PROTECTIVE EFFECTS OF A GLUCOCORTICOID ON DOWN-REGULATION OF PULMONARY BETA(2)-ADRENERGIC RECEPTORS IN-VIVO
PROTECTIVE EFFECTS OF A GLUCOCORTICOID ON DOWN-REGULATION OF PULMONARY BETA(2)-ADRENERGIC RECEPTORS IN-VIVO
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DOI：
10.1172/jci118084
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发表时间：
1995-07-01
影响因子：
15.9
通讯作者：
BARNES, PJ
中科院分区：
文献类型：
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作者：
MAK, JCW;NISHIKAWA, M;BARNES, PJ
我们研究了糖皮质激素对大鼠肺中β激动剂诱导的β（1）和β（2）肾上腺素能受体下调（通过[I-125]碘氰基吲哚酚结合测定）、mRNA表达（通过北方印迹法评估）和基因转录（使用核连续试验）的体内影响。地塞米松（Dex）（0.2 mg/kg/d，第1-8天）使β（1）和β（2）受体数量分别比对照组增加70%和69%，但未改变其mRNA表达。异丙肾上腺素（Iso）（0.96 mg/kg/d，第2-8天）使β（1）和β（2）受体数量分别减少48%和51%，并使mRNA表达分别减少69%和57%。Dex和Iso的组合导致β 2受体数量及其mRNA表达没有净变化，尽管β 1受体数量和mRNA表达显著减少。通过受体放射自显影术绘制的β（1）和β（2）受体图谱证实了肺泡、上皮、内皮、气道和血管平滑肌的这些发现。我们还测量了激活的转录因子，环磷酸腺苷反应元件结合蛋白（CREB）使用电泳迁移率变动分析，CREB样DNA结合活性降低后，异丙肾上腺素治疗，但这种减少后，与地塞米松治疗。细胞核连续分析显示，β（1）受体基因的转录率在地塞米松治疗后没有改变，但在异丙肾上腺素治疗后降低。β 2受体基因的转录率在Dex治疗后增加了约两倍，但在Iso治疗后没有变化。我们的结论是，糖皮质激素可以防止同源下调β（2）-受体的数量和mRNA的表达在转录水平上不影响β（1）-受体和转录因子CREB可能参与了这一现象。这种作用可能对预防接受β受体激动剂支气管扩张剂治疗的哮喘患者对β受体激动剂产生耐受性具有临床意义。
We investigated the in vivo effects of a glucocorticoid on beta-agonist-induced downregulation of beta(1)- and beta(2)-adrenergic receptors( determined by [I-125] iodocyanopindolol binding), mRNA expression (assessed by Northern blotting), and gene transcription (using nuclear run-on assays) in rat lung. Dexamethasone (Dex) (0.2 mg/kg/d, days 1-8) increased beta(1)- and beta(2)-receptor numbers by 70 and 69% above control, respectively, but did not change their mRNA expression. Isoproterenol (Iso) (0.96 mg/kg/d, days 2-8) decreased beta(1) and beta(2)-receptor numbers by 48 and 51%; respectively, and also reduced mRNA expression by 69 and 57%, respectively. The combination of Dex and Iso resulted in no net change in beta 2-receptor number and its mRNA expression, although there was a significant reduction in beta 1-receptor number and mRNA expression. The mapping of beta(1)- and beta(2)-receptors by receptor autoradiography confirmed these findings over alveoli, epithelium, endothelium, and airway and vascular smooth muscle. We also measured the activation of the transcription factor, cyclic AMP response element binding protein (CREB) using an electrophoretic mobility shift assay, CREB-like DNA-binding activity was decreased after Iso treatment but this decrease was prevented after treatment with Dex. Nuclear run-on assays revealed that the transcription rate of the beta(1)-receptor gene did not alter after Dex treatment, but was reduced after Iso treatment. The transcription rate of the beta(2)-receptor gene was increased after Dex treatment by approximately twofold, but there was no change after Iso treatment. We conclude that glucocorticoids can prevent homologous downregulation of beta(2)-receptor number and mRNA expression at the transcriptional level without affecting beta(1)-receptors and that the transcription factor CREB may be involved in this phenomenon. Such an effect may have clinical implications for preventing the development of tolerance to beta(2)-agonists in asthmatic patients treated with beta-agonist bronchodilators.