祛风宣肺方治疗感染后咳嗽的疗效观察及对气道神经源性炎症的作用研究
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摘要
研究背景
感染后咳嗽患者以刺激性干咳,咽痒,无痰或少量白粘痰为主要临床表现,且多可因吸入油烟、粉尘等刺激性气味、冷空气、语速加快、说笑等诱发或加重,许多学者认为感染后咳嗽与咳嗽敏感性增高密切相关,而气道神经源性炎症又是引起咳嗽敏感性增高的重要机制。目前对该病尚无特异性治疗方法。因此,临床实践中正确认识感染后咳嗽、给予规范的诊治,对于提高疗效、缩短病程、改善患者生活质量尤为重要。
从感染后咳嗽的临床症状特点可以看出,其反映了“风之善行数变”、“无风不作痒”“风性挛急”等风邪致病特点,现代医家多将其归属于“外感咳嗽”范畴,多以“风咳”论治,认为病因虽有六淫致病之说,但以风邪为主导；病变部位主要在肺；总的病机为“风邪犯肺、肺气失宣”；辨证虽有风寒、风热、风燥、甚至兼夹证之别,但以风邪犯肺者居多；治疗主以“祛风宣肺”。
感染后咳嗽的研究目前呈现以下特点：该病临床常见,但误诊率高,临床中存在着认识的盲区和诊治的不规范性。中医辨证论治该病积累了大量的临床经验,取得了显著的疗效,但对于该病的研究多以中药临床疗效观察总结为主,针对该病的病因病机方面的探讨较少,实验研究更是罕见。
目的
本研究以风邪致咳理论为基础,从气道神经源性炎症调控机制角度出发,以咳嗽敏感性增高为切入点,采用祛风宣肺方为干预手段,通过临床研究,探讨感染后咳嗽风邪犯肺证的病证特点,并观察祛风宣肺方治疗感染后咳嗽的疗效；通过动物实验,研究祛风宣肺方对气道神经源性炎症的干预作用及作用环节。
方法
临床研究方面,选取感染后咳嗽风邪犯肺证患者为研究对象,通过临床问卷调查的方式,收集患者的临床信息,包括咳嗽诱发或加重因素、咳嗽出现的时间、持续时间、发作或加重的时间、入组前诊疗情况等,探讨感染后咳嗽风邪犯肺证的病证特点；并通过与阿斯美、孟鲁司特钠分组对照研究,观察祛风宣肺方治疗感染后咳嗽的疗效。
实验研究方面,应用咳嗽动物模型,采用随机对照的方法,分为空白对照组、模型组、中药治疗组(祛风宣肺方组)、西药对照组(孟鲁司特钠组),通过对咳嗽频次、气道反应性、肺组织病理(光镜下及电镜下)、肥大细胞的数量、分布及脱颗粒百分率、肺组织磷酸化P38MAPK蛋白的表达及平均积分光密度等检测,研究祛风宣肺方对气道神经源性炎症的干预作用及作用环节。
结果
1.临床研究
(1)一般资料：按照纳入标准,纳入病例90例,最终完成观察病例84例,脱落病例6例。祛风宣肺方组30例,阿斯美组28例,孟鲁司特钠组26例。其中男性28例,占33.33%,女性56例,占66.67%。18-44岁青年组患者最多,占54.76%；45-59岁中年组患者次之,占25.00%；60岁以上的老年组患者最少,占20.24%。
(2)临床信息：84例观察病例中,有明显的诱发或加重因素的病例80例,占95.24%,其中油烟、粉尘等刺激性气味、冷空气、语速加快、说笑等因素均是主要的诱发或加重因素。咳嗽出现的平均时间为感染后(3.01±1.72)天,其中在感染后3天内出现咳嗽症状者最多,有39例,占46.43%。咳嗽持续的平均时间为(23.17±12.50)天,其中持续3～8周者居多,有52例,占61.90%。咳嗽夜间发作或加重的有47例,占55.95%；白天发作或加重的有25例,占29.76%。该病入组前常被误诊为慢性支气管炎、上呼吸道感染、慢性咽炎等,误诊为慢性支气管炎支者最多,占46.43%。大部分患者在入组前经过抗生素、止咳镇咳药物、茶碱或β2受体激动剂或多种中成药物治疗,但效果均不明显。入组患者中淡红舌、薄白苔的正常舌象居多,脉象以弦脉为主,伴有滑脉、细脉。
(3)疗效评价：在疾病疗效方面,祛风宣肺方组咳嗽总有效率为90.00%,日间咳嗽总有效率为93.33%,夜间咳嗽总有效率为86.67%；阿斯美组咳嗽总有效率为85.71%,日间咳嗽总有效率为82.14%,夜间咳嗽总有效率为78.57%；孟鲁司特钠组咳嗽总有效率为80.77%,日间咳嗽总有效率为76.92%,夜间咳嗽总有效率为84.61%；结果显示祛风宣肺方治疗感染后咳嗽,无论是日间咳嗽还是夜间咳嗽,均优于西药对照组,差异有统计学意义(P<0.05)。在咳嗽缓解及消失时间方面,祛风宣肺方组的咳嗽缓解时间为(3.400±1.329)天、消失时间为(7.421±1.575)天；阿斯美组的咳嗽缓解时间为(4.565±1.343)天、消失时间为(8.583±0.9003)天；孟鲁司特钠组咳嗽缓解时间为(5.217±1.413)天、消失时间为(8.900±0.9944)天,结果显示祛风宣肺方在缩短病程方面优于西药对照组,差异有统计学意义(P<0.05)。在中医证候疗效方面,治疗后中医证候总积分,祛风宣肺方组为(5.000±3.494)分,阿斯美组为(11.00±4.595)分,孟鲁司特钠组为(11.62±6.530)分,结果显示祛风宣肺方在改善感染后咳嗽症状方面优于西药对照组,差异有统计学意义(P<0.05)。通过视觉模拟评分,制成咳嗽、咽痒、咳嗽遇风加重等症状随时间变化趋势图,结果显示祛风宣肺方在起效时间及改善程度方面均优于西药对照组。在咳嗽对生活质量的影响方面,治疗后祛风宣肺方组总积分为(79.80±7.237)分,阿斯美组为(70.93±4.363)分,孟鲁司特钠组为(68.54±3.252)分,结果显示祛风宣肺方在改善感染后咳嗽患者生活质量方面优于西药对照组,差异有统计学意义(P<0.05)。
2.实验研究
(1)咳嗽频次：模型组咳嗽最多,其次由多到少依次为西药对照组、中药治疗组、空白对照组,差异有统计学意义(P<0.05)。
(2)气道反应性：四组分别于不同时相依次给予氯化乙酰胆碱(ACh)静脉注射后(剂量按照递增顺序为400μg/kg体重、600μg/kg体重、800μg/kg体重、1000μg/kg体重),结果显示四组Re均增高,其中模型组最高,其次由高到低依次为西药对照组、中药治疗组、空白对照组,差异有统计学意义(P<0.05)。
(3)肺组织病理：在光镜下,四组均见不同程度的支气管管腔狭窄、上皮细胞脱落、黏膜皱襞增厚、支气管黏膜层及黏膜下层、肺泡腔内及周围等炎症细胞浸润,病理变化程度由重到轻依次为模型组、西药对照组、中药治疗组、空白对照组。在电镜下,四组均可见不同程度的肺毛细血管增厚、基底膜增厚、肺泡炎症浸润及Ⅱ型肺泡上皮细胞结构改变,病理变化程度由重到轻依次为模型组、西药对照组、中药治疗组、空白对照组。
(4)肺组织肥大细胞数量、分布及脱颗粒百分率：经甲苯胺蓝染色后,四组均可见肥大细胞浸润,主要集中在气管粘膜下及血管周围。模型组肥大细胞数量及脱颗粒百分率均最多,其次由多到少依次为西药对照组、中药治疗组、空白对照组,且差异均有统计学意义(P<0.05)。
(5)肺组织磷酸化p38MAPK蛋白的表达及平均积分光密度：采用SP法免疫组织化学技术,光镜下四组均有P38MAPk的阳性表达,主要表达于支气管、肺泡、肺毛细血管等周围。模型组阳性表达程度最强,其次由强到弱依次为西药对照组、中药治疗组、空白对照组。采用Image-Pro Plus6.0软件系统计算各组磷酸化p38MAPK平均积分光密度(Average IOD value/per field),模型组最高,其次由高到低依次为西药对照组、中药治疗组、空白对照组,差异均有统计学意义(P<0.05)。
结论
1.临床研究
(1)感染后咳嗽风邪犯肺证的病证特点：感染后咳嗽风邪犯肺证临床常见,女性更为多见,中青年组发病率最高。有明显的诱发或加重因素,其中油烟、粉尘等刺激性气味、冷空气、语速加快、说笑等因素为最主要因素；咳嗽症状出现时间短,持续时间长；昼夜可发,多以夜间加重。“风邪”为其主要病因,病变脏腑主要在肺,“风邪犯肺、肺气失宣”为其基本病机。
(2)祛风宣肺方对感染后咳嗽的疗效：祛风宣肺方在治疗感染后咳嗽方面具有显著疗效,可以改善症状、缩短病程,改善患者生活质量。
2.实验研究
祛风宣肺方可能通过修复气道损伤、抑制肥大细胞脱颗粒引起的炎症介质的释放及影响磷酸化P38MAPK蛋白的表达水平等几个方面,从而减轻气道神经源性炎症,降低咳嗽敏感性,发挥对感染后咳嗽的治疗作用。
Background
According to main clinical manifestations of patients with cough post infectious as stimulating dry cough, throat itching, without phlegm or a small amount of white phlegm, which can be induced or aggravated by inhaling excitant odour such as oil smoke and powder dust, inhaling cold air, speeding up and laughing, many scholars expect that cough post infectious is closely related to increased cough reflex sensitivity, while airway neurogenic inflammation is an important mechanism of increased cough reflex sensitivity. There is no specific treatment for cough post infectious. Therefore it is particularly important for clinicians to correctly understand cough post infectious, disseminate the standardization of diagnosis and treatment, improve the curative effect, shorten the length of the disease and improve the quality of life for pat ients.
The characteristics of cough post infectious reflect wind evil pathogenic characteristics, such as "be good at moving and changing","itch","urgent", so it belongs to the exogenous cough category and should be treated basing on syndrome differentiation from "wind cough". The causes of cough post infectious include six exogenous factors, but which is dominated by the wind evil. Pathological change is mainly in the lung. The pathogenesis is wind evil invading the lung and pulmonary qi impairment. Expelling wind and releasing pulmonary treatment is a main treatment.
The present study of cough post infectious shows the following characteristics:cough post infectious is a kind of clinical common but high misdiagnosis rate diseases, there is blind spots of clinical understanding and nonstandard diagnosis and treatment. At present, the research of cough post infectious is mainly to TCM clinical curative effect observation, lack of discussions of etiology and pathogenesis and experimental studies researches.
Objective
Based on the theory of wind cough, from the perspective of airway neurogenic inflammation regulatory mechanism, as the breakthrough point of increased cough reflex sensi t ivi ty, us ing intervention by expelling wind and re leas ing pulmonary formula, through clinical experiment, we discuss syndrome characteristics of cough post infectious and observe clinical curative effects of expelling wind and releasing pulmonary formula on cough post infectious; through animal ex per iment, we s tudy the effect of expelling wi nd and releasing pulmonary formula on airway neurogenic inflammation.
Methods
In clinical research, by taking the patients with wind evil invading the lung syndrome of cough post infectious as the research object, through clinical questionnaire, collecting clinical information, including induced or aggravated factors, the time of cough to appear, last and attack even aggravate, the diagnosis and treatment before grouped, we discuss syndrome characteristics of cough post infectious; by grouping with control for comparing with asmeton and montelukas t, we observe clinical cura t i ve effects of expelling wind and re leas ing pulmonary formula on cough post infectious.
In experimental study, a randomized control study, using cough animal model, divided into the blank control group, the model group, the traditional chinese medicine group(expelling wind and releasing pulmonary formula group) and the western medicine control group (montelukast group), by detect ing cough frequency, airway responsiveness, lung tissue pathology (under light and electron microscopy), number, distribution and degranulation percentage of mast cell, and phosphoryla ted p38MAPK protein express ion of lung tissue,we study the effect of expelling wind and releasing pulmonary formula on airway neurogenic inflammation.
Results
1. Clinical Research
(1)General information:According to the inclusive criteria, we accepted90cases of patients with wind evil invading the lung syndrome of cough post infectious, eventually completed84cases, failed off6cases. There arc30cases in expelling wind and releasing pulmonary group,28cases in asmeton group and26cases in montelukast group.28men cases account for33.33%,56women cases account for66.67%. Young patients from18to44account for54.76%, middle-aged pa t ients from45to59account for25.00%and older pat ients over60years account for20.24%.
(2)Clinical information:In eventually completed84cases, there are80cases with obvious induced or aggravated factors, accounting for95.24%, most main factors such as inhaling excitant odour such as oil smoke and powder dust, inhaling cold air, speeding up and laughing. An average time of the time of cough post infectious to appear is (3.01±1.72) days after infection, while cough symptoms Within3days is most, accounting for46.43%. An average time of the time of cough to last is (23.17±12.50) days, while lasting3-8weeks is most,52cases accounting for61.90%. Cough attacks even aggravates at night in47cases, accounting for55.95, while during the day in25cases, accounting for29.76%. Cough post infectious are usually misdiagnosed as chronic bronchitis, infection of the upper respiratory tract and chronic pharyngitis, etc. The misdiagnosis rate as chronic bronchitis is most, accounting for46.43%. The majori ty of pat ients are treated by ant ibiot ics, cough medicine, theophylline, beta2agonists or a variety of traditional chinese medicines, but the effect is not obvious. The normal tongue such as reddish tongue with thin white moss is most, string pulse accompanied by smooth pulse or thready pulse is most.
(3) Clinical curative effects evaluat ion:In the aspect of disease clinical curative effect, in expelling wind and releasing pulmonary group, the total effective rate of cough is90.00%, the total effective rate of daytime cough is93.33%, the total effect ive ra te of nighttime cough is86.67%; in a sine ton group, the total effect ive rate of cough is85.71%, the total effect ive rate of dayt ime cough is82.14%, the total effective rate of nighttime cough is78.57%; in montelukast group, the total effective rate of cough is80.77%, the total effective rate of daytime cough i s76.92%, the total effect ive rate of night t ime cough is84.61%; the results show that expelling wind and releasing pulmonary formula is superior to western medicine control groups in the treatment of cough post infectious, whether daytime or nighttime cough cough, with statistical significance (P<0.05). In the rel ief and disappearance time of cough, in expel ling wind and releasing pulmonary group, the relief time of cough is (3.400±1.329) days, the disappearance time of cough is (7.421±1.575) days; in asmeton group, therel ief time of cough is (4.565±1.343) days, the disappearance time of cough is (8.583±0.9003)days; in montelukast group, the rel ief time of cough is(5.217±1.413) days, the disappearance time of cough is (8.900±0.9944) days; the results show that expelling wind and releasing pulmonary formula is superior to western medicine control groups in shortening the period of treatment, with statistical significance (P<0.05). In the aspect of TCM syndrome curat ive effect, in expelling wind and releasing pulmonary group, TCM syndrome total score after treatment is (5.000±3.494); in asmeton group, TCM syndrome total score after treatment is(11.00±4.595); inmonlclukast group, TCMsyndrome total score after t reatment is (11.62±6.530),the result shows t ha t expell ing wind and re leas ing pulmonary formula is superior to western medicine control groups in improving the symptoms of cough post infectious,with statistical significance (P<0.05). By visual analgesia score, making trend chart of symptoms vary with time, all results show that expelling wind and releasing pulmonary formula is superior to western medicine control groups in the effect-acting period and the degree of improvement. In the aspect of cough influence on the quality of life, in expelling wind and releasing pulmonary group, total score after treatment is (79.80±7.237); in asmeton group, total score after treatment is (70.93±4.363); in montelukas t group, total score after treatment is (68.54±3.252), the result shows that expelling wind and releasing pulmonary formula is superior to western medicine control groups in improv ing quality of life of pat ien Is with cough post infectious, with statistical significance (P<0.05).
2. Experimental Study
(1) Cough frequency:In four groups, cough frequency in the model group is the most, the second order from more to less is the western medicine control group, the traditional Chinese medicine treatment group and the blank control group, with statistical significance(P<0.05).
(2)Airway responsiveness:Given different doses of chlorinated acetylcholine (ACh) intravenous injection at different time phase respectively in four groups (the dose of ACh in an increasing order respectively is400ug/kg,600ug/kg,800ug/kg and1000ug/kg), all results show that in four groups, the airway resistance (Re) in the model group is the highest, the second order from high to low is the western medicine control group, the traditional Chinese medicine treatment group and the blank control group, with statistical signif icance (P<0.05).
(3)Lung tissue pathology:Under light microscopy, there are different degrees pathological changes in bronchostenosis, desquamation of epithelial cells, thickening of bronchial mucosa dupl icature, the condi t ion of inflammatory cell infiltration in bronchial mucosa, submucosa layer, the alveolar cavity and the surrounding,etc. The order of pathological changes from heavy to light is the model group, the western medicine control group, the traditional Chinese medicine treatment group and the blank control group. Under electron microscopy, there are different degrees pathological changes in thickening of pulmonary capillary, thickening of basement membrane, inflammatory cell infiltration in alveolar and the structure changes of alveolar type II cell, etc. The order of pathological changes from heavy to light is the model group, the western medicine control group, the traditional chinese medicine treatment group and the blank control group.
(4)Number, distribution and degranulation percentage of mast cell:By toluid ine blue staining, mast cellinfiltrat ion is visible in four groups, mainly concentrating under the tracheal mucous membrane and around the blood vessels. The number and degranulation percentage of mast cell in the model group is the most, the second order from high to low is the western medicine control group, the traditional chinese medicine treatment group and the blank control group, with statistical significance (P<0.05).
(5) Phosphorylated p38MAPK protein expression and average IOD value of lung tissue:By SP immunohistochemistry technique, under light microscopy, the pos i t ive express ion of Phosphorylated P38MAPk is visible in four groups, mainly expressing around bronchus, alveolar and pulmonary capillaries, etc.The positive expression level of Phosphorylated p38MAPK protein in the model group is the strongest, the second order from strong to weak is the western medicine control group, the traditional Chinese medicine treatment group and the blank control group. By Image-Pro Plus6.0software system, calculating phosphorylated p38MAPK average IOD value in each group, the value in the model group is the highest, the second order from high to low is the western medicine control group, the traditional Chinese medicine treatment group and the blank control group, with statistical significance (P<0.05).
Conclusion:
1. Clinical Research
(1)Syndrome characteristics of cough post infectious:wind evil invading the lung syndrome of cough post infectious is very common in clinic, is more likely to occur in females and young patients. There are obvious induced or aggravated factors, most main factors such as inhaling excitant odour such as oil smoke and powder dust, inhaling cold air, speeding up and laughing. The time of cough post infectious to appear is short, but last longer. Cough attacks even aggravates during the day or at night, but more severe at night. Wind evil is the ma in cause, pathological change i s ma inly in the lung, the hasic pathogencsis is wind evil invading the lung and pulmonary qi impairment.
(2) Clinical curative effects of expelling wind and releasing pulmonary formula on cough post infectious:Expelling wind and releasing pulmonary formula has significant clinical curative effects on cough post infectious, such as improving symptoms, short teping period of t reatment and improving quality of life of patients with cough post infectious.
2. Experimental Study
Expelling wind and releasing pulmonary formula may repaire damaged airway, inhibit the release of inflammatory mediators caused by mas t cell degranulat ion, influence the expression level of phosphoryla ted p38MAPK protein,etc. Accordingly, expelling wind and releasing pulmonary formula may inhibit airway neurogenic inflammation, and then reduce increased cough reflex sensitivity, further play a role of treatment on cough post infectious.
感染后咳嗽患者以刺激性干咳,咽痒,无痰或少量白粘痰为主要临床表现,且多可因吸入油烟、粉尘等刺激性气味、冷空气、语速加快、说笑等诱发或加重,许多学者认为感染后咳嗽与咳嗽敏感性增高密切相关,而气道神经源性炎症又是引起咳嗽敏感性增高的重要机制。目前对该病尚无特异性治疗方法。因此,临床实践中正确认识感染后咳嗽、给予规范的诊治,对于提高疗效、缩短病程、改善患者生活质量尤为重要。
从感染后咳嗽的临床症状特点可以看出,其反映了“风之善行数变”、“无风不作痒”“风性挛急”等风邪致病特点,现代医家多将其归属于“外感咳嗽”范畴,多以“风咳”论治,认为病因虽有六淫致病之说,但以风邪为主导；病变部位主要在肺；总的病机为“风邪犯肺、肺气失宣”；辨证虽有风寒、风热、风燥、甚至兼夹证之别,但以风邪犯肺者居多；治疗主以“祛风宣肺”。
感染后咳嗽的研究目前呈现以下特点：该病临床常见,但误诊率高,临床中存在着认识的盲区和诊治的不规范性。中医辨证论治该病积累了大量的临床经验,取得了显著的疗效,但对于该病的研究多以中药临床疗效观察总结为主,针对该病的病因病机方面的探讨较少,实验研究更是罕见。
目的
本研究以风邪致咳理论为基础,从气道神经源性炎症调控机制角度出发,以咳嗽敏感性增高为切入点,采用祛风宣肺方为干预手段,通过临床研究,探讨感染后咳嗽风邪犯肺证的病证特点,并观察祛风宣肺方治疗感染后咳嗽的疗效；通过动物实验,研究祛风宣肺方对气道神经源性炎症的干预作用及作用环节。
方法
临床研究方面,选取感染后咳嗽风邪犯肺证患者为研究对象,通过临床问卷调查的方式,收集患者的临床信息,包括咳嗽诱发或加重因素、咳嗽出现的时间、持续时间、发作或加重的时间、入组前诊疗情况等,探讨感染后咳嗽风邪犯肺证的病证特点；并通过与阿斯美、孟鲁司特钠分组对照研究,观察祛风宣肺方治疗感染后咳嗽的疗效。
实验研究方面,应用咳嗽动物模型,采用随机对照的方法,分为空白对照组、模型组、中药治疗组(祛风宣肺方组)、西药对照组(孟鲁司特钠组),通过对咳嗽频次、气道反应性、肺组织病理(光镜下及电镜下)、肥大细胞的数量、分布及脱颗粒百分率、肺组织磷酸化P38MAPK蛋白的表达及平均积分光密度等检测,研究祛风宣肺方对气道神经源性炎症的干预作用及作用环节。
结果
1.临床研究
(1)一般资料：按照纳入标准,纳入病例90例,最终完成观察病例84例,脱落病例6例。祛风宣肺方组30例,阿斯美组28例,孟鲁司特钠组26例。其中男性28例,占33.33%,女性56例,占66.67%。18-44岁青年组患者最多,占54.76%；45-59岁中年组患者次之,占25.00%；60岁以上的老年组患者最少,占20.24%。
(2)临床信息：84例观察病例中,有明显的诱发或加重因素的病例80例,占95.24%,其中油烟、粉尘等刺激性气味、冷空气、语速加快、说笑等因素均是主要的诱发或加重因素。咳嗽出现的平均时间为感染后(3.01±1.72)天,其中在感染后3天内出现咳嗽症状者最多,有39例,占46.43%。咳嗽持续的平均时间为(23.17±12.50)天,其中持续3～8周者居多,有52例,占61.90%。咳嗽夜间发作或加重的有47例,占55.95%；白天发作或加重的有25例,占29.76%。该病入组前常被误诊为慢性支气管炎、上呼吸道感染、慢性咽炎等,误诊为慢性支气管炎支者最多,占46.43%。大部分患者在入组前经过抗生素、止咳镇咳药物、茶碱或β2受体激动剂或多种中成药物治疗,但效果均不明显。入组患者中淡红舌、薄白苔的正常舌象居多,脉象以弦脉为主,伴有滑脉、细脉。
(3)疗效评价：在疾病疗效方面,祛风宣肺方组咳嗽总有效率为90.00%,日间咳嗽总有效率为93.33%,夜间咳嗽总有效率为86.67%；阿斯美组咳嗽总有效率为85.71%,日间咳嗽总有效率为82.14%,夜间咳嗽总有效率为78.57%；孟鲁司特钠组咳嗽总有效率为80.77%,日间咳嗽总有效率为76.92%,夜间咳嗽总有效率为84.61%；结果显示祛风宣肺方治疗感染后咳嗽,无论是日间咳嗽还是夜间咳嗽,均优于西药对照组,差异有统计学意义(P<0.05)。在咳嗽缓解及消失时间方面,祛风宣肺方组的咳嗽缓解时间为(3.400±1.329)天、消失时间为(7.421±1.575)天；阿斯美组的咳嗽缓解时间为(4.565±1.343)天、消失时间为(8.583±0.9003)天；孟鲁司特钠组咳嗽缓解时间为(5.217±1.413)天、消失时间为(8.900±0.9944)天,结果显示祛风宣肺方在缩短病程方面优于西药对照组,差异有统计学意义(P<0.05)。在中医证候疗效方面,治疗后中医证候总积分,祛风宣肺方组为(5.000±3.494)分,阿斯美组为(11.00±4.595)分,孟鲁司特钠组为(11.62±6.530)分,结果显示祛风宣肺方在改善感染后咳嗽症状方面优于西药对照组,差异有统计学意义(P<0.05)。通过视觉模拟评分,制成咳嗽、咽痒、咳嗽遇风加重等症状随时间变化趋势图,结果显示祛风宣肺方在起效时间及改善程度方面均优于西药对照组。在咳嗽对生活质量的影响方面,治疗后祛风宣肺方组总积分为(79.80±7.237)分,阿斯美组为(70.93±4.363)分,孟鲁司特钠组为(68.54±3.252)分,结果显示祛风宣肺方在改善感染后咳嗽患者生活质量方面优于西药对照组,差异有统计学意义(P<0.05)。
2.实验研究
(1)咳嗽频次：模型组咳嗽最多,其次由多到少依次为西药对照组、中药治疗组、空白对照组,差异有统计学意义(P<0.05)。
(2)气道反应性：四组分别于不同时相依次给予氯化乙酰胆碱(ACh)静脉注射后(剂量按照递增顺序为400μg/kg体重、600μg/kg体重、800μg/kg体重、1000μg/kg体重),结果显示四组Re均增高,其中模型组最高,其次由高到低依次为西药对照组、中药治疗组、空白对照组,差异有统计学意义(P<0.05)。
(3)肺组织病理：在光镜下,四组均见不同程度的支气管管腔狭窄、上皮细胞脱落、黏膜皱襞增厚、支气管黏膜层及黏膜下层、肺泡腔内及周围等炎症细胞浸润,病理变化程度由重到轻依次为模型组、西药对照组、中药治疗组、空白对照组。在电镜下,四组均可见不同程度的肺毛细血管增厚、基底膜增厚、肺泡炎症浸润及Ⅱ型肺泡上皮细胞结构改变,病理变化程度由重到轻依次为模型组、西药对照组、中药治疗组、空白对照组。
(4)肺组织肥大细胞数量、分布及脱颗粒百分率：经甲苯胺蓝染色后,四组均可见肥大细胞浸润,主要集中在气管粘膜下及血管周围。模型组肥大细胞数量及脱颗粒百分率均最多,其次由多到少依次为西药对照组、中药治疗组、空白对照组,且差异均有统计学意义(P<0.05)。
(5)肺组织磷酸化p38MAPK蛋白的表达及平均积分光密度：采用SP法免疫组织化学技术,光镜下四组均有P38MAPk的阳性表达,主要表达于支气管、肺泡、肺毛细血管等周围。模型组阳性表达程度最强,其次由强到弱依次为西药对照组、中药治疗组、空白对照组。采用Image-Pro Plus6.0软件系统计算各组磷酸化p38MAPK平均积分光密度(Average IOD value/per field),模型组最高,其次由高到低依次为西药对照组、中药治疗组、空白对照组,差异均有统计学意义(P<0.05)。
结论
1.临床研究
(1)感染后咳嗽风邪犯肺证的病证特点：感染后咳嗽风邪犯肺证临床常见,女性更为多见,中青年组发病率最高。有明显的诱发或加重因素,其中油烟、粉尘等刺激性气味、冷空气、语速加快、说笑等因素为最主要因素；咳嗽症状出现时间短,持续时间长；昼夜可发,多以夜间加重。“风邪”为其主要病因,病变脏腑主要在肺,“风邪犯肺、肺气失宣”为其基本病机。
(2)祛风宣肺方对感染后咳嗽的疗效：祛风宣肺方在治疗感染后咳嗽方面具有显著疗效,可以改善症状、缩短病程,改善患者生活质量。
2.实验研究
祛风宣肺方可能通过修复气道损伤、抑制肥大细胞脱颗粒引起的炎症介质的释放及影响磷酸化P38MAPK蛋白的表达水平等几个方面,从而减轻气道神经源性炎症,降低咳嗽敏感性,发挥对感染后咳嗽的治疗作用。
Background
According to main clinical manifestations of patients with cough post infectious as stimulating dry cough, throat itching, without phlegm or a small amount of white phlegm, which can be induced or aggravated by inhaling excitant odour such as oil smoke and powder dust, inhaling cold air, speeding up and laughing, many scholars expect that cough post infectious is closely related to increased cough reflex sensitivity, while airway neurogenic inflammation is an important mechanism of increased cough reflex sensitivity. There is no specific treatment for cough post infectious. Therefore it is particularly important for clinicians to correctly understand cough post infectious, disseminate the standardization of diagnosis and treatment, improve the curative effect, shorten the length of the disease and improve the quality of life for pat ients.
The characteristics of cough post infectious reflect wind evil pathogenic characteristics, such as "be good at moving and changing","itch","urgent", so it belongs to the exogenous cough category and should be treated basing on syndrome differentiation from "wind cough". The causes of cough post infectious include six exogenous factors, but which is dominated by the wind evil. Pathological change is mainly in the lung. The pathogenesis is wind evil invading the lung and pulmonary qi impairment. Expelling wind and releasing pulmonary treatment is a main treatment.
The present study of cough post infectious shows the following characteristics:cough post infectious is a kind of clinical common but high misdiagnosis rate diseases, there is blind spots of clinical understanding and nonstandard diagnosis and treatment. At present, the research of cough post infectious is mainly to TCM clinical curative effect observation, lack of discussions of etiology and pathogenesis and experimental studies researches.
Objective
Based on the theory of wind cough, from the perspective of airway neurogenic inflammation regulatory mechanism, as the breakthrough point of increased cough reflex sensi t ivi ty, us ing intervention by expelling wind and re leas ing pulmonary formula, through clinical experiment, we discuss syndrome characteristics of cough post infectious and observe clinical curative effects of expelling wind and releasing pulmonary formula on cough post infectious; through animal ex per iment, we s tudy the effect of expelling wi nd and releasing pulmonary formula on airway neurogenic inflammation.
Methods
In clinical research, by taking the patients with wind evil invading the lung syndrome of cough post infectious as the research object, through clinical questionnaire, collecting clinical information, including induced or aggravated factors, the time of cough to appear, last and attack even aggravate, the diagnosis and treatment before grouped, we discuss syndrome characteristics of cough post infectious; by grouping with control for comparing with asmeton and montelukas t, we observe clinical cura t i ve effects of expelling wind and re leas ing pulmonary formula on cough post infectious.
In experimental study, a randomized control study, using cough animal model, divided into the blank control group, the model group, the traditional chinese medicine group(expelling wind and releasing pulmonary formula group) and the western medicine control group (montelukast group), by detect ing cough frequency, airway responsiveness, lung tissue pathology (under light and electron microscopy), number, distribution and degranulation percentage of mast cell, and phosphoryla ted p38MAPK protein express ion of lung tissue,we study the effect of expelling wind and releasing pulmonary formula on airway neurogenic inflammation.
Results
1. Clinical Research
(1)General information:According to the inclusive criteria, we accepted90cases of patients with wind evil invading the lung syndrome of cough post infectious, eventually completed84cases, failed off6cases. There arc30cases in expelling wind and releasing pulmonary group,28cases in asmeton group and26cases in montelukast group.28men cases account for33.33%,56women cases account for66.67%. Young patients from18to44account for54.76%, middle-aged pa t ients from45to59account for25.00%and older pat ients over60years account for20.24%.
(2)Clinical information:In eventually completed84cases, there are80cases with obvious induced or aggravated factors, accounting for95.24%, most main factors such as inhaling excitant odour such as oil smoke and powder dust, inhaling cold air, speeding up and laughing. An average time of the time of cough post infectious to appear is (3.01±1.72) days after infection, while cough symptoms Within3days is most, accounting for46.43%. An average time of the time of cough to last is (23.17±12.50) days, while lasting3-8weeks is most,52cases accounting for61.90%. Cough attacks even aggravates at night in47cases, accounting for55.95, while during the day in25cases, accounting for29.76%. Cough post infectious are usually misdiagnosed as chronic bronchitis, infection of the upper respiratory tract and chronic pharyngitis, etc. The misdiagnosis rate as chronic bronchitis is most, accounting for46.43%. The majori ty of pat ients are treated by ant ibiot ics, cough medicine, theophylline, beta2agonists or a variety of traditional chinese medicines, but the effect is not obvious. The normal tongue such as reddish tongue with thin white moss is most, string pulse accompanied by smooth pulse or thready pulse is most.
(3) Clinical curative effects evaluat ion:In the aspect of disease clinical curative effect, in expelling wind and releasing pulmonary group, the total effective rate of cough is90.00%, the total effective rate of daytime cough is93.33%, the total effect ive ra te of nighttime cough is86.67%; in a sine ton group, the total effect ive rate of cough is85.71%, the total effect ive rate of dayt ime cough is82.14%, the total effective rate of nighttime cough is78.57%; in montelukast group, the total effective rate of cough is80.77%, the total effective rate of daytime cough i s76.92%, the total effect ive rate of night t ime cough is84.61%; the results show that expelling wind and releasing pulmonary formula is superior to western medicine control groups in the treatment of cough post infectious, whether daytime or nighttime cough cough, with statistical significance (P<0.05). In the rel ief and disappearance time of cough, in expel ling wind and releasing pulmonary group, the relief time of cough is (3.400±1.329) days, the disappearance time of cough is (7.421±1.575) days; in asmeton group, therel ief time of cough is (4.565±1.343) days, the disappearance time of cough is (8.583±0.9003)days; in montelukast group, the rel ief time of cough is(5.217±1.413) days, the disappearance time of cough is (8.900±0.9944) days; the results show that expelling wind and releasing pulmonary formula is superior to western medicine control groups in shortening the period of treatment, with statistical significance (P<0.05). In the aspect of TCM syndrome curat ive effect, in expelling wind and releasing pulmonary group, TCM syndrome total score after treatment is (5.000±3.494); in asmeton group, TCM syndrome total score after treatment is(11.00±4.595); inmonlclukast group, TCMsyndrome total score after t reatment is (11.62±6.530),the result shows t ha t expell ing wind and re leas ing pulmonary formula is superior to western medicine control groups in improving the symptoms of cough post infectious,with statistical significance (P<0.05). By visual analgesia score, making trend chart of symptoms vary with time, all results show that expelling wind and releasing pulmonary formula is superior to western medicine control groups in the effect-acting period and the degree of improvement. In the aspect of cough influence on the quality of life, in expelling wind and releasing pulmonary group, total score after treatment is (79.80±7.237); in asmeton group, total score after treatment is (70.93±4.363); in montelukas t group, total score after treatment is (68.54±3.252), the result shows that expelling wind and releasing pulmonary formula is superior to western medicine control groups in improv ing quality of life of pat ien Is with cough post infectious, with statistical significance (P<0.05).
2. Experimental Study
(1) Cough frequency:In four groups, cough frequency in the model group is the most, the second order from more to less is the western medicine control group, the traditional Chinese medicine treatment group and the blank control group, with statistical significance(P<0.05).
(2)Airway responsiveness:Given different doses of chlorinated acetylcholine (ACh) intravenous injection at different time phase respectively in four groups (the dose of ACh in an increasing order respectively is400ug/kg,600ug/kg,800ug/kg and1000ug/kg), all results show that in four groups, the airway resistance (Re) in the model group is the highest, the second order from high to low is the western medicine control group, the traditional Chinese medicine treatment group and the blank control group, with statistical signif icance (P<0.05).
(3)Lung tissue pathology:Under light microscopy, there are different degrees pathological changes in bronchostenosis, desquamation of epithelial cells, thickening of bronchial mucosa dupl icature, the condi t ion of inflammatory cell infiltration in bronchial mucosa, submucosa layer, the alveolar cavity and the surrounding,etc. The order of pathological changes from heavy to light is the model group, the western medicine control group, the traditional Chinese medicine treatment group and the blank control group. Under electron microscopy, there are different degrees pathological changes in thickening of pulmonary capillary, thickening of basement membrane, inflammatory cell infiltration in alveolar and the structure changes of alveolar type II cell, etc. The order of pathological changes from heavy to light is the model group, the western medicine control group, the traditional chinese medicine treatment group and the blank control group.
(4)Number, distribution and degranulation percentage of mast cell:By toluid ine blue staining, mast cellinfiltrat ion is visible in four groups, mainly concentrating under the tracheal mucous membrane and around the blood vessels. The number and degranulation percentage of mast cell in the model group is the most, the second order from high to low is the western medicine control group, the traditional chinese medicine treatment group and the blank control group, with statistical significance (P<0.05).
(5) Phosphorylated p38MAPK protein expression and average IOD value of lung tissue:By SP immunohistochemistry technique, under light microscopy, the pos i t ive express ion of Phosphorylated P38MAPk is visible in four groups, mainly expressing around bronchus, alveolar and pulmonary capillaries, etc.The positive expression level of Phosphorylated p38MAPK protein in the model group is the strongest, the second order from strong to weak is the western medicine control group, the traditional Chinese medicine treatment group and the blank control group. By Image-Pro Plus6.0software system, calculating phosphorylated p38MAPK average IOD value in each group, the value in the model group is the highest, the second order from high to low is the western medicine control group, the traditional Chinese medicine treatment group and the blank control group, with statistical significance (P<0.05).
Conclusion:
1. Clinical Research
(1)Syndrome characteristics of cough post infectious:wind evil invading the lung syndrome of cough post infectious is very common in clinic, is more likely to occur in females and young patients. There are obvious induced or aggravated factors, most main factors such as inhaling excitant odour such as oil smoke and powder dust, inhaling cold air, speeding up and laughing. The time of cough post infectious to appear is short, but last longer. Cough attacks even aggravates during the day or at night, but more severe at night. Wind evil is the ma in cause, pathological change i s ma inly in the lung, the hasic pathogencsis is wind evil invading the lung and pulmonary qi impairment.
(2) Clinical curative effects of expelling wind and releasing pulmonary formula on cough post infectious:Expelling wind and releasing pulmonary formula has significant clinical curative effects on cough post infectious, such as improving symptoms, short teping period of t reatment and improving quality of life of patients with cough post infectious.
2. Experimental Study
Expelling wind and releasing pulmonary formula may repaire damaged airway, inhibit the release of inflammatory mediators caused by mas t cell degranulat ion, influence the expression level of phosphoryla ted p38MAPK protein,etc. Accordingly, expelling wind and releasing pulmonary formula may inhibit airway neurogenic inflammation, and then reduce increased cough reflex sensitivity, further play a role of treatment on cough post infectious.
引文
[1]晁恩祥.“风咳”证治探要[J].江苏中医药,2008,40(7)：8-9.
[2]王辛秋,张洪春,陈燕.晁恩祥辨治“风咳”经验介绍[J].北京中医药,2010,29(9)：667-668.
[3]史利卿,刘志国,席宁,等.宣肺止咳方治疗呼吸道病毒感染后咳嗽临床观察[J].北京中医药大学学报(中医临床版),2004,11(3)：9-10.
[4]罗社文,李友林,吴继全,等.疏风宣肺法治疗咳嗽变异性哮喘的临床疗效研究[J].中华中医药杂志,2007,22(9)：609-612.
[5]李际强,韩云,张忠德,等.晃恩祥治疗风咳的临床经验探析[J].江西中医药,2010,41(7)：13-14.
[6]赵建磊,汪震.秦艽、徐长卿配伍治疗风咳浅议[J].中国中医急症,2012,21(3)：421-422.
[7]周兰.感染后咳嗽辨治心得[J].蚌埠医学院学报.2003,28(6)：533-534.
[8]王胜.胡国俊辨治感染后咳嗽经验介绍[J].辽宁中医药大学学报.2011,13(1)：112-114.
[9]王跃锋.郦永平教授治疗感染后咳嗽经验[J].中医临床研究,2011,3(7)：73.
[10]杨如玺,路德华.中西医结合治疗感冒后咳嗽效果观察[J].现代中西医结合杂志,2005,14(14)：1854-1855.
[11]臧敏.止嗽散配合西药治疗上呼吸道感染后咳嗽48例[J].中国中医急症.2010,19(4)：664-665.
[12]国家中医药管理局‘十一五’重点专科协作组咳嗽(感冒后咳嗽或感染后咳嗽)诊疗方案[M].国家中医药管理局.2012.
[13]郑磊.王真治疗四时风咳经验浅析[J].浙江中医杂志.2011,46(12)：866-867.
[14]章马兰.感冒后咳嗽中医证候学观察[D].北京中医药大学：2008.
[15]温绍惠.慢性咳嗽风咳证的证因规律研究[D].北京中医药大学：2011.
[16]陈文喜,高凌云,郑伟彬,等.中医辨治感染后咳嗽30例[J].福建中医药,2009,40(4)：26-27.
[17]李鸿泓.九味止咳汤治疗感染后咳嗽50例临床观察[J].北京中医药,2009,28(6)：447-448.
[18]张天嵩,杨蓓林.定咳汤治疗感染后咳嗽的临床研究[J].辽宁中医杂志,2007,34(9)：1275-1276.
[19]李际强,韩云,张忠德,等.晁恩祥治疗风咳的临床经验探析[J].江西中医药,2010,41(331)：13-14.
[20]张艳萍,晁燕.苏黄止咳胶囊治疗感冒后咳嗽的随机对照研究[J].中国中西医结合杂志,2008,28(8)：698-701.
[21]张奇男,王春平.运用晁恩祥教授验方治疗风咳80例[J].中国中医急症杂志,2008,17(5)：687-688.
[22]马建岭,史利卿,席宁.祛风宣肺颗粒治疗感染后咳嗽60例临床观察[J].北京中医药大学学报,2007,30(1)：67-69.
[23]孙学刚,马克林.祛风止咳汤治疗外感咳嗽178例[J].陕西中医学院学报,2005,8(5)：26-27.
[24]梁会贤.仙鱼镇咳汤治疗风邪犯肺型咳嗽110例临床观察[J].湖北中医杂志,2000,22(1)：20.
[25]杨小乐.感咳灵汤治疗外感咳嗽120例的体会[J].现代医药卫生,2005,21(8)：993-994.
[26]张书明.从风咳论治咳嗽变异性哮喘临床观察[J].吉林中医药,2004,24(9)：18.
[27]宋先仁,朱淼.祛风清肺法治疗风咳30例临床观察[J].湖北中医药大学学报,2011,13(4)：58.
[1]杨萌,林江涛.浅谈感染后咳嗽[J].中国实用内科杂志,2007,27(2)：144-145.
[2]中华医学会呼吸病学分会哮喘学组.咳嗽的诊断与治疗指南[J].中华结核与呼吸杂志,2005,28(11)：741.
[3]中华医学会呼吸病学分会哮喘学组.咳嗽的诊断与治疗指南[J].中华结核与呼吸杂志,2009,8(9)：609.
[4]赖克方,钟南山.慢性咳嗽[M].北京：人民卫生出版社,2008.
[5]赖克方,钟南山.加强不明原因慢性咳嗽的病因诊断研究[J].中华内科杂志,2003,42(7)：449.
[6]Zimmerman B, Silverman FS, Tarlo SM,et al. Induced Sputum:comparison of post infectious cough with allergic asthma in children[J]. Allergy Clin Immunol,200,105:405-499.
[7]张齐武,许苏丹.43例感染后咳嗽患者气道反应性检测结果[J].临床肺科杂志,2009,14(2)：241.
[8]Irwin RS, Madison JM. Anatomical diagnostic protocol in evaluating chronic cough with specific reference to gastroesophageal reflux disease[J].Am Med,2000,108 (suppl4a):126-130.
[9]Sekizawa K, Jia YX, Ebihara T, et a 1. Role of substance P in cough [J]. Pulm Pharmacol,1996,9(5-6):323-328.
[10]Braman ss. Post-infectious cough:ACCP evidence-based clinical practice guidelines. Chest.2006,129 (1 Suppl):138S-146S.
[11]Walsh JJ, Dietlein LF, Low FN,etal. Bronchotracheal response in human influenza:Type A, asian strain, as studied by light and electron microscopic examination of bronchoscopic biopsies [J].Arch Intern Med, 1961,108:376-388.
[12]齐彦芝,王增粉.呼吸道感染后咳嗽与咳嗽变异性哮喘患者痰炎性细胞和气道反应特点及其意义[J].河北医药,2009,31(15)：1917-1918.
[13]李靖,罗炜,杨灵,等.急性上呼吸道感染后咳嗽的合理用药[J].新医学,2007,38(3)：161-163.
[14]时翠芹,余莉,魏为利,等.气道炎症在上气道咳嗽综合征发生中的作用.中国呼吸与危重症监护杂志,2009,8(3)：256-258.
[15]Schm id L D, Rabe KF. The role of leukotrienes in the regulation of tone and responsiveness in isolated human airways[J]. Am J Respir Crit Care Med,2000,161(2 Pt 2):S62-S67.
[16]李明华.哮喘病治疗学[M].北京：人民卫生出版社,1998：201-225.
[17]Burki NK, Isreal ME. Leukotriene receptor antagonist and bronchial asthma. Chest,1996,275(4):931-936.
[18]Matsuse H, Hirose H, Tsuchida T, et al. Effects of respiratory syncytial virus infection on dendritic cells and cys-teinyl leukotrienes in lung tissues of a murine model of asthma[J]. Allergol In,2007,56 (2):165.
[19]王华,陈艳波,张孔.白三烯受体拮抗剂对哮喘患者血清IL-5水平及气道高反应性的影响[J].实用医学杂志,2005,21(21)：2392-2395.
[20]Birring SS, Parker D, Brightling CE,et al.Induced sputum inflame-matory mediator concentrations in chronic cough. Am J Respir Crit Care Med,2004,169(1):15-19.
[21]Moreaux B, NemmarA, Vincke G, et al. Role of substance P and tachykinin receptor antagonists in citric acid-induced cough in pigs[J].Eur J Pharmacol,2000,408:305-312.
[22]陈如冲,刘春丽,罗炜,等.感冒后咳嗽敏感性及气道神经源性炎症改变[J].中国实用内科杂志,2007,27(9)：674-679.
[23]韦杰.气道神经源性炎症介质在感染后慢性咳嗽发病机制中的作用[J].求恩军医学院学报,2012,10(5)：373-374.
[24]Jacoby DB. Pathophysiology of airway viral infect ions[J]. Pulm Pharmacol,2004,17(6):333-336.
[25]Carr MJ, Hunter DD, Jacoby DB, et al. Expression of tachykinins in nonnociceptive vagal afferent neurons during respiratory viral infection in guinea pigs[J].Am J Respir Crit Care Med,2002,165 (8):1071-1075.
[26]Lee LY.Respiratory sensations evoked by activation of bronchopulmonary C-fibers[J]. Respir Physiol Neurobiol,2009,167 (1):26-35.
[27]Cheng PingHu, Katrin Wed-Beer, Alexander Auais, et al. Nerve growth factor and nerve growth factor receptors in respiratory syncytial virus-infected lungs [J]. Am J Physiol Lung Cell Mol Physiol,2002,283(2):494-502.
[28]李东培,才丽平,方秀斌.哮喘豚鼠下呼吸道及内脏传入部位NGF表达的研究[J].解剖学报,2002,33(4)：350-354.
[29]De-Vries A, Dessing MC, Engels F, etal. Nerve growth factor induces a Neurokinin-1 receptor-mediated airway hyperresponsiveness in guinea Pigs. Am J Respir Crit Care Med,1999,159 (5Pt1):1541-1544.
[30]Kolch W. The regulation of the Ras/Raf/MEK/ERK pathway by protein interactions[J]. Biochem J,2000,351:289-305.
[31]汤渝玲,胡成平,冯俊涛,等.神经生长因子调控哮喘神经源性炎症Ras/MAPK信号转导通路.中南大学学报(临床版),2006,31(3)：319-325.
[32]Stephens RD, Loeb D, Copeland T, et al. Trk receptors use redundant signal transduction pathways involving SHC and PLC gamma 1 to mediate NGF responses [J]. Neuron,1994,12:691-705.
[33]李锋,周新.p38丝裂原活化蛋白激酶与慢性气道疾病[J].中华哮喘杂志,2010,4(4)：291-294.
[34]郑仰明,李昌崇,张维溪,等.哮喘气道重塑大鼠中磷酸化p38丝裂原活化蛋白激酶的表达对黏液细胞增殖的影响及布地奈德的干预作用[J].中国临床药理学与治疗学,2009,14(8)：866-871.
[35]NayakA.A review of montelukast in the treatment of asthma all daller-gicrhini t is. ExpeaOpinPhannacother,2002,5(3):679.
[36]美国胸科医师学会.ACCP.200年咳嗽循证指南[C].Chest,2006.
[37]Spector SL,Tan RA. Effetiveness of montelukast in the treatment of cough variant asthma. Ann Allergy Immunol,2004,93 (3):232-236.
[38]Kopriva F Sobolova L, Szotkowska J, et al.Treatment of chronic cough in children with montelukast,a leukotriene receptor antagonist [J].Asthma,2004,41(7):715-720.
[39]朱利清,况九龙,邓在春.孟鲁司特治疗感染后咳嗽的临床分析[J].中国药房,2011,22(22)：2067-2068.
[40]韩雪梅.孟鲁司特钠治疗感染后咳嗽疗效观察[J].海南医学,2011,22(8)：53-55.
[41]李英,周明浩.阿斯美治疗上呼吸道感染后咳嗽[J].医学信息(临床医学),2010,23(2)：499-500.
[42]黄艳红.复方甲氧那明治疗感染后咳嗽的疗效观察[J].当代医学,2012,18(13)：77-78.
[43]张丹参.诱发咳嗽动物模型方法及评价[J].神经药理学报.2011,1(2)：35-41.
[44]吴继光,黄漾,王岚等.不同类型支气管扩张剂对致敏豚鼠模型咳嗽反应的作用 [J].2008,29(5)：15-18.
[45]邱忠民,刘琦,郭德华,等.缓激肽β2受体拮抗剂对致敏豚鼠模型咳嗽反应性的影响[J].中华结核和呼吸杂志,2002,25(2).
[46]吕寒静,邱忠民,杨忠民,等.气道速激肽在卵蛋白致敏豚鼠模型咳嗽反应中的作用[J].中国病理生理杂志,2005,21(9)：1744-1747.
[1]中华医学会呼吸病学分会哮喘学组.咳嗽的诊断与治疗指南(2009版)[J].中华结核和呼吸杂志,2009,32(6)：407-413.
[2]周仲瑛.《中医内科学》[M].北京：中国中医药出版社,2003：71-78.
[3]国家中医药管理局.中华人民共和国中医药行业标准.中医内科.中医病证诊断疗效标准[M].南京：南京大学出版社,1994：1-2.
[4]国家中医药管理局医政司.24个专业105个病种中医诊疗方案(合订本试行版).肺病科中医诊疗方案.咳嗽(感冒后咳嗽或感染后咳嗽)诊疗方案[M].国家中医药管理局医政司,2012：71-78.
[5]郑筱萸.中药新药临床研究指导原则(试行).北京：中国医药科技出版社,2002：54-58.
[6]赖克方,钟南山.慢性咳嗽[M].北京：人民卫生出版社,2008：1.
[7]Wassmer G, Jorres RA, Heinrich J. et al. The association between baseline lung function and bronchial responsiveness to methacho-1ine [J].Eur J Med Res,1997,2 (2):47-54.
[8]甘慧娟,朱文锋.基于聚类分析的不同年龄咳嗽患者证素特征[R].朱文锋学术思想研讨会暨中医诊断师资班30周年纪念大会.2012.
[9]Little JW, Hall WJ, Douglas RG Jr,et al.Airway hyper reactivity and peripheral airway dysfunction in influenza A infect ion. Am Rev Respir Dis,1978,118(2):295-303.
[10]雷英.社区慢性咳嗽误诊误治21例分析[J].中国误诊学志,2009,9(21)：5153-5154.
[11]毕玉田,何庆华.咳嗽的评定方法及其临床应用[J].中华结核和呼吸杂志,2009,32(6)：460-462.
[1]赖克方,钟南山.慢性咳嗽[M].北京：人民卫生出版社,2008：39-40.
[2]陆月明.咳嗽的动物模型研究方法[J].临床肺科杂志,2007,12(5)：480-481.
[3]张丹参.诱发咳嗽动物模型方法及评价[J].神经药理学报.2011,1(2)：35-41.
[4]Matsuoka T, Hirata M, Tanaka H, et al.Prosrag land in D2 as A mediator of allergic asthma[J]. Science,2000,287(5460): 2013-2017.
[5]MATSUSE H, HIROSE H, TSUCHIDA T, et al. Effects of respiratory-syncytial virus infection on dendritic cells and cysteinyleukoltrienes in lung tissues of a murine model of asthma [J]. Allergol Int,2007,56 (2):165.
[6]汤渝玲,胡成平,冯俊涛,等.神经生长因子调控哮喘神经源性炎症Ras/MAPK信号转导通路.中南大学学报(临床版),2006,31(3)：319-325.
[7]李锋,周新.p38丝裂原活化蛋白激酶与慢性气道疾病[J].中华哮喘杂志(电子版),2010,4(4)：291-294.
[8]Han J, Lee JD, Bibbs L, et al. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science,1994,256(5173):808-811.
[9]黄翠萍,杨和平,张珍祥,等.p38蛋白激酶对支气管哮喘大鼠Th2类细胞因子表达的调控[J].中国病理生理杂志,2006,22(10)：311-313.
[2]王辛秋,张洪春,陈燕.晁恩祥辨治“风咳”经验介绍[J].北京中医药,2010,29(9)：667-668.
[3]史利卿,刘志国,席宁,等.宣肺止咳方治疗呼吸道病毒感染后咳嗽临床观察[J].北京中医药大学学报(中医临床版),2004,11(3)：9-10.
[4]罗社文,李友林,吴继全,等.疏风宣肺法治疗咳嗽变异性哮喘的临床疗效研究[J].中华中医药杂志,2007,22(9)：609-612.
[5]李际强,韩云,张忠德,等.晃恩祥治疗风咳的临床经验探析[J].江西中医药,2010,41(7)：13-14.
[6]赵建磊,汪震.秦艽、徐长卿配伍治疗风咳浅议[J].中国中医急症,2012,21(3)：421-422.
[7]周兰.感染后咳嗽辨治心得[J].蚌埠医学院学报.2003,28(6)：533-534.
[8]王胜.胡国俊辨治感染后咳嗽经验介绍[J].辽宁中医药大学学报.2011,13(1)：112-114.
[9]王跃锋.郦永平教授治疗感染后咳嗽经验[J].中医临床研究,2011,3(7)：73.
[10]杨如玺,路德华.中西医结合治疗感冒后咳嗽效果观察[J].现代中西医结合杂志,2005,14(14)：1854-1855.
[11]臧敏.止嗽散配合西药治疗上呼吸道感染后咳嗽48例[J].中国中医急症.2010,19(4)：664-665.
[12]国家中医药管理局‘十一五’重点专科协作组咳嗽(感冒后咳嗽或感染后咳嗽)诊疗方案[M].国家中医药管理局.2012.
[13]郑磊.王真治疗四时风咳经验浅析[J].浙江中医杂志.2011,46(12)：866-867.
[14]章马兰.感冒后咳嗽中医证候学观察[D].北京中医药大学：2008.
[15]温绍惠.慢性咳嗽风咳证的证因规律研究[D].北京中医药大学：2011.
[16]陈文喜,高凌云,郑伟彬,等.中医辨治感染后咳嗽30例[J].福建中医药,2009,40(4)：26-27.
[17]李鸿泓.九味止咳汤治疗感染后咳嗽50例临床观察[J].北京中医药,2009,28(6)：447-448.
[18]张天嵩,杨蓓林.定咳汤治疗感染后咳嗽的临床研究[J].辽宁中医杂志,2007,34(9)：1275-1276.
[19]李际强,韩云,张忠德,等.晁恩祥治疗风咳的临床经验探析[J].江西中医药,2010,41(331)：13-14.
[20]张艳萍,晁燕.苏黄止咳胶囊治疗感冒后咳嗽的随机对照研究[J].中国中西医结合杂志,2008,28(8)：698-701.
[21]张奇男,王春平.运用晁恩祥教授验方治疗风咳80例[J].中国中医急症杂志,2008,17(5)：687-688.
[22]马建岭,史利卿,席宁.祛风宣肺颗粒治疗感染后咳嗽60例临床观察[J].北京中医药大学学报,2007,30(1)：67-69.
[23]孙学刚,马克林.祛风止咳汤治疗外感咳嗽178例[J].陕西中医学院学报,2005,8(5)：26-27.
[24]梁会贤.仙鱼镇咳汤治疗风邪犯肺型咳嗽110例临床观察[J].湖北中医杂志,2000,22(1)：20.
[25]杨小乐.感咳灵汤治疗外感咳嗽120例的体会[J].现代医药卫生,2005,21(8)：993-994.
[26]张书明.从风咳论治咳嗽变异性哮喘临床观察[J].吉林中医药,2004,24(9)：18.
[27]宋先仁,朱淼.祛风清肺法治疗风咳30例临床观察[J].湖北中医药大学学报,2011,13(4)：58.
[1]杨萌,林江涛.浅谈感染后咳嗽[J].中国实用内科杂志,2007,27(2)：144-145.
[2]中华医学会呼吸病学分会哮喘学组.咳嗽的诊断与治疗指南[J].中华结核与呼吸杂志,2005,28(11)：741.
[3]中华医学会呼吸病学分会哮喘学组.咳嗽的诊断与治疗指南[J].中华结核与呼吸杂志,2009,8(9)：609.
[4]赖克方,钟南山.慢性咳嗽[M].北京：人民卫生出版社,2008.
[5]赖克方,钟南山.加强不明原因慢性咳嗽的病因诊断研究[J].中华内科杂志,2003,42(7)：449.
[6]Zimmerman B, Silverman FS, Tarlo SM,et al. Induced Sputum:comparison of post infectious cough with allergic asthma in children[J]. Allergy Clin Immunol,200,105:405-499.
[7]张齐武,许苏丹.43例感染后咳嗽患者气道反应性检测结果[J].临床肺科杂志,2009,14(2)：241.
[8]Irwin RS, Madison JM. Anatomical diagnostic protocol in evaluating chronic cough with specific reference to gastroesophageal reflux disease[J].Am Med,2000,108 (suppl4a):126-130.
[9]Sekizawa K, Jia YX, Ebihara T, et a 1. Role of substance P in cough [J]. Pulm Pharmacol,1996,9(5-6):323-328.
[10]Braman ss. Post-infectious cough:ACCP evidence-based clinical practice guidelines. Chest.2006,129 (1 Suppl):138S-146S.
[11]Walsh JJ, Dietlein LF, Low FN,etal. Bronchotracheal response in human influenza:Type A, asian strain, as studied by light and electron microscopic examination of bronchoscopic biopsies [J].Arch Intern Med, 1961,108:376-388.
[12]齐彦芝,王增粉.呼吸道感染后咳嗽与咳嗽变异性哮喘患者痰炎性细胞和气道反应特点及其意义[J].河北医药,2009,31(15)：1917-1918.
[13]李靖,罗炜,杨灵,等.急性上呼吸道感染后咳嗽的合理用药[J].新医学,2007,38(3)：161-163.
[14]时翠芹,余莉,魏为利,等.气道炎症在上气道咳嗽综合征发生中的作用.中国呼吸与危重症监护杂志,2009,8(3)：256-258.
[15]Schm id L D, Rabe KF. The role of leukotrienes in the regulation of tone and responsiveness in isolated human airways[J]. Am J Respir Crit Care Med,2000,161(2 Pt 2):S62-S67.
[16]李明华.哮喘病治疗学[M].北京：人民卫生出版社,1998：201-225.
[17]Burki NK, Isreal ME. Leukotriene receptor antagonist and bronchial asthma. Chest,1996,275(4):931-936.
[18]Matsuse H, Hirose H, Tsuchida T, et al. Effects of respiratory syncytial virus infection on dendritic cells and cys-teinyl leukotrienes in lung tissues of a murine model of asthma[J]. Allergol In,2007,56 (2):165.
[19]王华,陈艳波,张孔.白三烯受体拮抗剂对哮喘患者血清IL-5水平及气道高反应性的影响[J].实用医学杂志,2005,21(21)：2392-2395.
[20]Birring SS, Parker D, Brightling CE,et al.Induced sputum inflame-matory mediator concentrations in chronic cough. Am J Respir Crit Care Med,2004,169(1):15-19.
[21]Moreaux B, NemmarA, Vincke G, et al. Role of substance P and tachykinin receptor antagonists in citric acid-induced cough in pigs[J].Eur J Pharmacol,2000,408:305-312.
[22]陈如冲,刘春丽,罗炜,等.感冒后咳嗽敏感性及气道神经源性炎症改变[J].中国实用内科杂志,2007,27(9)：674-679.
[23]韦杰.气道神经源性炎症介质在感染后慢性咳嗽发病机制中的作用[J].求恩军医学院学报,2012,10(5)：373-374.
[24]Jacoby DB. Pathophysiology of airway viral infect ions[J]. Pulm Pharmacol,2004,17(6):333-336.
[25]Carr MJ, Hunter DD, Jacoby DB, et al. Expression of tachykinins in nonnociceptive vagal afferent neurons during respiratory viral infection in guinea pigs[J].Am J Respir Crit Care Med,2002,165 (8):1071-1075.
[26]Lee LY.Respiratory sensations evoked by activation of bronchopulmonary C-fibers[J]. Respir Physiol Neurobiol,2009,167 (1):26-35.
[27]Cheng PingHu, Katrin Wed-Beer, Alexander Auais, et al. Nerve growth factor and nerve growth factor receptors in respiratory syncytial virus-infected lungs [J]. Am J Physiol Lung Cell Mol Physiol,2002,283(2):494-502.
[28]李东培,才丽平,方秀斌.哮喘豚鼠下呼吸道及内脏传入部位NGF表达的研究[J].解剖学报,2002,33(4)：350-354.
[29]De-Vries A, Dessing MC, Engels F, etal. Nerve growth factor induces a Neurokinin-1 receptor-mediated airway hyperresponsiveness in guinea Pigs. Am J Respir Crit Care Med,1999,159 (5Pt1):1541-1544.
[30]Kolch W. The regulation of the Ras/Raf/MEK/ERK pathway by protein interactions[J]. Biochem J,2000,351:289-305.
[31]汤渝玲,胡成平,冯俊涛,等.神经生长因子调控哮喘神经源性炎症Ras/MAPK信号转导通路.中南大学学报(临床版),2006,31(3)：319-325.
[32]Stephens RD, Loeb D, Copeland T, et al. Trk receptors use redundant signal transduction pathways involving SHC and PLC gamma 1 to mediate NGF responses [J]. Neuron,1994,12:691-705.
[33]李锋,周新.p38丝裂原活化蛋白激酶与慢性气道疾病[J].中华哮喘杂志,2010,4(4)：291-294.
[34]郑仰明,李昌崇,张维溪,等.哮喘气道重塑大鼠中磷酸化p38丝裂原活化蛋白激酶的表达对黏液细胞增殖的影响及布地奈德的干预作用[J].中国临床药理学与治疗学,2009,14(8)：866-871.
[35]NayakA.A review of montelukast in the treatment of asthma all daller-gicrhini t is. ExpeaOpinPhannacother,2002,5(3):679.
[36]美国胸科医师学会.ACCP.200年咳嗽循证指南[C].Chest,2006.
[37]Spector SL,Tan RA. Effetiveness of montelukast in the treatment of cough variant asthma. Ann Allergy Immunol,2004,93 (3):232-236.
[38]Kopriva F Sobolova L, Szotkowska J, et al.Treatment of chronic cough in children with montelukast,a leukotriene receptor antagonist [J].Asthma,2004,41(7):715-720.
[39]朱利清,况九龙,邓在春.孟鲁司特治疗感染后咳嗽的临床分析[J].中国药房,2011,22(22)：2067-2068.
[40]韩雪梅.孟鲁司特钠治疗感染后咳嗽疗效观察[J].海南医学,2011,22(8)：53-55.
[41]李英,周明浩.阿斯美治疗上呼吸道感染后咳嗽[J].医学信息(临床医学),2010,23(2)：499-500.
[42]黄艳红.复方甲氧那明治疗感染后咳嗽的疗效观察[J].当代医学,2012,18(13)：77-78.
[43]张丹参.诱发咳嗽动物模型方法及评价[J].神经药理学报.2011,1(2)：35-41.
[44]吴继光,黄漾,王岚等.不同类型支气管扩张剂对致敏豚鼠模型咳嗽反应的作用 [J].2008,29(5)：15-18.
[45]邱忠民,刘琦,郭德华,等.缓激肽β2受体拮抗剂对致敏豚鼠模型咳嗽反应性的影响[J].中华结核和呼吸杂志,2002,25(2).
[46]吕寒静,邱忠民,杨忠民,等.气道速激肽在卵蛋白致敏豚鼠模型咳嗽反应中的作用[J].中国病理生理杂志,2005,21(9)：1744-1747.
[1]中华医学会呼吸病学分会哮喘学组.咳嗽的诊断与治疗指南(2009版)[J].中华结核和呼吸杂志,2009,32(6)：407-413.
[2]周仲瑛.《中医内科学》[M].北京：中国中医药出版社,2003：71-78.
[3]国家中医药管理局.中华人民共和国中医药行业标准.中医内科.中医病证诊断疗效标准[M].南京：南京大学出版社,1994：1-2.
[4]国家中医药管理局医政司.24个专业105个病种中医诊疗方案(合订本试行版).肺病科中医诊疗方案.咳嗽(感冒后咳嗽或感染后咳嗽)诊疗方案[M].国家中医药管理局医政司,2012：71-78.
[5]郑筱萸.中药新药临床研究指导原则(试行).北京：中国医药科技出版社,2002：54-58.
[6]赖克方,钟南山.慢性咳嗽[M].北京：人民卫生出版社,2008：1.
[7]Wassmer G, Jorres RA, Heinrich J. et al. The association between baseline lung function and bronchial responsiveness to methacho-1ine [J].Eur J Med Res,1997,2 (2):47-54.
[8]甘慧娟,朱文锋.基于聚类分析的不同年龄咳嗽患者证素特征[R].朱文锋学术思想研讨会暨中医诊断师资班30周年纪念大会.2012.
[9]Little JW, Hall WJ, Douglas RG Jr,et al.Airway hyper reactivity and peripheral airway dysfunction in influenza A infect ion. Am Rev Respir Dis,1978,118(2):295-303.
[10]雷英.社区慢性咳嗽误诊误治21例分析[J].中国误诊学志,2009,9(21)：5153-5154.
[11]毕玉田,何庆华.咳嗽的评定方法及其临床应用[J].中华结核和呼吸杂志,2009,32(6)：460-462.
[1]赖克方,钟南山.慢性咳嗽[M].北京：人民卫生出版社,2008：39-40.
[2]陆月明.咳嗽的动物模型研究方法[J].临床肺科杂志,2007,12(5)：480-481.
[3]张丹参.诱发咳嗽动物模型方法及评价[J].神经药理学报.2011,1(2)：35-41.
[4]Matsuoka T, Hirata M, Tanaka H, et al.Prosrag land in D2 as A mediator of allergic asthma[J]. Science,2000,287(5460): 2013-2017.
[5]MATSUSE H, HIROSE H, TSUCHIDA T, et al. Effects of respiratory-syncytial virus infection on dendritic cells and cysteinyleukoltrienes in lung tissues of a murine model of asthma [J]. Allergol Int,2007,56 (2):165.
[6]汤渝玲,胡成平,冯俊涛,等.神经生长因子调控哮喘神经源性炎症Ras/MAPK信号转导通路.中南大学学报(临床版),2006,31(3)：319-325.
[7]李锋,周新.p38丝裂原活化蛋白激酶与慢性气道疾病[J].中华哮喘杂志(电子版),2010,4(4)：291-294.
[8]Han J, Lee JD, Bibbs L, et al. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science,1994,256(5173):808-811.
[9]黄翠萍,杨和平,张珍祥,等.p38蛋白激酶对支气管哮喘大鼠Th2类细胞因子表达的调控[J].中国病理生理杂志,2006,22(10)：311-313.