Dataset Information

Rosiglitazone reverses salbutamol-induced ?(2) -adrenoceptor tolerance in airway smooth muscle.

ABSTRACT: BACKGROUND AND PURPOSE: ??-Adrenoceptor agonists are important therapeutic agents in the treatment of asthma and chronic obstructive pulmonary disease. The regular use of these drugs has been associated with proasthmatic-like changes that limit their efficacy and increase the risk of severe adverse reactions. We investigated whether the peroxisome-proliferator-activated receptor (PPAR)? agonist rosiglitazone modulated salbutamol-induced ??-adrenoceptor desensitization in vivo and in vitro. EXPERIMENTAL APPROACH: An in vivo model of homologous ??-adrenoceptor desensitization, established in guinea-pigs by administering salbutamol continuously, was used to study the ability of rosiglitazone to prevent ??-adrenoceptor tolerance. In vitro experiments on human bronchial smooth muscle cells were performed to increase the clinical relevance of the study. KEY RESULTS: In tracheal smooth muscle tissues from desensitized animals, we observed a decrease in the protective effect of salbutamol on carbachol-induced contraction, a hyperresponsiveness to cholinergic stimuli, a modest underexpression of ??-adrenoceptor gene and a marked decrease in ?-adrenoceptor number, relative to control values. Treatment with rosiglitazone preserved salbutamol relaxant activity, mitigated carbachol hyperresponsiveness and partially restored ??-adrenoceptor binding sites in tracheal tissues from homologously desensitized animals. The highly selective PPAR? agonist, GW1929, reproduced the effect of rosiglitazone, in vivo. In vitro ??-adrenoceptor desensitization decreased salbutamol-mediated cAMP production, without affecting forskolin responses and ??-adrenoceptor expression. Rosiglitazone and 15-deoxy-?¹²(,)¹?-prostaglandin J? restored salbutamol sensitivity in homologously desensitized cells. CONCLUSIONS AND IMPLICATIONS: These data suggest a potential pharmacodynamic interaction between PPAR? agonists and salbutamol on airway smooth muscle responsiveness, supporting the therapeutic potential of this combination in chronic airway disease.

SUBMITTER: Fogli S

PROVIDER: S-EPMC3031059 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Rosiglitazone reverses salbutamol-induced β(2) -adrenoceptor tolerance in airway smooth muscle.

Fogli Stefano S Pellegrini Silvia S Adinolfi Barbara B Mariotti Veronica V Melissari Erika E Betti Laura L Fabbrini Laura L Giannaccini Gino G Lucacchini Antonio A Bardelli Claudio C Stefanelli Fabio F Brunelleschi Sandra S Breschi Maria Cristina MC

British journal of pharmacology 20110101 2

<h4>Background and purpose</h4>β₂-Adrenoceptor agonists are important therapeutic agents in the treatment of asthma and chronic obstructive pulmonary disease. The regular use of these drugs has been associated with proasthmatic-like changes that limit their efficacy and increase the risk of severe adverse reactions. We investigated whether the peroxisome-proliferator-activated receptor (PPAR)γ agonist rosiglitazone modulated salbutamol-induced β₂-adrenoceptor desensitization in vivo and in vitro ...[more]

PMID: 20840543

Similar Datasets

Project description:Rhinovirus (RV) infections account for approximately two thirds of all virus-induced asthma exacerbations and often result in an impaired response to ?2 agonist therapy. Using an in vitro model of RV infection, we investigated the mechanisms underlying RV-induced ?2 adrenoceptor desensitization in primary human airway smooth muscle cells (ASMC). RV infection of primary human bronchial epithelial cells (HBEC) for 24 hours produced conditioned medium that caused ?2 adrenoceptor desensitization on ASMCs without an effect on ASMCs viability. Less than 3 kDa size fractionation together with trypsin digestion of RV-induced conditioned medium did not prevent ?2 adrenoceptor desensitization, suggesting it could potentially be mediated by a small peptide or lipid. RV infection of BECs, ASMCs and fibroblasts produced prostaglandins, of which PGE2, PGF2? and PGI2 had the ability to cause ?2 adrenoceptor desensitization on ASMCs. RV-induced conditioned medium from HBECs depleted of PGE2 did not prevent ASMC ?2 adrenoceptor desensitization; however this medium induced PGE2 from ASMCs, suggesting that autocrine prostaglandin production may be responsible. Using inhibitors of cyclooxygenase and prostaglandin receptor antagonists, we found that ?2 adrenoceptor desensitization was mediated through ASMC derived COX-2 induced prostaglandins. Since ASMC prostaglandin production is unlikely to be caused by RV-induced epithelial derived proteins or lipids we next investigated activation of toll-like receptors (TLR) by viral RNA. The combination of TLR agonists poly I:C and imiquimod induced PGE2 and ?2 adrenoceptor desensitization on ASMC as did the RNA extracted from RV-induced conditioned medium. Viral RNA but not epithelial RNA caused ?2 adrenoceptor desensitization confirming that viral RNA and not endogenous human RNA was responsible. It was deduced that the mechanism by which ?2 adrenoceptor desensitization occurs was by pattern recognition receptor activation of COX-2 induced prostaglandins.

Dataset Information

Rosiglitazone reverses salbutamol-induced ?(2) -adrenoceptor tolerance in airway smooth muscle.

Publications

Rosiglitazone reverses salbutamol-induced β(2) -adrenoceptor tolerance in airway smooth muscle.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets