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Liver X Receptor Agonists Increase Airway Reactivity in a Model of Asthma via Increasing Airway Smooth Muscle Growth¹

Mark A. Birrell^*, Jorge De Alba^*, Matthew C. Catley^*, Elizabeth Hardaker^*, Sissie Wong^*, Michael Collins^*, Deborah L. Clarke^*, Stuart N. Farrow, Timothy M. Willson, Jon L. Collins and Maria G. Belvisi^2,*

^* Respiratory Pharmacology, Airway Disease Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom; Department of Asthma Biology, GlaxoSmithKline PLC, Stevenage, United Kingdom; and Research Triangle Park, NC 27709

The liver X receptors (LXR/β) are orphan nuclear receptors that are expressed in a large number of cell types and have been shown to have anti-inflammatory properties. Nuclear receptors have previously proved to be amenable targets for small molecular mass pharmacological agents in asthma, and so the effect of an LXR ligand was assessed in models of allergic airway inflammation. LXR agonist, GW 3965, was profiled in rat and mouse models of allergic asthma. In the Brown Norway rats, GW 3965 (3–30 mg/kg) was unable to reduce the bronchoalveolar lavage eosinophilia associated with this model and had no impact on inflammatory biomarkers (eotaxin and IL-1β). The compound did significantly stimulate ABCA-1 (ATP-binding cassette A1) mRNA expression, indicating that there was adequate exposure/LXR activation. In the mouse model, the LXR ligand surprisingly increased airway reactivity, an effect that was apparent in both the Ag and nonchallenged groups. This increase was not associated with a change in lung tissue inflammation or number of mucus-containing cells. There was, however, a marked increase in airway smooth muscle thickness in both treated groups. We demonstrated an increase in contractile response to exogenous methacholine in isolated airways taken from LXR agonist-treated animals compared with the relevant control tissue. We corroborated these findings in a human system by demonstrating increased proliferation of cultured airway smooth muscle. This phenomenon, if evidenced in man, would indicate that LXR ligands may directly increase airway reactivity, which could be detrimental, especially in patients with existing respiratory disease and with already compromised lung function.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ The authors were funded by Imperial College, Imperial College Trust.

² Address correspondence and reprint requests to Dr. Maria G. Belvisi, Respiratory Pharmacology Group, Imperial College, Faculty of Medicine, National Heart & Lung Institute, Dovehouse Street, London SW3 6LY, United Kingdom. E-mail address: m.belvisi{at}imperial.ac.uk

³ Abbreviations used in this paper: LXR, liver X receptor; ABCA-1, ATP-binding cassette A1; AHR, airway hyperreactivity; ASM, airway smooth muscle; HASM, human airway smooth muscle; MCh, methacholine.