to be frightened, dietingdecrease, dry stools, after taking Chinese herbs, the stools becomes loose andstool frequency increases, breath frequency increases after injecting LPS, pinkexcrete fluid from the nose, but the second day after the model was made, thebreath frequency of the mice in each team decreased.
Lung moisture became higher obviously after the model was made, model team ishigher than that of treating team, and treating team is higher than that of blankteam, there are obvious differences between each team.(p＜0.05)。
2). Blood gas analysis: PaO_2 of the model team is obviously lower than that ofother teams (p＜0.01), no differences exist between the treating team and blank team,both of them are in the normal range.
3). Weight moisture of the lung: after the animal was killed, choose the upperpart of the right lung, weighs it, and then dry it for 24 hours, then weighs it andcalculate the moisture of the lung.
4). Pathological changes of the lung organization of each team: the micro-vessel of thelung of the mice in the model team expanded obviously and obvious congestionformed, amounts of inflammatory cells infiltrated in the pulmonary, parts of thealveolar were filled with exudation, transparent membranes formed, changes of thepathological characteristics in each treating teams are lighter than that of the modelteam, alveolar in the blank team has no exudation observed with optic microscope,little of inflammatory cells infiltrated in the pulmonary, no micro-vessel congestedand expanded in the pulmonary.
5). Super-micro structure change observation: observed with TEM, we found thatⅠcells of the alveolar in the model team was intumescent, the core of some of the cellsbroken,Ⅱcells of the alveolar appeared LB caving, and ceils intumescence,meanwhile, basilar membrane thickened, micro-vessel became weak and congested.The Changes of alveolar cells in each Treating teams was not obvious, but basilarmembrane thickened, micro-vessel became weak and congested. No changesappeared in the alveolar, basilar membrane and micro-vessel in the blank team.
6). Counting of BALF white cells and PMN: counting of white cells is obviouslylower in the treating teams than that of the model team(p＜0.05), compared withblank team, no obvious difference (p＞0.05), counting of white cells is obviouslyhigher in the model team than that of the blank team(p＜0.05). PMN cells countingresult is that the model team is obviously higher than that of other teams(p＜0.05).
7). Determination of TNF-a: TNF in the model team is higher than that of treatingteam, and treating team higher than that of blank team (p＜0.05).
8). Determination of IL-4:IL-4 in the model team is higher than that of treatingteam, and treating team higher than that of blank team (p＜0.05).
4. Conclusions
1). ALI/ARDS correlated with dysfunction of the descending and clearingfunctions of the lung. Impairment of clearing and descending function of the lung isthe pathological basis of ALI, and the phlegm stays in the chest is the key mechanism.
2). Formulas of exorcizing the phlegm and water can protect the lungorganization of ALI, and can relieve the pathological injury of the lung and theedema. It can obviously relieve TNF-a and the gathering of inflammatory ceils inthe lung organization, which proved that it can relieve the symptoms of ALl by lowerthe TNF-a and PMN. Meanwhile, it can restrict and protect the over-inflammatoryreaction, so, its effect mechanism probably exists in make the balance of adjustinginflammation and anti-inflammation. But, if it is effective to anti-inflammation factorsor inflammation factors has not been researched. But further research could beconsidered in the future.
3). To deal with diseases such as pulmonary emphysema, chronic pneumocardialdisease, Lobar Pneumonia and acute lung injury in TCM clinics, we can not only usethe method of descending and clearing the lung qi, but also the method of treat withphlegm. In the TCM clinics, when deal with the related diseases caused by upperrespiratory infection, such as acute lung injury, which has the main pathologicalcharacteristics of loses its descending and clearing function, we can choose themethod of exorcizing phlegm and water and recover the stools, thus to make thephlegm excreted and protect the lung qi. This method represents the basic experienceof TCM to deal with respiratory system diseases since Zhang zhongjing's time.
4). TCM and western medicine are the two different systems, the lung in theZangxiang theories of TCM can not be simply equaled to that of western medicine. So,in TCM clinics, when deal with lung system disease, we must focus on the integrationviews and the method of differentiating and treating syndromes according to Zangfutheories of TCM, which need to differentiate the exterior and interior, deficiency andexcess, cold and heat, but not just deal with bacteria or virus and just use the methodof dealing with inflammation and virus.
5. Creativity
1). Systematically clarified the key pathological mechanism of the lung when it losesits descending and clearing functions and specially mentioned the relationshipbetween the phlegm and it, thus, supply theoretical basis for using the method ofexorcizing phlegm and water to treat with ALI.
2). From the research, we expand the idea of how to carry out the study ondysfunction of the descending and clearing functions of the lung, and find a newentry point that some classical empirical Chinese medical formula will be used to treatALI/ARDS.
3). Using strong exorcizing and warm exorcizing method for the first time and discussed the effect and mechanism of TCM to deal with ALI and ARDS from thesphere of RIA, pathology and micro-structure, thus did important basic research forTCM to participate in dealing with acute severe respiratory system diseases andsupplied material for the coming clinical job.
引文
1．田秉坤．肺气虚证十年研究述评，现代中医药，2005，25(6)：55～57．
2．Boriosi G，Cantoni T．针灸经络在胚胎学方面对脏器形成的作用．国外医学中医中药分册，1981，3(3)：165～167．
3．毛宝龄，钱桂生，陈正堂等．急性呼吸窘迫综合征．北京，人民卫生出版社，2002，10．
4. Bone RC, Balk RA, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis: The ACCP/SCCM Consensus Conference Committee [J]. Chest, 1992, 101:1644～1655.
5. Reinhart K, Bayer O, et al. Markers of endothelial damage in organ dysfunction and sepsis. Crit Care Med, 2002,30:S302～S312.
6. Abraham E, Albert R, Amato M, et al. Round table conference: Acute lung injury. Am J Respir Crit Care Med, 1998,158:675～679.
7. Hack CE Zeerleder S. The endotheliumin sepsis: Source of and a target for inflammation. Crit Care Med, 2001,29:S21～S27.
8. Mavrommatis AC, Theodoridis T, Orfanidou A. Coagulation system and platelets are fully activated in uncomplicated sepsis. Crit Care Med, 2000,28:451～457.
9. Tschaikowsky K, Sagner S, Lehnert N, et al. Endothelin in septic patients: Effects on cardiovascular and renal function and its relationship to proinflammatory cytokines. Crit Care Med. 2000, 28: 1854～1860.
10. Brauner JS, Rohde LE, Clausell N. Circulating endothelin-1 and tumor necrosis factor-alpha: Early predictors of mortality in patients with septic shock. Intensive Care Med, 2000,26:305～313.
11. Idell S. Coagulation, fibrinolysis, and fibrin deposition in acute lung injury. Crit Care Med, 2003,31:S213～S220.
12. Kim KJ. Malik AB. Protein transport across the lung epithelial barrier. Am J Physiol Lung Cell Mol Physiol, 2003,284:L247～259.
13. Johnson MD, Widdicombe JH, Allen L, et al. Alveolar epithelial type Ⅰ cells contain transport proteins and transport sodium, supporting an active role for type Ⅰ cells in regulation of lung liquid homeostasis. Proc Natl Acad Sci USA, 2002,99:1996—1971.
14.Borok Z, Liebler JM, Lubman RL, et al. Na transport proteins are expressed by rat alveolar epithelial type I cells. Am J Physiol, 2002, 282:599.
15. Ridge KM, Olivera WG, Saldias F, et al. Alveolar Type 1 Cells Express the [alpha]- Na, K-ATPase, which Contributes to Lung Liquid Clearance. Circulation Res, 2003,92:453—460.
16. Ma T, Fukuda N, Song Y, et al. Lung fluid transport in aquaporin-5 knockout mice. J Clin Invest, 2000, 105: 93—100.
17. Shetty S, Idell S. Posttranscriptional regulation of plas minogen activator inhibitor-1 in human lung carcinoma cells in vitro. Am J Physiol Lung Cell Mol Physiol, 2000,278:L148-L156.
18. Creuwels LA, Van Golde LM, Haagsman HP. The pulmonary surfactant system: biochemical and clincical aspects. [J]. Lung, 1997,175:1— 39.
19.Lewis JF, Jobe AH. Surfactant and the adult respiratory distress syndrome [J]. Am J Respir Crit Care Med, 1993, 147: 218—233.
20. Goodman RB, Pugin J, Lee JS, et al. Cytokine-mediated inflammation in acute lung injury [J]. Cytokine Growth Factor Rev, 2003,14(6):523—535.
21. Ware LB, Matthay MA. The acute respiratory distress syndrome [J]. N Engl J Med, 2000, 342 (18): 1334-1349.
22. Suffredini AF, Reda D, Bands SM, et al. Effects of recombinant dimeric TNF receptor on inflammatory responses following intravenous endotoxin administration [J]. J Immunol, 1995,155:5038—5045.
23. Suter PM, Suter S, Girardin E, et al. High bronchoalveolar levels of tumor necrosis factor and its inhibitors, interleukin-1, interferon, and elastase, in patients with adult respiratory distress syndrome after trauma, shock, or sepsis. Am Rev Respir Dis, 1992,145:1016—1022.
24. Hyers TM, Tricomi SM, Dettenmeier PA, et al. Tumor necrosis factor levels in serum and bronchoalveolar lavage fluid of patients with the adult respiratory distress syndrome. Am J Respir Crit Care Med, 1991, 144:268-271.
25. 崔社怀,郭先键,钱桂生.肺表面张力与肿瘤坏死因子在急性低氧油酸性肺损
-59- 伤时的变化[J]．中国危重病急救医学，2000，12(1)：3～6．
26. Kang JL, Park W, Pask IS, et al. Inhaled nitric oxide attenuates acute lung injury via inhibition of nuclear factor-kappa B and inflammation. J Appl Physiol, 2002,92(2):795～801.
27. Gosain A, Gamelli RL. A Primer in Cytokines [J]. Burn Care Rehabil, 2005,26(2):7～12.
28. Li B, Toumier C, Divis RJ, et al. Regulation of IL-4 expression by the transcription factor Jun B during T helper cell differentiation [J].EM BO J, 1999, 18(2):420～432.
29. Christian MD, Danielle JD, Embolic pneumopathy induced by oleic acid [J] Am J Pathol, 1997,87:143～1581.
30. Donnelly SC, Strieter RM, Reid PT, et al. The association between mortality rates and decreased concentrations of interleukin-1 receptor antagonist in the lung fluids of patients with the adult respiratory distress syndrome. Am Intern Med, 1996,125:191～196.
31. Donnelly RP, Dickensheets H, Finbloom DS. The interleukin-10 signal transduction pathway and regulation of gene expression in mononuclear phagocytes. J Interferon Cytokine Res, 1999,19:563～573.
32. Bhatia M, Mocchhala S. Role of inflammatory mediators in the patho-Physiology of acute respiratory distress syndrome [J].Pathol, 2004, 202(2):145～156.
33. Shanley TP, Vasi N, Denenberg A. Regulation of chemokine expression By IL-IO in lung inflammation [J]. Cytokine, 2000,12(7):1054～1064.
34. Stuber F, Wrigge H, Schroeder S, et al. Kinetic and reversibility of mechanical ventilation-associated pulmonary and systemic inflammatory response in patients with acute lung injury [J]. Intensive Care Med 2002,28(7):834～841.
35．张明静，王兴勇，卢仲毅等．内毒素休克肺损伤与INF—γ／IL-4失衡．重庆医科大学学报，2004，29(1)：15～17．
36. No authors listed. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome [J].N Engl J Med, 2000,342(18):1301～1308.
37. Bernard GR, Artigas A, Brigham KL, et al. The American-Europe consensus conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination [J]. Am J Respir Crit Care Med, 1994,149: 818～824.
38．中华医学会呼吸病学分会．急性肺损伤／急性呼吸窘迫综合征的诊断标准(草案)．中华结核和呼吸杂志，2000，23：203．
39. Hotochkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med, 2003,348(2):138～150.
40. Luce JM. Acute lung injury and the acute respiratory distress syndrome [J]. Crit Care Med, 1998,26(2):369～376.
41. Gregory TJ, Steinberg KP, Spragy H, et al. Boring surfactant therapy for patients with acute respiratory distress syndrome[J]. Am J Respir Crit Care Med, 1997,155:1309～1315.
42. Bigatello LM, Zapol WM. New approaches to acute lung injury [J]. Bri J Anaesthesia, 1996,77:99～109.
43. Ameto MB, Barbas CS, Medeiros DM, et al. Effect of a protective ventilation strategy on mortality in the acute respiratory distress syndrome [J]. N Eng J Med, 1998,38(6):347～354.
44. Kopp R, Kuhlen R, Max M. Evidence-based medicine in the therapy of the acute respiratory distress syndrome. Intens Care Med, 2002,28(3):244～255.
45. Malarkkan N,. Snook.NJ, Lumb AB. New aspects of ventilation in acute lung injury. Anaesthesia, 2003, 58(7):647～667.
46. Haitsma J, Lachmann RA, Lchmann B. Open lung in ARDS. Acta Pharmacol Sin, 2003,24(12):1304～1307.
47．李明富，杨明钧，李堂圃等．中医对呼吸窘迫综合征的认识[J]．成都中医学院学报，1998，1：3．
48．薛芳．急性呼吸窘迫综合征和阳明腑实证[J]．辽宁中医杂志，1982，(4)：10．
49．耿耘，魏星．急性肺损伤、急性呼吸窘迫综合征的中医发病机理探讨[J]．江西中医药，2002，33(5)：11～12．
50．李金坡，周立群．针刺治疗脑水肿继发ARDS20例临床报告[J]．中国针灸，1992，12(5)：27．
51．阎田玉，龚明敏，林胡春等．活血化瘀治疗小儿病毒性肺炎的机理探讨与电镜观察[J]．中西医结合杂志，1984，4(3)：139～142．
52．李荣成，王今达，崔乃杰等．清心泻肝法治疗急性呼吸窘迫综合征22例临床观 察[J]．中西医结合实用临床急救，1997，4(10)：453．
53．叶汉兰，潘可欣．中西医结合治疗成人呼吸窘迫综合征20例[J]．北京中医药大学学报，1998，21(1)：48～49．
54．谭余庆，赵一，林启云等．青蒿提取物抗内毒素实验研究．中国中药杂志．1999，24(3)：166．
55．周晓红，翟佳，凌亦凌等．黄芩甙抗内毒素休克的实验研究．河北中医药学报，2001，16(1)：32．
56．刘红菊，李元桂，毛文光．中药热毒清对兔急性肺损伤的保护作用．中国中西医结合杂志，1996，16(11)：679～680．
57．刘青，熊家平．田美玉辨治急性呼吸窘迫综合征的经验[J]．湖北中医杂志，2000，22(4)：3～4．
58．刘树雄，金本炽，王新声．流行性出血热危重症研究．成人呼吸窘迫综合征[J]．陕西中医，1988，9(11)：484～485．
59．刁人政，邹建东，韦宏庆等．中西医结合治疗急性呼吸衰竭临床观察[J]．中国中医急症，1999，8(1)：9～10．
60．马超英，朱力平．流行性出血热常见危重症的中西医治疗体会[J]．中国中医急症，1994，3(4)：166～167．
61．耿耘，马超英．中西医结合治疗成人呼吸窘迫综合征临床观察[J]．江西中医学院学报，1997，9(1)：4，22．
62．张世范，高炜，徐克劲等．复方红景天防治急性肺损伤的前瞻性研究[J]．中华外科杂志，1999，37(4)：238～240．
63．蒋俊明，张瑞明，黄宗文等．益活清下法治疗重症胰腺炎-32例报告．中国中西医结合外科杂志，1994，15(1)：9．
64．吴伟胜，林宏．中药灌肠结合西药治疗急性呼吸窘迫综合征50例疗效观察．新中医，2004，36(5)：20～21．
65．江学成，张育才，徐德明等．大剂量654-2、硝普钠和丹参注射液辅助呼吸支持治疗ARDS[J]．徐州医学院学报，1999，19(4)：316～319．
66．籍文强，王泽惠，侯云生．成功抢救急性呼吸窘迫综合征体会[J]．现代中西医结合杂志，2001，10(11)：1048．
67．王今达，高天元，崔乃杰等．成人呼吸窘迫综合征43例临床分析[J]．中华医学杂志，1981，61(2)：74～78．
68．张杰，张玉兰，赵佳辉．中西医结合治疗脓毒败血症40例．黑龙江医学，2001，25(12)：930．
69．唐召力．川芎嗪注射液对实验性急性呼吸窘迫综合征动物模型的保护作用．现 代中西医结合杂志，2004，13(19)：2535～2537．
70．虎晓岷，尹文，梁继河等．川芎嗪对失血性休克再灌注肺损伤IκB激酶—β表达的调节干预研究．中国医师杂志，2005，7(2)：151～153．
71．史雪梅，黄亮，曹春水等．丹参酮IIA对大鼠急性肺损伤保护的实验研究．中华结核和呼吸杂志，2005，28(5)：350～351．
72．许梅，张国忠，闻心培等．丹参水提物对急性肺损伤保护作用的实验研究．中华结核和呼吸杂志，2004，27(2)：124～125．
73．陈畅，夏中元，孟庆涛．赤芍对大鼠内毒素性急性肺损伤保护作用机制的研究．中国急救医学，2005，25(1)：38～40．
74．李春盛，桂培春，何新华等．大黄对内毒素诱导急性肺损伤大鼠的保护作用．基础医学与临床，2001，21(1)：65～68．
75．宋秀琴，谢卫星，时兢等．大黄对急性呼吸窘迫综合征患者的治疗价值．现代诊断与治疗，2004，15(3)：293～294．
76．陈德昌，景炳文，杨兴易等．大黄对危重症患者系统炎症反应治疗作用的临床研究．中国危重病急救医学，2000，12(10)：584～587．
77．李新宇，景炳文，陈德昌等．大黄对大鼠肠缺血一再灌注所致肺损伤过程肿瘤坏死因子、一氧化氮和磷脂酶A2的影响．中国危重急救医学，1999，11(2)：71．
78．马超英，王宁，肖诚等．泻热通瘀、逐水扶正法对ARDS大鼠Bax和Bcl-2表达的影响．中国中医基础医学杂志，2005，11(2)：116～118．
79．耿耘，卫敏，马超英．泻热通瘀、逐水扶正法对ARDS大鼠Fas和Fas-L表达的影响．四川中医，2005，23(1)：13～14．
80．李澎涛，张娜，朱晓磊等．痰热清注射液抗内毒素所致急性肺损伤的实验研究．中国药学杂志，2005，40(7)：519～522．
81．李风雷，刘晓晴，柳青等．鱼腥草对油酸性急性肺损伤大鼠肺组织TNF—α表达的影响．中国病理生理杂志，2003，19(4)：547～548．
82．邱桐，江瑛，白娟等．红芪治疗呼吸窘迫综合征的实验研究．甘肃中医学院学报，1996，13(2)：48～50．
83．白娟，明彩荣，井欢等．红芪改善大鼠呼吸窘迫综合征的实验研究．中国中医药信息杂志，2003，10(2)：23～28．
84．李宏杰，孔小燕，景有伶等．黄芪抗缺血／再灌注后肺损伤机制的实验研究．山东医药，2005，45(12)：17～18．
85. Beciani M, Tedesco A. Cardiac troponin I(2nd generation assay)in chronic haemodialysis patients: prevalence and prognostic value[J]. Nephrol Dial Transplant, 2003, 18(5): 942～946.
86．吴飞跃，韩明，吕新生等．急性出血坏死性胰腺炎早期细菌、内毒素易位及甘遂治疗作用的实验研究．中国现代医学杂志，1996，6(5)：7～10．
87．郑维发，王莉，石枫等．芫花根乙醇提取物的抗炎活性．中草药，2004，35(11)：1262～1269．
88．吴葆杰．中药药理学，人民卫生出版社．1983：197．
89．左风．大戟提取物的抗炎作用．国外医学中医药分册，1998，20(3)：39．
90．孙颂三，赵燕洁，周佩卿，等．巴豆霜对泻下和免疫功能的影响．中草药．1993，24(5)：251．
91．孙颂三，赵燕洁，袁士琴．巴豆霜对抗炎、免疫、镇痛及致突变的影响．中药药理与临床．1993，9(3)：36．
92．应帮智，张卫华，张振凌．现代中西医结合杂志．2003，12(20)2155～2156．
93．王文俊，吴咸中，姚智等．中药有效成分对IL-2及IFN-γ分泌的影响．天津中医，1995，12(2)：23～24．
94．曲爱君，吴铁军，刘桂清，等．大黄对SIRS和MODS患者肿瘤坏死因子-α及白介素的影响．中国中西医结合急救杂志，2000，7(1)：43～45．
95．陈季武，胡天喜．大黄清除活性氧的作用．中国药学杂志，1996，31(8)：461．
96. Domenici-Lombardo L, Adembri C, Consalvo M, et al. Evolution of endotoxin induced acute lung injury in the rat [J]. Int J Exp Pathol, 1995,76:38～390.
97．陈军．内毒素性急性肺损伤的研究进展，国外医药抗生素分册．2005，26(3)：137～141．
98．尚东，王宝枝，毕伟等．全身炎性反应综合征时中性粒细胞凋亡的异常，大连医科大学学报．2006，28(3)：161～163．
99. Downey GP, Dong Q, Kruger J,et al. Regulation of neutrophi activation in acute lung injury [J]. Chest, 1999,116(1Suppl):46～54.
100. Lee WL, Downey GP. Neutrophil activation and acute lung injury [J].Curt Opin Crit Care, 2001,7(1):1～7.
101. Doerschuk CM, Mizgerd JP, Kubo H, et al. Adhension molecules and cellular biomechanica1 changes in acute lung injury [J]. Chest, 1999, 166(suppl1):37～43.
102. Kubo H, Graham L, Doyle NA, et al. Complement fragment-induced release of neutrophils from bone marrow and sequestration within pulmonary capillaries in rabbits [J]. Blood,1998,92:283～290.
103．吴英达，赵文胜，等．急性肺损伤发病机制研究新进展．浙江医学，2000， 22(4):249～251.
104. Zimmerman GA, Albertine KH, Carveth HJ, et al. Endothelia activation in ARDS[J]. Chest, 1999,116(1suppl):18～24.
105. Ward PA, Hunninghake GW. Lung in flammation and fibrosis [J]. Am J Respir Crit Care Med, 1998,157:123～129.
106. Lowell CA, Berton G. Integrin signal transduction in myeloid leukocytes [J]. J Leukoc Biol, 1999,65:313～320.
107. Williams MA, Solomkin JS. Integrin-mediated signaling in human neutrophil functioning [J]. J Leukoc Biol, 1999,65:725～736.
108. Fujishima S, Aikawa N. Neutrophil-mediated tissue injury and its modulation [J]. Intensive Care Med, 1995,21(3):277～285.
109. Mecklenburgh K, Murray J, Brazil T, et al. Role of neutrophil apoptosis in the resolution of pulmonary in flammation [J]. Monaldi Arc Chest Dis, 1999,54(4):345～349.
110．许淑云．细胞因子和急性肺损伤．国外医学呼吸系统分册，2001，21(4)：197～199．
111．刘红菊．肿瘤坏死因子在急性肺损伤发病机制中的作用．国外医学免疫学分册，1996，5：229～231．
112. Wan S, Leclerc JL, Vincent JL. Cytokine responses to cardiopulmonary bypass lessons leamed from cardiac transplantation [J]. Ann Thorac Surg, 1997,63:269～276.
113. Abraham E, Carmody A, Shenkar R, et al. Neutrophils as early immunologic effector in hemorrhage-or endotoxemia-induced acute lung injury [J]. Am J Physiol Lung Cell Mol Physiol, 2000, 279:1137～1145.
114. Song Y, Ao L, Calkins CM, et al. Differential Cardiopulmonary Recruitment of neutrophils during hemorrhagic shock: a role for ICAM-1 [J]. Shock, 2001,16:444～448.
115. Choi P, Reiser H. IL-4: role in disease and regulation of production [J]. Clin Exp Immunol, 1998,113(3):317～319.
116. Seder RA, Paul WE, Davis MM, et al. The preserce of interleukin-4 during in vitro priming determines the lymphokine-producing potential of CD4~+ T Cells from T Cell receptor transagenic mice [J]. J Exp Med, 1992,176(4):1091～1098.
117．钟晓方．干扰素-γ和白介素-4对RSV下呼吸道感染免疫病理中IgE调节作 用的研究．国外医学妇幼保健分册，2000，11(2)：77～80．
118. Zedler S, Bone RC, Baue AE, et al. T-cell reactivity and its predictive role in immunosuppression after burns[J]. Crit Care Med, 1999,27(1):66～721.
119．李洪霞，张进川，赵亚力，等．急性肺损伤大鼠TNF-α、IL-1β、IL-1ramRNA的表达及药物干预[J]．解放军医学杂志，2005，30(4)：306～309．
120. Dragana Jankovic, Liu ZG,. William CG, et al. Th1-and Th2-cell commitment during infectious disease: asymmetry in divergent pathways [J]. Trendsin Immunology. 2001,22(8):450～457.
2．Boriosi G，Cantoni T．针灸经络在胚胎学方面对脏器形成的作用．国外医学中医中药分册，1981，3(3)：165～167．
3．毛宝龄，钱桂生，陈正堂等．急性呼吸窘迫综合征．北京，人民卫生出版社，2002，10．
4. Bone RC, Balk RA, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis: The ACCP/SCCM Consensus Conference Committee [J]. Chest, 1992, 101:1644～1655.
5. Reinhart K, Bayer O, et al. Markers of endothelial damage in organ dysfunction and sepsis. Crit Care Med, 2002,30:S302～S312.
6. Abraham E, Albert R, Amato M, et al. Round table conference: Acute lung injury. Am J Respir Crit Care Med, 1998,158:675～679.
7. Hack CE Zeerleder S. The endotheliumin sepsis: Source of and a target for inflammation. Crit Care Med, 2001,29:S21～S27.
8. Mavrommatis AC, Theodoridis T, Orfanidou A. Coagulation system and platelets are fully activated in uncomplicated sepsis. Crit Care Med, 2000,28:451～457.
9. Tschaikowsky K, Sagner S, Lehnert N, et al. Endothelin in septic patients: Effects on cardiovascular and renal function and its relationship to proinflammatory cytokines. Crit Care Med. 2000, 28: 1854～1860.
10. Brauner JS, Rohde LE, Clausell N. Circulating endothelin-1 and tumor necrosis factor-alpha: Early predictors of mortality in patients with septic shock. Intensive Care Med, 2000,26:305～313.
11. Idell S. Coagulation, fibrinolysis, and fibrin deposition in acute lung injury. Crit Care Med, 2003,31:S213～S220.
12. Kim KJ. Malik AB. Protein transport across the lung epithelial barrier. Am J Physiol Lung Cell Mol Physiol, 2003,284:L247～259.
13. Johnson MD, Widdicombe JH, Allen L, et al. Alveolar epithelial type Ⅰ cells contain transport proteins and transport sodium, supporting an active role for type Ⅰ cells in regulation of lung liquid homeostasis. Proc Natl Acad Sci USA, 2002,99:1996—1971.
14.Borok Z, Liebler JM, Lubman RL, et al. Na transport proteins are expressed by rat alveolar epithelial type I cells. Am J Physiol, 2002, 282:599.
15. Ridge KM, Olivera WG, Saldias F, et al. Alveolar Type 1 Cells Express the [alpha]- Na, K-ATPase, which Contributes to Lung Liquid Clearance. Circulation Res, 2003,92:453—460.
16. Ma T, Fukuda N, Song Y, et al. Lung fluid transport in aquaporin-5 knockout mice. J Clin Invest, 2000, 105: 93—100.
17. Shetty S, Idell S. Posttranscriptional regulation of plas minogen activator inhibitor-1 in human lung carcinoma cells in vitro. Am J Physiol Lung Cell Mol Physiol, 2000,278:L148-L156.
18. Creuwels LA, Van Golde LM, Haagsman HP. The pulmonary surfactant system: biochemical and clincical aspects. [J]. Lung, 1997,175:1— 39.
19.Lewis JF, Jobe AH. Surfactant and the adult respiratory distress syndrome [J]. Am J Respir Crit Care Med, 1993, 147: 218—233.
20. Goodman RB, Pugin J, Lee JS, et al. Cytokine-mediated inflammation in acute lung injury [J]. Cytokine Growth Factor Rev, 2003,14(6):523—535.
21. Ware LB, Matthay MA. The acute respiratory distress syndrome [J]. N Engl J Med, 2000, 342 (18): 1334-1349.
22. Suffredini AF, Reda D, Bands SM, et al. Effects of recombinant dimeric TNF receptor on inflammatory responses following intravenous endotoxin administration [J]. J Immunol, 1995,155:5038—5045.
23. Suter PM, Suter S, Girardin E, et al. High bronchoalveolar levels of tumor necrosis factor and its inhibitors, interleukin-1, interferon, and elastase, in patients with adult respiratory distress syndrome after trauma, shock, or sepsis. Am Rev Respir Dis, 1992,145:1016—1022.
24. Hyers TM, Tricomi SM, Dettenmeier PA, et al. Tumor necrosis factor levels in serum and bronchoalveolar lavage fluid of patients with the adult respiratory distress syndrome. Am J Respir Crit Care Med, 1991, 144:268-271.
25. 崔社怀,郭先键,钱桂生.肺表面张力与肿瘤坏死因子在急性低氧油酸性肺损
-59- 伤时的变化[J]．中国危重病急救医学，2000，12(1)：3～6．
26. Kang JL, Park W, Pask IS, et al. Inhaled nitric oxide attenuates acute lung injury via inhibition of nuclear factor-kappa B and inflammation. J Appl Physiol, 2002,92(2):795～801.
27. Gosain A, Gamelli RL. A Primer in Cytokines [J]. Burn Care Rehabil, 2005,26(2):7～12.
28. Li B, Toumier C, Divis RJ, et al. Regulation of IL-4 expression by the transcription factor Jun B during T helper cell differentiation [J].EM BO J, 1999, 18(2):420～432.
29. Christian MD, Danielle JD, Embolic pneumopathy induced by oleic acid [J] Am J Pathol, 1997,87:143～1581.
30. Donnelly SC, Strieter RM, Reid PT, et al. The association between mortality rates and decreased concentrations of interleukin-1 receptor antagonist in the lung fluids of patients with the adult respiratory distress syndrome. Am Intern Med, 1996,125:191～196.
31. Donnelly RP, Dickensheets H, Finbloom DS. The interleukin-10 signal transduction pathway and regulation of gene expression in mononuclear phagocytes. J Interferon Cytokine Res, 1999,19:563～573.
32. Bhatia M, Mocchhala S. Role of inflammatory mediators in the patho-Physiology of acute respiratory distress syndrome [J].Pathol, 2004, 202(2):145～156.
33. Shanley TP, Vasi N, Denenberg A. Regulation of chemokine expression By IL-IO in lung inflammation [J]. Cytokine, 2000,12(7):1054～1064.
34. Stuber F, Wrigge H, Schroeder S, et al. Kinetic and reversibility of mechanical ventilation-associated pulmonary and systemic inflammatory response in patients with acute lung injury [J]. Intensive Care Med 2002,28(7):834～841.
35．张明静，王兴勇，卢仲毅等．内毒素休克肺损伤与INF—γ／IL-4失衡．重庆医科大学学报，2004，29(1)：15～17．
36. No authors listed. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome [J].N Engl J Med, 2000,342(18):1301～1308.
37. Bernard GR, Artigas A, Brigham KL, et al. The American-Europe consensus conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination [J]. Am J Respir Crit Care Med, 1994,149: 818～824.
38．中华医学会呼吸病学分会．急性肺损伤／急性呼吸窘迫综合征的诊断标准(草案)．中华结核和呼吸杂志，2000，23：203．
39. Hotochkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med, 2003,348(2):138～150.
40. Luce JM. Acute lung injury and the acute respiratory distress syndrome [J]. Crit Care Med, 1998,26(2):369～376.
41. Gregory TJ, Steinberg KP, Spragy H, et al. Boring surfactant therapy for patients with acute respiratory distress syndrome[J]. Am J Respir Crit Care Med, 1997,155:1309～1315.
42. Bigatello LM, Zapol WM. New approaches to acute lung injury [J]. Bri J Anaesthesia, 1996,77:99～109.
43. Ameto MB, Barbas CS, Medeiros DM, et al. Effect of a protective ventilation strategy on mortality in the acute respiratory distress syndrome [J]. N Eng J Med, 1998,38(6):347～354.
44. Kopp R, Kuhlen R, Max M. Evidence-based medicine in the therapy of the acute respiratory distress syndrome. Intens Care Med, 2002,28(3):244～255.
45. Malarkkan N,. Snook.NJ, Lumb AB. New aspects of ventilation in acute lung injury. Anaesthesia, 2003, 58(7):647～667.
46. Haitsma J, Lachmann RA, Lchmann B. Open lung in ARDS. Acta Pharmacol Sin, 2003,24(12):1304～1307.
47．李明富，杨明钧，李堂圃等．中医对呼吸窘迫综合征的认识[J]．成都中医学院学报，1998，1：3．
48．薛芳．急性呼吸窘迫综合征和阳明腑实证[J]．辽宁中医杂志，1982，(4)：10．
49．耿耘，魏星．急性肺损伤、急性呼吸窘迫综合征的中医发病机理探讨[J]．江西中医药，2002，33(5)：11～12．
50．李金坡，周立群．针刺治疗脑水肿继发ARDS20例临床报告[J]．中国针灸，1992，12(5)：27．
51．阎田玉，龚明敏，林胡春等．活血化瘀治疗小儿病毒性肺炎的机理探讨与电镜观察[J]．中西医结合杂志，1984，4(3)：139～142．
52．李荣成，王今达，崔乃杰等．清心泻肝法治疗急性呼吸窘迫综合征22例临床观 察[J]．中西医结合实用临床急救，1997，4(10)：453．
53．叶汉兰，潘可欣．中西医结合治疗成人呼吸窘迫综合征20例[J]．北京中医药大学学报，1998，21(1)：48～49．
54．谭余庆，赵一，林启云等．青蒿提取物抗内毒素实验研究．中国中药杂志．1999，24(3)：166．
55．周晓红，翟佳，凌亦凌等．黄芩甙抗内毒素休克的实验研究．河北中医药学报，2001，16(1)：32．
56．刘红菊，李元桂，毛文光．中药热毒清对兔急性肺损伤的保护作用．中国中西医结合杂志，1996，16(11)：679～680．
57．刘青，熊家平．田美玉辨治急性呼吸窘迫综合征的经验[J]．湖北中医杂志，2000，22(4)：3～4．
58．刘树雄，金本炽，王新声．流行性出血热危重症研究．成人呼吸窘迫综合征[J]．陕西中医，1988，9(11)：484～485．
59．刁人政，邹建东，韦宏庆等．中西医结合治疗急性呼吸衰竭临床观察[J]．中国中医急症，1999，8(1)：9～10．
60．马超英，朱力平．流行性出血热常见危重症的中西医治疗体会[J]．中国中医急症，1994，3(4)：166～167．
61．耿耘，马超英．中西医结合治疗成人呼吸窘迫综合征临床观察[J]．江西中医学院学报，1997，9(1)：4，22．
62．张世范，高炜，徐克劲等．复方红景天防治急性肺损伤的前瞻性研究[J]．中华外科杂志，1999，37(4)：238～240．
63．蒋俊明，张瑞明，黄宗文等．益活清下法治疗重症胰腺炎-32例报告．中国中西医结合外科杂志，1994，15(1)：9．
64．吴伟胜，林宏．中药灌肠结合西药治疗急性呼吸窘迫综合征50例疗效观察．新中医，2004，36(5)：20～21．
65．江学成，张育才，徐德明等．大剂量654-2、硝普钠和丹参注射液辅助呼吸支持治疗ARDS[J]．徐州医学院学报，1999，19(4)：316～319．
66．籍文强，王泽惠，侯云生．成功抢救急性呼吸窘迫综合征体会[J]．现代中西医结合杂志，2001，10(11)：1048．
67．王今达，高天元，崔乃杰等．成人呼吸窘迫综合征43例临床分析[J]．中华医学杂志，1981，61(2)：74～78．
68．张杰，张玉兰，赵佳辉．中西医结合治疗脓毒败血症40例．黑龙江医学，2001，25(12)：930．
69．唐召力．川芎嗪注射液对实验性急性呼吸窘迫综合征动物模型的保护作用．现 代中西医结合杂志，2004，13(19)：2535～2537．
70．虎晓岷，尹文，梁继河等．川芎嗪对失血性休克再灌注肺损伤IκB激酶—β表达的调节干预研究．中国医师杂志，2005，7(2)：151～153．
71．史雪梅，黄亮，曹春水等．丹参酮IIA对大鼠急性肺损伤保护的实验研究．中华结核和呼吸杂志，2005，28(5)：350～351．
72．许梅，张国忠，闻心培等．丹参水提物对急性肺损伤保护作用的实验研究．中华结核和呼吸杂志，2004，27(2)：124～125．
73．陈畅，夏中元，孟庆涛．赤芍对大鼠内毒素性急性肺损伤保护作用机制的研究．中国急救医学，2005，25(1)：38～40．
74．李春盛，桂培春，何新华等．大黄对内毒素诱导急性肺损伤大鼠的保护作用．基础医学与临床，2001，21(1)：65～68．
75．宋秀琴，谢卫星，时兢等．大黄对急性呼吸窘迫综合征患者的治疗价值．现代诊断与治疗，2004，15(3)：293～294．
76．陈德昌，景炳文，杨兴易等．大黄对危重症患者系统炎症反应治疗作用的临床研究．中国危重病急救医学，2000，12(10)：584～587．
77．李新宇，景炳文，陈德昌等．大黄对大鼠肠缺血一再灌注所致肺损伤过程肿瘤坏死因子、一氧化氮和磷脂酶A2的影响．中国危重急救医学，1999，11(2)：71．
78．马超英，王宁，肖诚等．泻热通瘀、逐水扶正法对ARDS大鼠Bax和Bcl-2表达的影响．中国中医基础医学杂志，2005，11(2)：116～118．
79．耿耘，卫敏，马超英．泻热通瘀、逐水扶正法对ARDS大鼠Fas和Fas-L表达的影响．四川中医，2005，23(1)：13～14．
80．李澎涛，张娜，朱晓磊等．痰热清注射液抗内毒素所致急性肺损伤的实验研究．中国药学杂志，2005，40(7)：519～522．
81．李风雷，刘晓晴，柳青等．鱼腥草对油酸性急性肺损伤大鼠肺组织TNF—α表达的影响．中国病理生理杂志，2003，19(4)：547～548．
82．邱桐，江瑛，白娟等．红芪治疗呼吸窘迫综合征的实验研究．甘肃中医学院学报，1996，13(2)：48～50．
83．白娟，明彩荣，井欢等．红芪改善大鼠呼吸窘迫综合征的实验研究．中国中医药信息杂志，2003，10(2)：23～28．
84．李宏杰，孔小燕，景有伶等．黄芪抗缺血／再灌注后肺损伤机制的实验研究．山东医药，2005，45(12)：17～18．
85. Beciani M, Tedesco A. Cardiac troponin I(2nd generation assay)in chronic haemodialysis patients: prevalence and prognostic value[J]. Nephrol Dial Transplant, 2003, 18(5): 942～946.
86．吴飞跃，韩明，吕新生等．急性出血坏死性胰腺炎早期细菌、内毒素易位及甘遂治疗作用的实验研究．中国现代医学杂志，1996，6(5)：7～10．
87．郑维发，王莉，石枫等．芫花根乙醇提取物的抗炎活性．中草药，2004，35(11)：1262～1269．
88．吴葆杰．中药药理学，人民卫生出版社．1983：197．
89．左风．大戟提取物的抗炎作用．国外医学中医药分册，1998，20(3)：39．
90．孙颂三，赵燕洁，周佩卿，等．巴豆霜对泻下和免疫功能的影响．中草药．1993，24(5)：251．
91．孙颂三，赵燕洁，袁士琴．巴豆霜对抗炎、免疫、镇痛及致突变的影响．中药药理与临床．1993，9(3)：36．
92．应帮智，张卫华，张振凌．现代中西医结合杂志．2003，12(20)2155～2156．
93．王文俊，吴咸中，姚智等．中药有效成分对IL-2及IFN-γ分泌的影响．天津中医，1995，12(2)：23～24．
94．曲爱君，吴铁军，刘桂清，等．大黄对SIRS和MODS患者肿瘤坏死因子-α及白介素的影响．中国中西医结合急救杂志，2000，7(1)：43～45．
95．陈季武，胡天喜．大黄清除活性氧的作用．中国药学杂志，1996，31(8)：461．
96. Domenici-Lombardo L, Adembri C, Consalvo M, et al. Evolution of endotoxin induced acute lung injury in the rat [J]. Int J Exp Pathol, 1995,76:38～390.
97．陈军．内毒素性急性肺损伤的研究进展，国外医药抗生素分册．2005，26(3)：137～141．
98．尚东，王宝枝，毕伟等．全身炎性反应综合征时中性粒细胞凋亡的异常，大连医科大学学报．2006，28(3)：161～163．
99. Downey GP, Dong Q, Kruger J,et al. Regulation of neutrophi activation in acute lung injury [J]. Chest, 1999,116(1Suppl):46～54.
100. Lee WL, Downey GP. Neutrophil activation and acute lung injury [J].Curt Opin Crit Care, 2001,7(1):1～7.
101. Doerschuk CM, Mizgerd JP, Kubo H, et al. Adhension molecules and cellular biomechanica1 changes in acute lung injury [J]. Chest, 1999, 166(suppl1):37～43.
102. Kubo H, Graham L, Doyle NA, et al. Complement fragment-induced release of neutrophils from bone marrow and sequestration within pulmonary capillaries in rabbits [J]. Blood,1998,92:283～290.
103．吴英达，赵文胜，等．急性肺损伤发病机制研究新进展．浙江医学，2000， 22(4):249～251.
104. Zimmerman GA, Albertine KH, Carveth HJ, et al. Endothelia activation in ARDS[J]. Chest, 1999,116(1suppl):18～24.
105. Ward PA, Hunninghake GW. Lung in flammation and fibrosis [J]. Am J Respir Crit Care Med, 1998,157:123～129.
106. Lowell CA, Berton G. Integrin signal transduction in myeloid leukocytes [J]. J Leukoc Biol, 1999,65:313～320.
107. Williams MA, Solomkin JS. Integrin-mediated signaling in human neutrophil functioning [J]. J Leukoc Biol, 1999,65:725～736.
108. Fujishima S, Aikawa N. Neutrophil-mediated tissue injury and its modulation [J]. Intensive Care Med, 1995,21(3):277～285.
109. Mecklenburgh K, Murray J, Brazil T, et al. Role of neutrophil apoptosis in the resolution of pulmonary in flammation [J]. Monaldi Arc Chest Dis, 1999,54(4):345～349.
110．许淑云．细胞因子和急性肺损伤．国外医学呼吸系统分册，2001，21(4)：197～199．
111．刘红菊．肿瘤坏死因子在急性肺损伤发病机制中的作用．国外医学免疫学分册，1996，5：229～231．
112. Wan S, Leclerc JL, Vincent JL. Cytokine responses to cardiopulmonary bypass lessons leamed from cardiac transplantation [J]. Ann Thorac Surg, 1997,63:269～276.
113. Abraham E, Carmody A, Shenkar R, et al. Neutrophils as early immunologic effector in hemorrhage-or endotoxemia-induced acute lung injury [J]. Am J Physiol Lung Cell Mol Physiol, 2000, 279:1137～1145.
114. Song Y, Ao L, Calkins CM, et al. Differential Cardiopulmonary Recruitment of neutrophils during hemorrhagic shock: a role for ICAM-1 [J]. Shock, 2001,16:444～448.
115. Choi P, Reiser H. IL-4: role in disease and regulation of production [J]. Clin Exp Immunol, 1998,113(3):317～319.
116. Seder RA, Paul WE, Davis MM, et al. The preserce of interleukin-4 during in vitro priming determines the lymphokine-producing potential of CD4~+ T Cells from T Cell receptor transagenic mice [J]. J Exp Med, 1992,176(4):1091～1098.
117．钟晓方．干扰素-γ和白介素-4对RSV下呼吸道感染免疫病理中IgE调节作 用的研究．国外医学妇幼保健分册，2000，11(2)：77～80．
118. Zedler S, Bone RC, Baue AE, et al. T-cell reactivity and its predictive role in immunosuppression after burns[J]. Crit Care Med, 1999,27(1):66～721.
119．李洪霞，张进川，赵亚力，等．急性肺损伤大鼠TNF-α、IL-1β、IL-1ramRNA的表达及药物干预[J]．解放军医学杂志，2005，30(4)：306～309．
120. Dragana Jankovic, Liu ZG,. William CG, et al. Th1-and Th2-cell commitment during infectious disease: asymmetry in divergent pathways [J]. Trendsin Immunology. 2001,22(8):450～457.