Maarsingh Harm, Zuidhof Annet B, Bos I Sophie T, van Duin Marcel, Boucher Jean-Luc, Zaagsma Johan, Meurs Herman
Department of Molecular Pharmacology, University Center for Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
Am J Respir Crit Care Med. 2008 Sep 15;178(6):565-73. doi: 10.1164/rccm.200710-1588OC. Epub 2008 Jun 26.
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.
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.
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 PC(100) (provocative concentration causing a 100% increase of pleural pressure) values.
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.
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.
在过敏性哮喘豚鼠模型中，我们使用离体灌注气管制剂证明，变应原诱导的早期和晚期哮喘反应后，由于精氨酸酶活性增加导致的L-精氨酸限制是支气管舒张性一氧化氮（NO）缺乏和气道高反应性（AHR）的基础。
使用相同的动物模型，我们研究了特异性精氨酸酶抑制剂2(S)-氨基-6-硼代己酸（ABH）和L-精氨酸对体内早期和晚期反应后AHR的急性影响。此外，我们研究了药物预处理对变应原诱导的哮喘反应、AHR和气道炎症的保护作用。
在变应原激发前24小时对卵清蛋白致敏的永久性植入仪器、自由活动的豚鼠，以及在变应原诱导的早期和晚期哮喘反应后，通过评估组胺PC(100)（引起胸膜压力增加100%的激发浓度）值，测量气道对吸入组胺的反应性。
吸入ABH可使早期反应后对组胺的AHR从4.77±0.56倍急性逆转至2.04±0.34倍（P<0.001），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-精氨酸获得了定量相似的结果。值得注意的是，用ABH预处理后，诱导气道阻塞所需的变应原剂量高33倍（P<0.01）。因此，在变应原激发前0.5小时和激发后8小时吸入ABH可预防变应原诱导的早期和晚期哮喘反应、AHR和炎症细胞浸润。
吸入ABH或L-精氨酸可在早期和晚期哮喘反应后急性逆转变应原诱导的AHR，可能是通过减轻精氨酸酶诱导的气道中NO合酶底物缺乏。此外，ABH可显著降低气道对吸入变应原的敏感性，并预防变应原诱导的支气管阻塞反应、AHR和气道炎症。这是第一项表明精氨酸酶抑制剂在过敏性哮喘中可能具有治疗潜力的体内研究。
