Department of Pediatrics, Medical Faculty, RWTH Aachen, University Hospital Aachen, Pauwelsstraße 30, 52074, Aachen, Germany.
Institute of Pharmacology and Toxicology, Medical Faculty, RWTH Aachen, University Hospital Aachen, Aachen, Germany.
Respir Res. 2023 Oct 31;24(1):262. doi: 10.1186/s12931-023-02580-6.
The standard therapy for bronchial asthma consists of combinations of acute (short-acting ß-sympathomimetics) and, depending on the severity of disease, additional long-term treatment (including inhaled glucocorticoids, long-acting ß-sympathomimetics, anticholinergics, anti-IL-4R antibodies). The antidepressant amitriptyline has been identified as a relevant down-regulator of immunological T2-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.
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 (ß-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.
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.
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 T2-allergic phenotype and on acute airway hyperresponsiveness with bronchoconstriction, especially when inhaled.
支气管哮喘的标准治疗包括急性（短效β-拟交感神经药）和，取决于疾病的严重程度，额外的长期治疗（包括吸入糖皮质激素、长效β-拟交感神经药、抗胆碱能药、抗 IL-4R 抗体）。抗抑郁药阿米替林已被确定为哮喘中免疫 T2 表型的重要下调因子，其作用至少部分通过抑制酸性鞘磷脂酶（ASM），ASM 是一种参与鞘脂代谢的酶。在这里，我们研究了阿米替林在急性支气管收缩中的非免疫作用，急性支气管收缩是哮喘气道高反应性的主要特征。
用内源性和外源性乙酰胆碱、氨甲酰胆碱、血清素、内皮素、组氨酸、血栓烷受体激动剂 U46619 和白三烯 LTD4 等介质刺激来自小鼠（野生型和 ASM 敲除型）、大鼠、豚鼠和人肺的离体肺切片（PCLS）后，监测无或有阿米替林浓度升高时气道面积。用氨甲酰胆碱预先收缩来研究大鼠 PCLS 的气道扩张。作为最大松弛的支气管扩张剂，我们使用 IBMX（PDE 抑制剂）和沙丁胺醇（β-肾上腺素能激动剂），并将这些作用与阿米替林治疗的影响进行比较。用阿米替林通过血管系统（灌流液）或气管内给药（吸入）处理野生型小鼠的离体灌注肺（IPL）。为此，通过 pariboy 将阿米替林雾化，并在吸入阿米替林后立即通过 flexiVent 装置对其进行通气，监测肺功能。
我们的结果表明，阿米替林是一种潜在的支气管收缩抑制剂，可抑制各种物种的 PCLS 中外源性或内源性（EFS）乙酰胆碱、血清素和组氨酸诱导的支气管收缩。内皮素、血栓烷和白三烯的作用不能被阻断。在急性支气管收缩中，阿米替林似乎是 ASM 非依赖性的，因为 ASM 缺乏（Smdp1）并没有改变乙酰胆碱对气道收缩的作用。全身和吸入阿米替林均可改善 IPL 在乙酰胆碱刺激后的阻力。使用 flexiVent 装置，我们证明在未治疗的动物中，乙酰胆碱引起的中心和组织阻力升高比在阿米替林治疗的动物中更为明显。此外，我们提供了明确的证据表明，阿米替林扩张预先收缩的气道与 IBMX 和沙丁胺醇等典型支气管扩张剂的组合一样有效。
阿米替林是一种具有高潜力的药物，可抑制急性支气管收缩并诱导预先收缩的气道扩张。它可能是哮喘疾病中第一种对 T2 过敏表型和急性气道高反应性（伴有支气管收缩）具有强大作用的治疗药物之一，特别是在吸入时。
