title: 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.affiliation: Department of Anesthesia and General Intensive Care, Medical University of Vienna, Vienna, Austria.
authors.forename: Katharina
authors.initials: K
authors.lastname: Krenn
authors.affiliation: Department of Cardiovascular Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gmeiner
authors.affiliation: Department of Cardiovascular Research, Medical University of Vienna, Vienna, Austria; Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, Goethe University Hospital, Frankfurt, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Paulus
authors.affiliation: Department of Cardiovascular Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Nezir
authors.initials: N
authors.lastname: Sela
authors.affiliation: Department of Cardiovascular Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Linda
authors.initials: L
authors.lastname: Torres
authors.affiliation: Department of Cardiovascular Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Karin
authors.initials: K
authors.lastname: Zins
authors.affiliation: Department of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Dekan
authors.affiliation: Department of Cardiovascular Research, Medical University of Vienna, Vienna, Austria; Department of Cardiac Surgery, Medical University of Vienna, Vienna, Austria. Electronic address: seyedhossein.aharinejad@meduniwien.ac.at.
authors.forename: Seyedhossein
authors.initials: S
authors.lastname: Aharinejad
mesh_terms: D000818:Animals; D017963:Azithromycin / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001989:Bronchiolitis Obliterans / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005355:Fibrosis; D006085:Graft Survival / Q000187:drug effects; D018664:Interleukin-12 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000601:surgery; D016040:Lung Transplantation; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D010654:Phenylbutyrates / Q000494:pharmacology*; D011916:Rats, Inbred F344; D011921:Rats, Inbred WKY; D013997:Time Factors
chemical_list: D001713:Biphenyl Compounds; D020381:Interleukin-17; D061965:Matrix Metalloproteinase Inhibitors; D010654:Phenylbutyrates; D018664:Interleukin-12; D017963:Azithromycin; C113281:Bay 12-9566; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat