Department of Physiology and Pharmacology and Robarts Research Institute, University of Western Ontario, London, Ontario, Canada
Anesthesiology. 2013 May;118(5):1065-75. doi: 10.1097/ALN.0b013e31828e180e.
Volatile anesthetics act primarily through upregulating the activity of γ-aminobutyric acid type A (GABAA) receptors. They also exhibit antiinflammatory actions in the lung. Rodent alveolar type II (ATII) epithelial cells express GABAA receptors and the inflammatory factor cyclooxygenase-2 (COX-2). The goal of this study was to determine whether human ATII cells also express GABAA receptors and whether volatile anesthetics upregulate GABAA receptor activity, thereby reducing the expression of COX-2 in ATII cells.
The expression of GABAA receptor subunits and COX-2 in ATII cells of human lung tissue and in the human ATII cell line A549 was studied with immunostaining and immunoblot analyses. Patch clamp recordings were used to study the functional and pharmacological properties of GABAA receptors in cultured A549 cells.
ATII cells in human lungs and cultured A549 cells expressed GABAA receptor subunits and COX-2. GABA induced currents in A549 cells, with half-maximal effective concentration of 2.5 µM. Isoflurane (0.1-250 µM) enhanced the GABA currents, which were partially inhibited by bicuculline. Treating A549 cells with muscimol or with isoflurane (250 µM) reduced the expression of COX-2, an effect that was attenuated by cotreatment with bicuculline.
GABAA receptors expressed by human ATII cells differ pharmacologically from those in neurons, exhibiting a higher affinity for GABA and lower sensitivity to bicuculline. Clinically relevant concentrations of isoflurane increased the activity of GABAA receptors and reduced the expression of COX-2 in ATII cells. These findings reveal a novel mechanism that could contribute to the antiinflammatory effect of isoflurane in the human lung.
挥发性麻醉剂主要通过上调 γ-氨基丁酸 A 型（GABAA）受体的活性起作用。它们在肺部也表现出抗炎作用。啮齿动物肺泡 II 型（ATII）上皮细胞表达 GABAA 受体和炎症因子环氧化酶-2（COX-2）。本研究的目的是确定人 ATII 细胞是否也表达 GABAA 受体，以及挥发性麻醉剂是否上调 GABAA 受体活性，从而降低 ATII 细胞中 COX-2 的表达。
通过免疫染色和免疫印迹分析研究人肺组织 ATII 细胞和人 ATII 细胞系 A549 中 GABAA 受体亚基和 COX-2 的表达。使用膜片钳记录研究培养的 A549 细胞中 GABAA 受体的功能和药理学特性。
人肺中的 ATII 细胞和培养的 A549 细胞表达 GABAA 受体亚基和 COX-2。GABA 在 A549 细胞中诱导电流，半数有效浓度为 2.5µM。异氟烷（0.1-250µM）增强 GABA 电流，该电流部分被 Bicuculline 抑制。用 Muscimol 或异氟烷（250µM）处理 A549 细胞可降低 COX-2 的表达，这种作用可被 Bicuculline 共同处理所减弱。
人 ATII 细胞表达的 GABAA 受体在药理学上与神经元中的 GABAA 受体不同，对 GABA 的亲和力更高，对 Bicuculline 的敏感性更低。临床相关浓度的异氟烷增加了 GABAA 受体的活性，并降低了 ATII 细胞中 COX-2 的表达。这些发现揭示了一种新的机制，可能有助于异氟烷在人肺中的抗炎作用。
