Vermont Lung Center, Department of Medicine, University of Vermont, 149 Beaumont Ave, Burlington, VT 05401, USA.
Respir Res. 2011 Mar 7;12(1):27. doi: 10.1186/1465-9921-12-27.
Inhaled short acting β2-agonists (SABA), e.g. albuterol, are used for quick reversal of bronchoconstriction in asthmatics. While SABA are not recommended for maintenance therapy, it is not uncommon to find patients who frequently use SABA over a long period of time and there is a suspicion that long term exposure to SABA could be detrimental to lung function. To test this hypothesis we studied the effect of long-term inhaled albuterol stereoisomers on immediate allergic response (IAR) and airway hyperresponsiveness (AHR) in mouse models of asthma.
Balb/C mice were sensitized and challenged with ovalbumin (OVA) and then we studied the IAR to inhaled allergen and the AHR to inhaled methacholine. The mice were pretreated with nebulizations of either racemic (RS)-albuterol or the single isomers (S)- and (R)-albuterol twice daily over 7 days prior to harvest.
We found that all forms of albuterol produced a significant increase of IAR measured as respiratory elastance. Similarly, we found that AHR was elevated by albuterol. At the same time a mouse strain that is intrinsically hyperresponsive (A/J mouse) was not affected by the albuterol isomers nor was AHR induced by epithelial disruption with Poly-L-lysine affected by albuterol.
We conclude that long term inhalation treatment with either isomer of albuterol is capable of precipitating IAR and AHR in allergically inflamed airways but not in intrinsically hyperresponsive mice or immunologically naïve mice. Because (S)-albuterol, which lacks affinity for the β2-receptor, did not differ from (R)-albuterol, we speculate that isomer-independent properties of the albuterol molecule, other than β2-agonism, are responsible for the effect on AHR.
吸入短效β2-激动剂（如沙丁胺醇）可迅速逆转哮喘患者的支气管收缩。虽然不建议将 SABA 用于维持治疗，但经常发现患者在很长一段时间内频繁使用 SABA，并且有人怀疑长期暴露于 SABA 可能对肺功能有害。为了验证这一假设，我们研究了长期吸入沙丁胺醇立体异构体对哮喘小鼠模型中即刻过敏反应（IAR）和气道高反应性（AHR）的影响。
Balb/C 小鼠用卵清蛋白（OVA）致敏和激发，然后研究吸入变应原的 IAR 和吸入乙酰甲胆碱的 AHR。在收获前 7 天，每天两次用沙丁胺醇外消旋体（RS）或单一对映体（S）-和（R）-沙丁胺醇雾化预处理小鼠。
我们发现，所有形式的沙丁胺醇都显著增加了呼吸弹性所测量的 IAR。同样，我们发现 AHR 也被沙丁胺醇升高。与此同时，一种内在高反应性的小鼠品系（A/J 小鼠）不受沙丁胺醇对映体的影响，上皮破坏用聚赖氨酸诱导的 AHR 也不受沙丁胺醇的影响。
我们得出结论，长期吸入治疗任何一种沙丁胺醇对映体都能在过敏炎症气道中引发 IAR 和 AHR，但在内在高反应性小鼠或免疫未致敏小鼠中则不会。由于缺乏β2-受体亲和力的（S）-沙丁胺醇与（R）-沙丁胺醇没有区别，我们推测除了β2-激动作用外，沙丁胺醇分子的对映体非依赖性特性是其对 AHR 产生影响的原因。
