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Abstract：
BACKGROUND: The standard therapy for bronchial asthma consists of combinations of acute (short-acting ß2-sympathomimetics) and, depending on the severity of disease, additional long-term treatment (including inhaled glucocorticoids, long-acting ß2-sympathomimetics, anticholinergics, anti-IL-4R antibodies). The antidepressant amitriptyline has been identified as a relevant down-regulator of immunological TH2-phenotype in asthma, acting-at least partially-through inhibition of acid sphingomyelinase (ASM), an enzyme involved in sphingolipid metabolism. Here, we investigated the non-immunological role of amitriptyline on acute bronchoconstriction, a main feature of airway hyperresponsiveness in asthmatic disease.
METHODS: After stimulation of precision cut lung slices (PCLS) from mice (wildtype and ASM-knockout), rats, guinea pigs and human lungs with mediators of bronchoconstriction (endogenous and exogenous acetylcholine, methacholine, serotonin, endothelin, histamine, thromboxane-receptor agonist U46619 and leukotriene LTD4, airway area was monitored in the absence of or with rising concentrations of amitriptyline. Airway dilatation was also investigated in rat PCLS by prior contraction induced by methacholine. As bronchodilators for maximal relaxation, we used IBMX (PDE inhibitor) and salbutamol (ß2-adrenergic agonist) and compared these effects with the impact of amitriptyline treatment. Isolated perfused lungs (IPL) of wildtype mice were treated with amitriptyline, administered via the vascular system (perfusate) or intratracheally as an inhalation. To this end, amitriptyline was nebulized via pariboy in-vivo and mice were ventilated with the flexiVent setup immediately after inhalation of amitriptyline with monitoring of lung function.
RESULTS: Our results show amitriptyline to be a potential inhibitor of bronchoconstriction, induced by exogenous or endogenous (EFS) acetylcholine, serotonin and histamine, in PCLS from various species. The effects of endothelin, thromboxane and leukotrienes could not be blocked. In acute bronchoconstriction, amitriptyline seems to act ASM-independent, because ASM-deficiency (Smdp1-/-) did not change the effect of acetylcholine on airway contraction. Systemic as well as inhaled amitriptyline ameliorated the resistance of IPL after acetylcholine provocation. With the flexiVent setup, we demonstrated that the acetylcholine-induced rise in central and tissue resistance was much more marked in untreated animals than in amitriptyline-treated ones. Additionally, we provide clear evidence that amitriptyline dilatates pre-contracted airways as effectively as a combination of typical bronchodilators such as IBMX and salbutamol.
CONCLUSIONS: Amitriptyline is a drug of high potential, which inhibits acute bronchoconstriction and induces bronchodilatation in pre-contracted airways. It could be one of the first therapeutic agents in asthmatic disease to have powerful effects on the TH2-allergic phenotype and on acute airway hyperresponsiveness with bronchoconstriction, especially when inhaled.
METHODS: After stimulation of precision cut lung slices (PCLS) from mice (wildtype and ASM-knockout), rats, guinea pigs and human lungs with mediators of bronchoconstriction (endogenous and exogenous acetylcholine, methacholine, serotonin, endothelin, histamine, thromboxane-receptor agonist U46619 and leukotriene LTD4, airway area was monitored in the absence of or with rising concentrations of amitriptyline. Airway dilatation was also investigated in rat PCLS by prior contraction induced by methacholine. As bronchodilators for maximal relaxation, we used IBMX (PDE inhibitor) and salbutamol (ß2-adrenergic agonist) and compared these effects with the impact of amitriptyline treatment. Isolated perfused lungs (IPL) of wildtype mice were treated with amitriptyline, administered via the vascular system (perfusate) or intratracheally as an inhalation. To this end, amitriptyline was nebulized via pariboy in-vivo and mice were ventilated with the flexiVent setup immediately after inhalation of amitriptyline with monitoring of lung function.
RESULTS: Our results show amitriptyline to be a potential inhibitor of bronchoconstriction, induced by exogenous or endogenous (EFS) acetylcholine, serotonin and histamine, in PCLS from various species. The effects of endothelin, thromboxane and leukotrienes could not be blocked. In acute bronchoconstriction, amitriptyline seems to act ASM-independent, because ASM-deficiency (Smdp1-/-) did not change the effect of acetylcholine on airway contraction. Systemic as well as inhaled amitriptyline ameliorated the resistance of IPL after acetylcholine provocation. With the flexiVent setup, we demonstrated that the acetylcholine-induced rise in central and tissue resistance was much more marked in untreated animals than in amitriptyline-treated ones. Additionally, we provide clear evidence that amitriptyline dilatates pre-contracted airways as effectively as a combination of typical bronchodilators such as IBMX and salbutamol.
CONCLUSIONS: Amitriptyline is a drug of high potential, which inhibits acute bronchoconstriction and induces bronchodilatation in pre-contracted airways. It could be one of the first therapeutic agents in asthmatic disease to have powerful effects on the TH2-allergic phenotype and on acute airway hyperresponsiveness with bronchoconstriction, especially when inhaled.
摘要：
背景：支气管哮喘的标准治疗包括急性（短效β2-拟交感神经药）和，根据疾病的严重程度，额外的长期治疗（包括吸入型糖皮质激素，长效β2-拟交感神经，抗胆碱能药,抗IL-4R抗体)。抗抑郁剂阿米替林已被确定为哮喘免疫学TH2表型的相关下调因子,至少部分通过抑制酸性鞘磷脂酶（ASM）起作用，一种参与鞘脂代谢的酶。这里,我们研究了阿米替林对急性支气管收缩的非免疫作用，喘息性疾病气道高反应性的主要特征。
方法：在刺激小鼠（野生型和ASM敲除）的精确切割肺片（PCLS）后，老鼠,豚鼠和人的肺与支气管收缩的介质（内源性和外源性乙酰胆碱，乙酰甲胆碱,血清素,内皮素,组胺,血栓烷受体激动剂U46619和白三烯LTD4,在没有阿米替林或阿米替林浓度升高的情况下监测气道面积.还通过乙酰甲胆碱诱导的预先收缩在大鼠PCLS中研究了气道扩张。作为最大松弛的支气管扩张剂，我们使用了IBMX(PDE抑制剂)和沙丁胺醇(β2-肾上腺素能激动剂),并将这些效果与阿米替林治疗的影响进行了比较.用阿米替林处理野生型小鼠的分离的灌注肺(IPL),通过血管系统（灌注液）或气管内吸入给药。为此,在体内通过pariboy雾化阿米替林，并在吸入阿米替林并监测肺功能后立即对小鼠进行灵活通气。
结果：我们的结果显示阿米替林是一种潜在的支气管收缩抑制剂，由外源性或内源性（EFS）乙酰胆碱诱导，血清素和组胺,在来自各种物种的PCLS中。内皮素的作用，血栓素和白三烯无法阻断.在急性支气管收缩中，阿米替林似乎独立于ASM，因为ASM缺乏（Smdp1-/-）没有改变乙酰胆碱对气道收缩的影响。全身和吸入阿米替林改善了乙酰胆碱激发后IPL的抗性。有了灵活的Vent设置，我们证明,与阿米替林治疗的动物相比,在未经治疗的动物中,乙酰胆碱诱导的中枢和组织抗性的升高更为显著.此外,我们提供了明确的证据表明,阿米替林扩张预收缩气道的效果与IBMX和沙丁胺醇等典型支气管扩张剂的组合相当.
结论：阿米替林是一种具有高潜力的药物，抑制急性支气管收缩并诱导预收缩气道中的支气管扩张。它可能是喘息性疾病的首批治疗剂之一，对TH2过敏表型和支气管收缩的急性气道高反应性具有强大作用，尤其是吸入的时候。
方法：在刺激小鼠（野生型和ASM敲除）的精确切割肺片（PCLS）后，老鼠,豚鼠和人的肺与支气管收缩的介质（内源性和外源性乙酰胆碱，乙酰甲胆碱,血清素,内皮素,组胺,血栓烷受体激动剂U46619和白三烯LTD4,在没有阿米替林或阿米替林浓度升高的情况下监测气道面积.还通过乙酰甲胆碱诱导的预先收缩在大鼠PCLS中研究了气道扩张。作为最大松弛的支气管扩张剂，我们使用了IBMX(PDE抑制剂)和沙丁胺醇(β2-肾上腺素能激动剂),并将这些效果与阿米替林治疗的影响进行了比较.用阿米替林处理野生型小鼠的分离的灌注肺(IPL),通过血管系统（灌注液）或气管内吸入给药。为此,在体内通过pariboy雾化阿米替林，并在吸入阿米替林并监测肺功能后立即对小鼠进行灵活通气。
结果：我们的结果显示阿米替林是一种潜在的支气管收缩抑制剂，由外源性或内源性（EFS）乙酰胆碱诱导，血清素和组胺,在来自各种物种的PCLS中。内皮素的作用，血栓素和白三烯无法阻断.在急性支气管收缩中，阿米替林似乎独立于ASM，因为ASM缺乏（Smdp1-/-）没有改变乙酰胆碱对气道收缩的影响。全身和吸入阿米替林改善了乙酰胆碱激发后IPL的抗性。有了灵活的Vent设置，我们证明,与阿米替林治疗的动物相比,在未经治疗的动物中,乙酰胆碱诱导的中枢和组织抗性的升高更为显著.此外,我们提供了明确的证据表明,阿米替林扩张预收缩气道的效果与IBMX和沙丁胺醇等典型支气管扩张剂的组合相当.
结论：阿米替林是一种具有高潜力的药物，抑制急性支气管收缩并诱导预收缩气道中的支气管扩张。它可能是喘息性疾病的首批治疗剂之一，对TH2过敏表型和支气管收缩的急性气道高反应性具有强大作用，尤其是吸入的时候。
