Faisy Christophe, Pinto Francisco, Danel Claire, Naline Emmanuel, Risse Paul-Andre, Leroy Ingrid, Israel-Biet Dominique, Fagon Jean-Yves, Candenas Maria-Luz, Advenier Charles
UPRES EA220, UFR Biomédicale des Saints-Pères, 45 rue des Saints-Pères, 75006 Paris, France.
Am J Respir Cell Mol Biol. 2006 Apr;34(4):410-6. doi: 10.1165/rcmb.2005-0091OC. Epub 2005 Dec 9.
Chronic exposure of human isolated bronchi to beta(2)-adrenergic agonists, especially fenoterol, potentiates smooth muscle contraction in response to endothelin-1 (ET-1), a peptide implicated in chronic inflammatory airway diseases. Our objective was to determine whether ET-1 receptors ETA and ETB are involved in fenoterol enhancement. Twenty-two human bronchi were sensitized to ET-1 by prolonged incubation with 0.1 microM fenoterol (15 h, 21 degrees C). Removing the epithelium after fenoterol incubation limited the maximal contraction (0.10+/-0.36 g without epithelium versus 1.18+/-0.22 with, n=8, P=0.04). After 15 h incubation, 14 and 8 paired rings were fixed, respectively, for immunolabeling of bronchial ETA and ETB receptors, and to determine the mRNA expression levels using real-time quantitative reverse transcription polymerase chain reaction. ETA and ETB receptor mRNA expressions were 1.27- +/- 0.14-fold (not significant) and 2.24- +/- 0.28-fold (P<0.01) higher, respectively, in fenoterol-treated bronchi than in paired controls. Fenoterol incubation significantly increased epithelial ETA and ETB receptor labeling intensity scores (P=0.001 and P=0.002, respectively, versus controls), and enhanced the diffuse localization of ETA receptors on the epithelial cells (P=0.002 versus controls), but did not change the ETB-receptor immunolabeling intensity on airway smooth muscle. We conclude that fenoterol-induced sensitization of human isolated bronchi involves epithelial ETA and ETB receptors, which suggests perturbation of the epithelial regulation of airway smooth muscle contraction in response to ET-1.
人体离体支气管长期暴露于β₂肾上腺素能激动剂，尤其是非诺特罗，会增强其对内皮素-1（ET-1）的平滑肌收缩反应，ET-1是一种与慢性炎症性气道疾病有关的肽。我们的目的是确定ET-1受体ETA和ETB是否参与非诺特罗增强作用。将22条人体支气管与0.1微摩尔非诺特罗长时间孵育（15小时，21摄氏度）使其对ET-1致敏。非诺特罗孵育后去除上皮细胞可限制最大收缩幅度（无上皮细胞时为0.10±0.36克，有上皮细胞时为1.18±0.22克，n = 8，P = 0.04）。孵育15小时后，分别固定14对和8对环，用于支气管ETA和ETB受体的免疫标记，并使用实时定量逆转录聚合酶链反应确定mRNA表达水平。与配对对照相比，非诺特罗处理的支气管中ETA和ETB受体mRNA表达分别高出1.27±0.14倍（无显著差异）和2.24±0.28倍（P<0.01）。非诺特罗孵育显著增加上皮细胞ETA和ETB受体标记强度评分（分别与对照相比，P = 0.001和P = 0.002），并增强ETA受体在上皮细胞上的弥漫性定位（与对照相比，P = 0.002），但未改变气道平滑肌上ETB受体的免疫标记强度。我们得出结论，非诺特罗诱导的人体离体支气管致敏涉及上皮细胞ETA和ETB受体，这表明在对ET-1的反应中，气道平滑肌收缩的上皮调节受到了干扰。
