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 - Abstract

Sep 30, 2026

Uploaded by Mary Man

To fill the knowledge gap between clinical studies and pre-clinical mechanistic work on combined LABA/LAMA therapy, the study tests whether the combination better attenuates excitation-contraction (E-C) coupling than either agent alone in human airway smooth muscle cells. In primary HASM and human precision-cut lung slices, umeclidinium plus vilanterol robustly reduces carbachol-induced E-C coupling markers with lower effective concentrations than monotherapy, including under β2AR desensitization.

LanguageEnglish

CategoryHealthcare

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Pages11

Reading Time28 min

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Abstract

Background and clinical rationale

Study mechanistic focus on E-C coupling

Jude et al. Respiratory Research (2026) 27:6 [https://doi.org/10.1186/s12931-025-03427-y](https://doi.org/10.1186/s12931-025-03427-y) Respiratory Research RESEARCH Open Access 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 Joseph Jude 1,3*†, Nikhil Karmacharya 1†, RinzhinT. Sherpa 1, Thomas G. O’Riordan2, Cynthia J. Koziol-White 1 and Reynold A. Jr. Panettieri 1 Abstract 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 umeclidiniumor 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. Keywords Asthma, Chronic obstructive lung disease, β2 agonist tolerance, Bronchodilation, Bronchoconstriction, Persistent airflow obstruction †Joseph Jude and Nikhil Karmacharya contributed equally as co-first authors. *Correspondence: Joseph Jude [joseph.antonyjude@rutgers.edu](joseph.antonyjude@rutgers.edu) 1Rutgers Institute for Translational Medicine and Science (RITMS), Rutgers, The State University of New Jersey, 89 French Street, Room 4212, New Brunswick, NJ 08901, USA 2Aerogen Pharma Corporation, 1660 S. Amphlett Blvd, Suite 360, San Mateo, CA 94402, USA 3Room \#4276, 89, French Street, New Brunswick, NJ 08901, USA © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creati](http://creati)[vecommons.org/l](vecommons.org/l)icenses/by-nc-nd/4.0/. Jude et al. Respiratory Research (2026) 27:6 Introduction Bronchoconstriction mediated predominantly by airway smooth muscle shortening, inflammation and remodeling are the salient features of asthma and COPD. Clinical challenges remain in tre

FAQs

What hypothesis is tested about combined LABA/LAMA therapy?

The study hypothesizes that the LABA/LAMA combination attenuates excitation-contraction coupling more effectively than either LAMA or LABA alone in human airway smooth muscle cells.

How do umeclidinium and vilanterol affect E-C coupling in airway tissue?

The combination robustly attenuates carbachol-induced E-C coupling markers in primary HASM and human precision-cut lung slices, with reduced effective concentrations compared with either compound alone.

How does β2AR tachyphylaxis or desensitization influence bronchodilation results?

After overnight albuterol treatment that induces β2AR desensitization, umeclidinium or the umeclidinium-vilanterol combination still attenuates E-C coupling; the combination shows little change in dilating pre-constricted lung slices compared with relaxation to vilanterol alone, which is significantly attenuated under desensitization.

Sep 30, 2026

Uploaded by Mary Man