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首页> 外文期刊>American Journal of Physiology >TGF-beta potentiates airway smooth muscle responsiveness to bradykinin.
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TGF-beta potentiates airway smooth muscle responsiveness to bradykinin.

机译：TGF-β增强了气道平滑肌对缓激肽的反应性。

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The molecular mechanisms by which bradykinin induces excessive airway obstruction in asthmatics remain unknown. Transforming growth factor (TGF)-beta has been involved in regulating airway inflammation and remodeling in asthma, although it is unknown whether TGF-beta can modulate bradykinin-associated bronchial hyperresponsiveness. To test whether TGF-beta directly modulates airway smooth muscle (ASM) responsiveness to bradykinin, isolated murine tracheal rings were used to assess whether TGF-beta alters ASM contractile responsiveness to bradykinin. Interestingly, we found TGF-beta-treated murine rings (12.5 ng/ml, 18 h) exhibited increased expression of bradykinin 2 (B(2)) receptors and became hyperreactive to bradykinin, as shown by increases in maximal contractile responses and receptor distribution. We investigated the effect of TGF-beta on bradykinin-evoked calcium signals since calcium is a key molecule regulating ASM excitation-contraction coupling. We reported that TGF-beta, in a dose- (0.5-10 ng/ml) and time- (2-24 h) dependent manner, increased mRNA and protein expression of the B(2) receptor in cultured human ASM cells. Maximal B(2) receptor protein expression that colocalized with CD44, a marker of membrane cell surface, occurred after 18 h of TGF-beta treatment and was further confirmed using fluorescence microscopy. TGF-beta (2.5 ng/ml, 18 h) also increased bradykinin-induced intracellular calcium mobilization in fura-2-loaded ASM cells. TGF-beta-mediated enhancement of calcium mobilization was not attenuated with indomethacin, a cyclooxygenase inhibitor. These data demonstrate for the first time that TGF-beta may play a role in mediating airway hyperresponsiveness to bradykinin seen in asthmatics by enhancing ASM contractile responsiveness to bradykinin, possibly as a result of increased B(2) receptor expression and signaling.
机译：缓激肽诱导哮喘患者过度气道阻塞的分子机制仍然未知。转化生长因子（TGF）-β已参与调节哮喘的气道炎症和重塑，尽管尚不清楚TGF-β是否能调节缓激肽相关的支气管高反应性。为了测试TGF-β是否直接调节气道平滑肌（ASM）对缓激肽的反应性，使用了隔离的鼠气管环评估TGF-β是否改变了ASM对缓激肽的收缩反应性。有趣的是，我们发现TGF-β处理的鼠环（12.5 ng / ml，18 h）表现出缓激肽2（B（2））受体的表达增加，并且对缓激肽反应过度，如最大收缩反应和受体分布的增加所示。由于钙是调节ASM激发-收缩偶联的关键分子，因此我们研究了TGF-β对缓激肽诱发的钙信号的影响。我们报告说，TGF-β以剂量（0.5-10 ng / ml）和时间（2-24 h）依赖性，在培养的人ASM细胞中增加了B（2）受体的mRNA和蛋白质表达。 TGF-β处理18小时后发生与CD44（膜细胞表面标志物）共定位的最大B（2）受体蛋白表达，并使用荧光显微镜进一步证实。 TGF-beta（2.5 ng / ml，18 h）还在呋喃2加载的ASM细胞中增加了缓激肽诱导的细胞内钙动员。 TGF-β介导的钙动员增强并未被消炎痛（一种环加氧酶抑制剂）减弱。这些数据首次表明，TGF-β可能通过增强ASM对缓激肽的收缩反应，可能在介导哮喘患者对缓激肽的气道高反应性中发挥作用，这可能是由于B（2）受体表达和信号转导增加所致。

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