咳嗽为临床上常见症状,近年胸部影像无明显异常的慢性咳嗽发病率升高,其病因复杂,误诊误治率高,受到重视.目前研究认为咳嗽高敏感性是其重要的临床与病理生理学特征,与瞬时受体电位通路激活、气道炎症、神经通路及咳嗽中枢的易化等相关,然而其机制复杂,仍需深入研究.咳嗽机制的研究对于新药物的开发、临床疗效的提高、社会经济负担减轻等方面有着重要意义.而咳嗽动物模型对于咳嗽实验研究开展以及其机制阐明具有至关重要的作用,目前咳嗽动物模型分为单纯咳嗽模型和疾病咳嗽模型,但因为咳嗽发病机制复杂,病因较多,尚无统一的咳嗽模型制备标准,且仍处于不断的补充与完善之中.针对咳嗽动物模型建立的机制方法和研究进展,通过查阅和整理近年来国内外的相关文献,从模型动物的选择、单纯及疾病咳嗽动物模型的建立和应用等方面综合概述该类模型的研究现状,并进行比较评价,对当前咳嗽模型制备中的问题进行了思考与阐述,以期为实验研究中制备咳嗽动物模型、深入研究咳嗽的发病机制、治疗方法等提供参考.

目的 基于肺脾同治法探讨四君子汤合三子养亲汤改善慢性阻塞性肺疾病(COPD)小鼠气道黏液高分泌的作用机制.方法 将40只C57BL/6N雄性小鼠随机分为空白组、模型组、西药组(盐酸氨溴索)、中药组(四君子汤合三子养亲汤),每组10只,采用烟熏联合脂多糖的方法建立COPD小鼠模型.酶联免疫吸附测定法检测血清中白细胞介素-4(IL-4)、白细胞介素-8(IL-8)、白细胞介素-13(IL-13)水平;HE染色观察肺组织病理学变化;蛋白免疫印迹法检测肺组织STAT6、SPDEF、FOXA2蛋白表达水平;实时荧光定量聚合酶链式反应检测肺组织STAT6、Muc5ac mRNA水平.结果 与空白组比较,模型组血清中IL-4、IL-8、IL-13水平,肺组织STAT6、SPDEF蛋白表达水平,STAT6、Muc5ac mRNA显著升高(P＜0.01);FOXA2蛋白表达水平显著下降(P＜0.01).与模型组比较,中药组血清中IL-4、IL-8、IL-13和西药组血清中IL-4、IL-13水平明显下降(P＜0.05或P＜0.01),西药组血清中IL-8水平下降不明显(P＞0.05);与模型组比较,用药组STAT6、SPDEF蛋白表达水平,STAT6、Muc5ac mRNA较模型组显著下降(P＜0.01),FOXA2蛋白表达水平升高(P＜0.01).结论 四君子汤合三子养亲汤可能通过抑制STAT6-SPDEF-MUC5AC信号通路的活性改善COPD小鼠气道黏液高分泌.

Objective:To observe the effects of Qufeng Xuanfei recipe on cough frequency, airway responsiveness, and related indexes of transient receptor potential vanilloid 4 (TRPV4)/P2X3 signal pathway in guinea pigs with increased cough sensitivity, and to explore its therapeutic mechanism.Methods:This was an experimental study.Using the random number table method, 25 SPF male healthy guinea pigs were randomly divided into blank group, model group, traditional Chinese medicine group, TRPV4 inhibitor group, and P2X3 inhibitor group, with five animals in each group.Except for the blank group, a guinea pig model with increased cough sensitivity was established in other four groups.After successful modeling, the blank and model groups were given normal saline, the traditional Chinese medicine group was given Qufeng Xuanfei Recipe, and the TRPV4 inhibitor group and P2X3 inhibitor group were given GSK2193874 and AF-353, respectively, for 7 days of intervention.The TRPV4 agonist GSK1016790A was used to measure the number of coughs of guinea pigs in each group.Pulmonary function test was used to detect airway resistance in guinea pigs.The expression levels of serum IL-6, IL-8, IL-1β, and TRPV4, P2X3 and SP in bronchoalveolar lavage fluid (BALF) were detected by ELISA, and the protein expressions of TRPV4, P2X3, and SP in lung tissue were detected by Western Blot.Results:Compared with the blank group, the number of coughs ([4.00±0.82] times vs [14.75±2.22] times, P<0.01), airway resistance (acetylcholine chloride: concentration of 400 mg/L [2.32±1.07] cmH 2O·s/L vs [6.50±2.03] cmH 2O·s/L, 800 mg/L[2.88±0.86] cmH 2O·s/L vs [9.47±3.52] cmH 2O·s/L), serum inflammatory factors (IL-6, IL-8, IL-1β: [16.32±0.17] ng/L vs [24.49±0.19] ng/L, [33.48±1.36] ng/L vs [59.33±2.15] ng/L, [10.71±1.22] ng/L vs [38.79±2.22] ng/L respectively), and the expressions of TRPV4, P2X3, and SP in BALF ([46.14±0.35] μg/L vs [91.62±0.25] μg/L, [78.37±0.35] μg/L vs [156.62±0.25] μg/L, [38.20±1.75] μg/L vs [79.84±2.45] μg/L respectively) and lung tissue ([0.34±0.01] vs [1.09±0.12], [0.28±0.09] vs [0.77±0.18], [0.26±0.04] vs [0.87±0.09] respectively) were all increased ( P<0.01) in the model group.Compared with the model group, the number of coughs ([2.00±0.82] times), airway resistance (acetylcholine chloride: concentration of 400 mg/L [4.01±0.43] cmH 2O·s/L, 800 mg/L [3.77±0.73] cmH 2O·s/L), serum inflammatory factors (IL-6, IL-8, IL-1β: [18.94±0.43] ng/L, [36.42±1.60] ng/L, [25.20±3.22] ng/L respectively), and the expressions of TRPV4, P2X3, and SP in BALF ([82.24±0.33] μg/L, [141.09±0.88] μg/L, [59.74±2.75] μg/L respectively) and lung tissue ([0.45±0.02], [0.38±0.09], [0.47±0.05] respectively) were reduced ( P<0.05 or P<0.01) in traditional Chinese medicine group. Conclusions:Qufeng Xuanfei Recipe can reduce cough sensitivity and airway responsiveness of model guinea pigs, which may be related to inhibiting TRPV4/P2X3 signaling pathway and reducing neurogenic airway inflammation.

沈金鳌是清代著名医家,其代表作《杂病源流犀烛》设咳嗽专篇,汇诸家之言法古而创新.本文总结了沈金鳌对于咳嗽病因病机、临证辨治、选方用药的认识以及咳嗽病脉等.在病因病机上,外感咳嗽以风、寒、暑热、湿邪为主,强调湿邪,内伤咳嗽重视肺脾肾的联系.在治疗上,首以顺气消痰为要法,辛温散表,甘润养内.新咳实则泻之,久咳以虚为主从气血从论治,分别以补中益气汤及四物汤加减,以郁为主从火从痰论治,重视桔梗的使用.治疗五脏咳选用归经药,治疗六腑咳选引上引下药使得升降相应.协调肺脾肾,重视补水培土以养金.细分发病时间,选方多用二陈汤加减.同时重视脉诊,并创造性地使导引运功与药物治疗相辅相成.

上气道咳嗽综合征/鼻后滴流综合征是慢性咳嗽常见病因之一,鼻炎、鼻窦炎等是其主要原因.西医治疗本病不良反应较多,且复发率相对较高.中医治疗本病源流悠久,临床效果较好,且副作用相对较少.结合中医古籍文献、古今医家理论及课题组经验,提出以"鼻咳"来命名上气道咳嗽综合征/鼻后滴流综合征,认为本病病位主要在鼻、肺,基本病机为鼻窍壅塞、肺失宣降,病性属虚实夹杂,基本治则为祛邪通窍、宣肺止咳,临床可视具体情况辨证论治.