Department of Experimental Asthma and Allergy Research, Institute of Environmental Medicine, Scheeles väg 1, Karolinska Institutet, SE-17177 Stockholm, Sweden.
J Pharmacol Exp Ther. 2010 Apr;333(1):273-80. doi: 10.1124/jpet.109.156224. Epub 2010 Jan 8.
During asthma exacerbations, increased airway inflammation may impair the effects of beta(2)-adrenoceptor (beta(2)AR) agonists. It is unclear whether this impairment is prevented by inhaled glucocorticoids (GCs). We have investigated the relaxation of carbachol-contracted mouse tracheal segments to the beta(2)AR agonists formoterol, terbutaline, and salmeterol. The segments were pre-exposed for 4 days to the proinflammatory cytokines tumor necrosis factor alpha (100 ng/ml) and interleukin-1beta (10 ng/ml) with or without the GC, budesonide (1 microM). Formoterol and terbutaline induced greater maximal relaxation (R(max)) than salmeterol. The cytokines decreased R(max) of all beta(2)AR agonists, whereas budesonide had no effect. However, after concomitant treatment with cytokines and budesonide, the R(max) values of formoterol and terbutaline were not impaired, whereas budesonide did not prevent the decrease in the R(max) of salmeterol. A similar pattern was observed for cAMP production by the agonists. In tracheal smooth muscle, beta(2)AR mRNA was not affected by the cytokines but increased with budesonide. However, the cytokines markedly increased cyclooxygenase (COX)-2 mRNA expression, which may lead to heterologous desensitization of beta(2)AR. It is noteworthy that the cytokine-induced increase of COX-2 was blocked by concomitant budesonide suggesting that heterologous desensitization of beta(2)AR by the cytokines may be prevented by budesonide treatment. Budesonide prevented cytokine-induced impairment of the tracheal relaxation and beta(2)AR/cAMP signaling for formoterol but not for salmeterol. This suggests that differences exist between formoterol and salmeterol in beta(2)AR coupling/activation and/or signal transduction upstream of cAMP. These results imply that maximal bronchodilator effects of formoterol, but not of salmeterol, are maintained by budesonide treatment during periods with increased inflammation, such as asthma exacerbations.
在哮喘恶化期间，气道炎症的增加可能会损害β2-肾上腺素能受体（β2AR）激动剂的作用。目前尚不清楚吸入糖皮质激素（GCs）是否可以预防这种损害。我们已经研究了β2AR 激动剂福莫特罗、特布他林和沙美特罗对乙酰胆碱收缩的小鼠气管段的松弛作用。这些片段在 4 天内预先暴露于促炎细胞因子肿瘤坏死因子-α（100ng/ml）和白细胞介素-1β（10ng/ml）中，同时或不使用 GC 布地奈德（1μM）。福莫特罗和特布他林诱导的最大松弛度（Rmax）大于沙美特罗。细胞因子降低了所有β2AR 激动剂的 Rmax，而布地奈德没有影响。然而，在细胞因子和布地奈德同时治疗后，福莫特罗和特布他林的 Rmax 值没有受损，而布地奈德不能防止沙美特罗的 Rmax 值下降。激动剂产生的 cAMP 产生也观察到类似的模式。在气管平滑肌中，细胞因子对β2AR mRNA 没有影响，但布地奈德增加了β2AR mRNA 的表达。然而，细胞因子显著增加了环氧化酶（COX）-2 mRNA 的表达，这可能导致β2AR 的异源脱敏。值得注意的是，细胞因子诱导的 COX-2 增加被同时给予的布地奈德阻断，这表明细胞因子引起的β2AR 异源脱敏可能被布地奈德治疗所预防。布地奈德预防了福莫特罗但不是沙美特罗引起的细胞因子诱导的气管松弛和β2AR/cAMP 信号传导的损害。这表明，在炎症增加期间，如哮喘恶化期间，福莫特罗和沙美特罗之间存在β2AR 偶联/激活和/或 cAMP 上游信号转导的差异。这些结果表明，福莫特罗的最大支气管扩张剂作用，而不是沙美特罗的作用，在炎症增加期间，如哮喘恶化期间，通过布地奈德治疗得以维持。
