Long-acting beta agonists enhance allergic airway disease

John M. Knight, Garbo Mak, Joanne Shaw, Paul Porter, Catherine McDermott, Luz Roberts, Ran You, Xiaoyi Yuan, Valentine O. Millien, Yuping Qian, Li Zhen Song, Vincent Frazier, Choel Kim, Jeong Joo Kim, Richard A. Bond, Joshua D. Milner, Yuan Zhang, Pijus K. Mandal, Amber Luong, Farrah KheradmandJohn S. McMurray, David B. Corry

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Asthma is one of the most common of medical illnesses and is treated in part by drugs that activate the beta-2-adrenoceptor (β2-AR) to dilate obstructed airways. Such drugs include long acting beta agonists (LABAs) that are paradoxically linked to excess asthma-related mortality. Here we show that LABAs such as salmeterol and structurally related β2-AR drugs such as formoterol and carvedilol, but not short-acting agonists (SABAs) such as albuterol, promote exaggerated asthma-like allergic airway disease and enhanced airway constriction in mice. We demonstrate that salmeterol aberrantly promotes activation of the allergic disease- related transcription factor signal transducer and activator of transcription 6 (STAT6) in multiple mouse and human cells. A novel inhibitor of STAT6, PM-242H, inhibited initiation of allergic disease induced by airway fungal challenge, reversed established allergic airway disease in mice, and blocked salmeterol-dependent enhanced allergic airway disease. Thus, structurally related β2-AR ligands aberrantly activate STAT6 and promote allergic airway disease. This untoward pharmacological property likely explains adverse outcomes observed with LABAs, which may be overcome by agents that antagonize STAT6.

Original languageEnglish (US)
Article numbere0142212
JournalPLoS ONE
Volume10
Issue number11
DOIs
StatePublished - Nov 1 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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