TY - JOUR
T1 - Halofuginone treatment reduces interleukin-17A and ameliorates features of chronic lung allograft dysfunction in a mouse orthotopic lung transplant model
AU - Oishi, Hisashi
AU - Martinu, Tereza
AU - Sato, Masaaki
AU - Matsuda, Yasushi
AU - Hirayama, Shin
AU - Juvet, Stephen C.
AU - Guan, Zehong
AU - Saito, Tomohito
AU - Cypel, Marcelo
AU - Hwang, David M.
AU - Keller, Tracy L.
AU - Whitman, Malcolm R.
AU - Liu, Mingyao
AU - Keshavjee, Shaf
N1 - Funding Information:
The authors have no conflicts of interest to disclose. This research was supported by the Canadian Institutes of Health Research (OOP 312227) and Canadian Cystic Fibrosis Foundation. We thank Jerome Valero for assistance in editing the manuscript. We also thank Paul Chartrand, manager of the Latner Thoracic Surgery Research Laboratories, for organizing and facilitating lung tissue sample processing and analysis. We also acknowledge Deborah Scollard for assistance in micro-CT imaging.
Publisher Copyright:
© 2016 International Society for Heart and Lung Transplantation.
PY - 2016/4/1
Y1 - 2016/4/1
N2 - 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 alloantigen-mismatched 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-17A-positive 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-β1 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.
AB - 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 alloantigen-mismatched 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-17A-positive 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-β1 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.
KW - IL-17
KW - chronic lung allograft dysfunction
KW - halofuginone
KW - obliterative bronchiolitis
KW - restrictive allograft syndrome
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U2 - 10.1016/j.healun.2015.12.003
DO - 10.1016/j.healun.2015.12.003
M3 - Article
C2 - 26787621
AN - SCOPUS:84954348243
VL - 35
SP - 518
EP - 527
JO - Journal of Heart and Lung Transplantation
JF - Journal of Heart and Lung Transplantation
SN - 1053-2498
IS - 4
ER -