Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Miami and Miller School of Medicine, Florida, USA.
Am J Respir Cell Mol Biol. 2012 Apr;46(4):551-8. doi: 10.1165/rcmb.2011-0220OC. Epub 2011 Dec 8.
Although inhaled bronchodilators are commonly used in the treatment of airway disease to dilate airway smooth muscle, little is known regarding the mechanisms that regulate albuterol movement across the epithelium to reach its target, the airway smooth muscle. Because the rate of onset depends on the transepithelial transport of albuterol, to determine the mechanisms that regulate the transepithelial movement of albuterol is essential. Human bronchial epithelial cells, fully redifferentiated in culture at the air-liquid interface, were used to study the cellular uptake and total transepithelial flux of (3)H-albuterol from the apical to the basolateral surfaces. (3)H-mannitol and transepithelial electrical resistance were used to quantify changes in paracellular permeability. The majority of albuterol flux across the epithelium occurred via the paracellular route. The cellular uptake of albuterol was found to be saturable, whereas transepithelial flux was not. Cellular uptake could be inhibited by the amino acids lysine and histidine, with no effect on net transepithelial flux. Transepithelial flux was altered by maneuvers that collapsed or disrupted intercellular junctions. Acidification, usually seen in exacerbations of airway disease, decreased albuterol flux. In addition, albuterol increased its own paracellular permeability. The ability of albuterol to modulate paracellular permeability was blocked by the β(2)-adrenergic receptor-selective antagonist ICI 118551. Albuterol mainly crosses the epithelium via the paracellular pathway, but has the ability to modulate its own permeability through changes in the leakiness of tight junctions, which is modulated through the signaling of the β(2)-adrenergic receptor.
尽管吸入性支气管扩张剂常用于治疗气道疾病以扩张气道平滑肌，但对于调节沙丁胺醇穿过上皮细胞到达其作用靶点气道平滑肌的机制知之甚少。由于沙丁胺醇的起效速度取决于其跨上皮转运，因此确定调节其跨上皮转运的机制至关重要。本研究采用在气液界面完全分化的人支气管上皮细胞，研究（3）H-沙丁胺醇从顶侧向基底外侧的细胞内摄取和总跨上皮转运。（3）H-甘露醇和跨上皮电阻用于定量细胞旁通透性的变化。（3）H-沙丁胺醇大部分通过细胞旁途径穿过上皮细胞。发现沙丁胺醇的细胞内摄取是饱和的，而跨上皮转运不是。细胞内摄取可被氨基酸赖氨酸和组氨酸抑制，但对净跨上皮转运无影响。跨上皮转运可通过破坏细胞间连接的操作而改变。通常在气道疾病加重时发生的酸化可降低沙丁胺醇的转运。此外，沙丁胺醇可增加其自身的细胞旁通透性。β（2）-肾上腺素能受体选择性拮抗剂 ICI 118551 可阻断沙丁胺醇对细胞旁通透性的调节作用。沙丁胺醇主要通过细胞旁途径穿过上皮细胞，但可通过改变紧密连接的通透性来调节自身通透性，这种通透性的改变是通过β（2）-肾上腺素能受体的信号转导来调节的。
