Arginase inhibition protects against allergen-induced airway obstruction, hyperresponsiveness, and inflammation
Arginase inhibition protects against allergen-induced airway obstruction, hyperresponsiveness, and inflammation
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DOI：
10.1164/rccm.200710-1588oc
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发表时间：
2008-09-15
影响因子：
24.7
通讯作者：
Meurs, Herman
中科院分区：
文献类型：
--
作者：
Maarsingh, Harm;Zuidhof, Annet B.;Meurs, Herman
基本原理：在豚鼠过敏性哮喘模型中，使用离体灌注气管制备物，我们证明了在过敏原诱导的早期和晚期哮喘反应后，由于乙酰胆碱酯酶活性增加而导致的L-精氨酸限制是支气管扩张性一氧化氮（NO）和气道高反应性（AHR）缺乏的基础。目的：采用同一动物模型，观察了特异性乙酰胆碱酯酶抑制剂2（S）-氨基-6-硼己酸（ABH）和L-精氨酸对体内早期和晚期反应后AHR的急性作用。此外，我们还研究了药物预处理对过敏原诱导的哮喘反应、AHR和气道炎症的保护作用。气道反应性吸入组胺测定永久仪器，通过评估组胺PC 100，在变应原激发前24小时和变应原诱导的早期和晚期哮喘反应后，对卵白蛋白致敏的自由活动豚鼠进行了研究（引起胸膜压100%增加的激发浓度）值。测量和主要结果：吸入ABH可在早期反应后将AHR从4.77 +/- 0.56倍急性逆转为组胺2.04 +/- 0.34倍（P < 0.001），并且在晚期反应后观察到抑制趋势（从1.95 +/-0.56倍至1.56 +/-0.47倍，P < 0.10）。吸入L-精氨酸获得了类似的定量结果。值得注意的是，ABH预处理后，需要33倍的过敏原剂量才能诱导气道阻塞（P < 0.01）。因此，吸入ABH前0.5小时和8小时后过敏原的挑战保护对过敏原诱导的早期和晚期哮喘反应，AHR和炎性细胞infiltration.Conclusions：吸入ABH或L-精氨酸急性逆转过敏原诱导的AHR后，早期和晚期哮喘反应，大概是通过衰减酶诱导的底物缺乏NO合成酶在气道。此外，ABH显著降低气道对吸入过敏原的敏感性，并防止过敏原诱导的支气管阻塞反应、AHR和气道炎症。这是第一个体内研究表明，乙酰胆碱酯酶抑制剂可能具有治疗过敏性哮喘的潜力。
Rationale: In a guinea pig model of allergic asthma, using perfused tracheal preparations ex vivo, we demonstrated that L-arginine limitation due to increased arginase activity underlies a deficiency of bronchodilating nitric oxide (NO) and airway hyperresponsiveness (AHR) after the allergen-induced early and late asthmatic reaction.Objectives: Using the same animal model, we investigated the acute effects of the specific arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) and of L-arginine on AHR after the early and late reaction in vivo. In addition, we investigated the protection of allergen-induced asthmatic reactions, AHR, and airway inflammation by pretreatment with the drug.Methods: Airway responsiveness to inhaled histamine was measured in permanently instrumented, freely moving guinea pigs sensitized to ovalbumin at 24 hours before allergen challenge and after the allergen-induced early and late asthmatic reactions by assessing histamine PC100 (provocative concentration causing a 100% increase of pleural pressure) values.Measurements and Main Results: Inhaled ABH acutely reversed AHR to histamine after the early reaction from 4.77 +/- 0.56-fold to 2.04 +/- 0.34 fold (P < 0.001), and a tendency to inhibition was observed after the late reaction (from 1.95 +/- 0.56-fold to 1.56 +/- 0.47-fold, P < 0.10). Quantitatively similar results were obtained with inhaled L-arginine. Remarkably, after pretreatment with ABH a 33-fold higher dose of allergen was needed to induce airway obstruction (P < 0.01). Consequently, ABH inhalation 0.5 hour before and 8 hours after allergen challenge protected against the allergen-induced early and late asthmatic reactions, AHR and inflammatory cell infiltration.Conclusions: Inhalation of ABH or L-arginine acutely reverses allergen-induced AHR after the early and late asthmatic reaction, presumably by attenuating arginase-induced substrate deficiency to NO synthase in the airways. Moreover, ABH considerably reduces the airway sensitivity to inhaled allergen and protects against allergen-induced bronchial obstructive reactions, AHR, and airway inflammation. This is the first in vivo study indicating that arginase inhibitors may have therapeutic potential in allergic asthma.