Effects of azithromycin and tanomastat on experimental bronchiolitis obliterans.

Abstract

OBJECTIVE:

Azithromycin has become a standard of care in therapy of bronchiolitis obliterans following lung transplantation. Matrix metalloprotease-9 broncho-alveolar lavage levels increase in airway neutrophilia and bronchiolitis obliterans. Interleukin-17 may play a role in lung allograft rejection, and interleukin-12 is downregulated in bronchiolitis obliterans. Whether these mechanisms can be targeted by azithromycin remains unclear.

METHODS:

Bronchiolitis obliterans was induced by transplantation of Fischer F344 rat left lungs to Wistar Kyoto rats. Allografts with azithromycin therapy from day 1 to 28 or 56 and mono- or combination therapy with the broad-spectrum matrix metalloprotease inhibitor tanomastat from day 1 to 56 were compared to control allografts and isografts. Graft histology was assessed, and tissue cytokine expression studied using Western blotting and immunofluorescence.

RESULTS:

The chronic airway rejection score in the azithromycin group did not change between 4 and 8 weeks after transplantation, whereas it significantly worsened in control allografts (P = .041). Azithromycin+tanomastat prevented complete allograft fibrosis, which occurred in 40% of control allografts. Azithromycin reduced interleukin-17 expression (P = .049) and the number of IL-17(+)/CD8(+) lymphocytes at 4 weeks, and active matrix metalloprotease-9 at 8 weeks (P = .017), and increased interleukin-12 expression (P = .025) at 8 weeks following transplantation versus control allografts.

CONCLUSIONS:

The expression of interleukin-17 and matrix metalloprotease-9 in bronchiolitis obliterans may be attenuated by azithromycin, and the decrease in interleukin-12 expression was prevented by azithromycin. Combination of azithromycin with a matrix metalloprotease inhibitor is worth studying further because it prevented complete allograft fibrosis in this study.

• Authors: Katharina Krenn, Matthias Gmeiner, Patrick Paulus, Nezir Sela, Linda Torres, Karin Zins, Gerhard Dekan, Seyedhossein Aharinejad
• Journal: The Journal of thoracic and cardiovascular surgery (J Thorac Cardiovasc Surg) Vol. 149 Issue 4 Pg. 1194-202 (Apr 2015) ISSN: 1097-685X [Electronic] United States
• PMID: 25595376 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Chemical References

• Biphenyl Compounds
• Interleukin-17
• Matrix Metalloproteinase Inhibitors
• Phenylbutyrates
• Interleukin-12
• Azithromycin
• Bay 12-9566
• Matrix Metalloproteinase 9
• Mmp9 protein, rat

Topics

• Animals
• Azithromycin (pharmacology)
• Biphenyl Compounds (pharmacology)
• Bronchiolitis Obliterans (drug therapy, enzymology, etiology, pathology)
• Disease Models, Animal
• Drug Therapy, Combination
• Fibrosis
• Graft Survival (drug effects)
• Interleukin-12 (metabolism)
• Interleukin-17 (metabolism)
• Lung (drug effects, enzymology, pathology, surgery)
• Lung Transplantation
• Male
• Matrix Metalloproteinase 9 (metabolism)
• Matrix Metalloproteinase Inhibitors (pharmacology)
• Phenylbutyrates (pharmacology)
• Rats, Inbred F344
• Rats, Inbred WKY
• Time Factors