Pirfenidone inhibits obliterative airway disease in a murine heterotopic tracheal transplant model.
BACKGROUND
Chronic lung allograft rejection in the form of bronchiolitis obliterans syndrome and its histopathologic correlate, obliterative bronchiolitis (OB), are a major source of morbidity and mortality after lung transplantation. Murine heterotopic tracheal transplants into fully allogeneic mismatched recipients develop obliterative airway disease (OAD), which is a suitable model of OB. Using this murine heterotopic tracheal allograft model, we evaluated the effect of pirfenidone, a novel antifibrotic agent, on the development of OAD.


METHODS
Mice transplanted with complete MHC-mismatched tracheal allografts received pirfenidone (0.5%) in pulverized food according to different schedules: daily for the first 14 days after transplantation or daily for the duration of the study beginning on posttransplantation days 0, 5, or 10.


RESULTS
Mice on a continuous daily regimen of pirfenidone failed to develop evidence of chronic allograft rejection at the termination of the study (60 days). Mice receiving pirfenidone limited to the early posttransplantation period had delayed onset of OAD to 60 days. Forty percent (2/5) of mice receiving a continuous regimen of pirfenidone beginning on day 5 after transplantation had no evidence of OAD at 28 days. However, when the drug was started on day 10, all mice developed OAD by 28 days.


CONCLUSIONS
Our results demonstrate a delay of onset or abrogation of OAD when pirfenidone is administered in the early posttransplantation period. These findings suggest that pirfenidone is a candidate drug to be evaluated for prevention of the fibrotic changes seen in OB in human recipients of lung transplants.
McKane
Brice W
BW
Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.
Fernandez
Felix
F
Narayanan
Kishore
K
Marshbank
Shawn
S
Margolin
Solomon B
SB
Jendrisak
Martin
M
Mohanakumar
T
T
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001989:Bronchiolitis Obliterans / Q000188:drug therapy* / Q000517:prevention & control*; D002908:Chronic Disease; D004195:Disease Models, Animal; D006084:Graft Rejection; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011183:Postoperative Complications / Q000188:drug therapy / Q000517:prevention & control; D011728:Pyridones / Q000494:pharmacology*; D014132:Trachea / Q000637:transplantation*; D014184:Transplantation, Homologous
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011728:Pyridones; C093844:pirfenidone