Halofuginone treatment reduces interleukin-17A and ameliorates features of chronic lung allograft dysfunction in a mouse orthotopic lung transplant model.
J Heart Lung Transplant
; 35(4): 518-27, 2016 Apr.
Article
em En
| MEDLINE
| ID: mdl-26787621
ABSTRACT
BACKGROUND:
Increasing evidence suggests that interleukin (IL)-17A plays an important role in chronic lung allograft dysfunction (CLAD), characterized by airway and lung parenchymal fibrosis, after lung transplantation. Halofuginone is a plant derivative that has been shown to inhibit Th17 differentiation. The purpose of this study was to examine the effect of halofuginone on CLAD development using a minor alloantigenâmismatched mouse orthotopic lung transplant model.METHODS:
C57BL/6 recipient mice received an orthotopic left lung transplant from C57BL/10 donors, mismatched for minor antigens. Lung transplant recipients received daily intraperitoneal injections of 2.5 µg halofuginone or vehicle alone. Lung grafts were assessed on Days 7, 14, and 28 post-transplant.RESULTS:
Compared with control mice, on Day 28 post-transplant, lung grafts of mice treated with halofuginone showed a significant reduction in the percentage of obliterated airways (6.8 ± 4.7% vs 52.5 ± 13.8%, p < 0.01), as well as significantly reduced parenchymal fibrosis (5.5 ± 2.3% vs 35.9 ± 10.9%, p < 0.05). Immunofluorescent staining for IL-17A demonstrated a decreased number and frequency of IL-17Aâpositive cells in halofuginone-treated lung grafts on Day 28, as compared with controls. Halofuginone treatment also decreased IL-17A and IL-22 transcripts at Day 14, transforming growth factor-ß1 and matrix metalloproteinase-2 transcripts at Days 14 and 28.CONCLUSION:
The beneficial effect of halofuginone on development of airway and lung parenchymal fibrosis in the mouse lung transplant model highlights the important role of IL-17A in CLAD and merits further pre-clinical and clinical studies.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Piperidinas
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Transplante de Pulmão
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Interleucina-17
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Quinazolinonas
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Rejeição de Enxerto
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article