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Effects of Azithromycin on Glutathione S-Transferases in Cystic Fibrosis Airway Cells

¹ Cystic Fibrosis Center, Azienda Ospedaliera di Verona, Verona, Italy; ² Department of Pathology, General Pathology Section, University of Verona School of Medicine, Verona, Italy; ³ Department of Experimental Pathology & BMIE, General and Clinical Pathology Section, University of Pisa Medical School, Pisa, Italy; ⁴ Unit of Industrial Toxicology and Occupational Medicine, Université Catholique de Louvain, Brussels, Belgium; and ⁵ Department of Clinical Chemistry, Université Catholique de Louvain, Brussels, Belgium

Correspondence and requests for reprints should be addressed to Paola Melotti, M.D., Ph.D., Cystic Fibrosis Center - Azienda Ospedaliera di Verona, piazzale Stefani, 1 - 37126 Verona, Italy. E-mail: paolamelotti{at}libero.it

Anti-inflammatory properties of azithromycin (AZM) have been proposed as possible mechanisms of clinical beneficial effects in patients with cystic fibrosis (CF). Altered glutathione (GSH) transport in cystic fibrosis transmembrane regulator protein (CFTR)-deficient cells leads to the occurrence of oxidative stress that finally induces glutathione S-transferase (GST) activity. The present investigation was aimed to verify the effects of AZM on GST activity and expression in CF airway cells in vitro and in vivo. AZM exposure significantly decreased GSTT1 and GSTM1 mRNA and protein expression in IB3-1, restoring the levels to those observed in non-CF C38 cells, which also express lower levels of -glutamyltransferase (GGT) activity than IB3-1. In another CF cell line, 2CFSMEo-, AZM produced 45% reduction in GSTT1 and GSTM1 mRNA levels. AZM reduced GST activity by approximately 25% and 40% in IB3-1 and 2CFSMEo- cells, respectively. GSTP1 was similarly expressed in all CF and non-CF cells and was unaffected by AZM. The anti-inflammatory cytokine IL-10 down-modulated GST activity at similar levels, supporting a link between GST inhibition and anti-inflammatory properties of AZM. In bronchoalveolar lavage fluid of CF mice homozygous for the F508 del mutation, GSTM1 protein levels were undetectable after AZM treatment. The association between increased GST expression and activity, together with its reversal by AZM treatment in vitro and in vivo, suggest novel antioxidant properties for this drug. The issue whether decreased GST activity may directly concur to anti-inflammatory properties of AZM or is rather a marker of the oxidative status of CF cells will require additional studies.

Key Words: cystic fibrosis • azithromycin • inflammation • glutathione S-transferases • -glutamyltransferase

CLINICAL RELEVANCE Anti-inflammatory properties of this drug are consistent with the results of this work and relevant for the therapy of cystic fibrosis. The association between increased glutathione S-transferase expression and activity in cystic fibrosis, together with its reversal by azithromycin (AZM) treatment in vitro and in vivo, has been described. It suggests novel antioxidant properties for AZM.