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<p>To fill the gap in the knowledge between clinical studies and pre-clinical mechanistic studies using combined LABA/LAMA therapy, we hypothesized that the combination is more effective in attenuating excitation-contraction (E-C) coupling compared to either LAMA or LABA alone in human airway smooth muscle (HASM) cells. In primary HASM and human precision-cut lung slices (hPCLS) obtained from non-diseased donors, we show that the combination of umeclidinium (LAMA) and vilanterol (LABA) robustly attenuated carbachol-induced E-C coupling markers, compared to that induced by either compound individually. The effective concentrations of umeclidinium or vilanterol that attenuated E-C coupling signaling events were significantly decreased when the agents were combined as compared to dosing of either alone. In HASM cells treated overnight with albuterol to induce β<sub>2</sub>AR desensitization, umeclidinium or the umeclidinium-vilanterol combination attenuated carbachol-induced E-C coupling signaling. Furthermore, the umeclidinium-vilanterol combination showed little change in the ability to dilate pre-constricted hPCLS in the presence of albuterol-induced β<sub>2</sub>AR desensitization compared to relaxation to vilanterol alone, which was significantly attenuated by albuterol-induced desensitization. Our data suggest that targeting G<sub>αq</sub> and G<sub>αi</sub> signaling through muscarinic receptor antagonism serves as an effective therapy for obstructive lung diseases, even in the face of β<sub>2</sub>AR tachyphylaxis.</p>

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Long-acting β2 agonist (LABA) with a long-acting muscarinic receptor antagonist (LAMA) promotes human airway smooth muscle (HASM) relaxation and circumvents β2 adrenergic receptor tachyphylaxis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月3日

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  • Joseph Jude,
  • Nikhil Karmacharya,
  • Rinzhin T. Sherpa,
  • Thomas G. O’Riordan,
  • Cynthia J. Koziol-White,
  • Reynold A. Jr. Panettieri

摘要

To fill the gap in the knowledge between clinical studies and pre-clinical mechanistic studies using combined LABA/LAMA therapy, we hypothesized that the combination is more effective in attenuating excitation-contraction (E-C) coupling compared to either LAMA or LABA alone in human airway smooth muscle (HASM) cells. In primary HASM and human precision-cut lung slices (hPCLS) obtained from non-diseased donors, we show that the combination of umeclidinium (LAMA) and vilanterol (LABA) robustly attenuated carbachol-induced E-C coupling markers, compared to that induced by either compound individually. The effective concentrations of umeclidinium or vilanterol that attenuated E-C coupling signaling events were significantly decreased when the agents were combined as compared to dosing of either alone. In HASM cells treated overnight with albuterol to induce β2AR desensitization, umeclidinium or the umeclidinium-vilanterol combination attenuated carbachol-induced E-C coupling signaling. Furthermore, the umeclidinium-vilanterol combination showed little change in the ability to dilate pre-constricted hPCLS in the presence of albuterol-induced β2AR desensitization compared to relaxation to vilanterol alone, which was significantly attenuated by albuterol-induced desensitization. Our data suggest that targeting Gαq and Gαi signaling through muscarinic receptor antagonism serves as an effective therapy for obstructive lung diseases, even in the face of β2AR tachyphylaxis.