AUTHOR=Yoshiyasu Nobuyuki , Matsuki Rei , Sato Masaaki , Urushiyama Hirokazu , Toda Etsuko , Terasaki Yasuhiro , Suzuki Masaki , Shinozaki-Ushiku Aya , Terashima Yuya , Nakajima Jun 

TITLE=Disulfiram, an Anti-alcoholic Drug, Targets Macrophages and Attenuates Acute Rejection in Rat Lung Allografts

JOURNAL=Transplant International

VOLUME=Volume 37 - 2024

YEAR=2024

URL=https://www.frontierspartnerships.org/journals/transplant-international/articles/10.3389/ti.2024.12556

DOI=10.3389/ti.2024.12556

ISSN=1432-2277

ABSTRACT=Macrophages contribute to post-transplant lung rejection. Disulfiram (DSF), an antialcoholic drug, has an anti-inflammatory effect and regulates macrophage chemotactic activity. Here, we investigated DSF efficacy in suppressing acute rejection post-lung transplantation. Male Lewis rats (280-300 g) received orthotopic left lung transplants from Fisher 344 rats (minor histocompatibility antigenmismatched transplantation). DSF (0.75 mg/h) monotherapy or co-solvent only (50% hydroxypropyl-β-cyclodextrin) as control was subcutaneously administered for 7 days (n = 10/group). No post-transplant immunosuppressant was administered.Grades of acute rejection, infiltration of immune cells positive for CD68, CD3, or CD79a, and gene expression of monocyte chemoattractant protein and proinflammatory cytokines in the grafts were assessed 7 days post-transplantation. The DSF-treated group had significantly milder lymphocytic bronchiolitis than the control group. The infiltration levels of CD68+ or CD3+ cells to the peribronchial area were significantly lowerless in the DSF than in the control groups. The normalized expression of chemokine ligand 2 and interleukin-6 mRNA in allografts was lower in the DSF than in the control groups. Validation assay revealed interleukin-6 expression to be significantly lower in the DSF than in the control groups. DSF can alleviate acute rejection post-lung transplantation by reducing macrophage accumulation around peripheral bronchi and suppressing pro-inflammatory cytokine expression.