Pirfenidone inhibits obliterative airway disease in mouse tracheal allografts.
BACKGROUND
Obliterative bronchiolitis (OB) is the histologic correlate of chronic airway rejection, which remains the most significant cause of death in long-term survivors of lung transplantation. Using an established murine heterotopic tracheal transplant model of chronic airway rejection, the effects of the oral anti-fibrotic agent pirfenidone on development of the OB-like lesion were evaluated.


METHODS
Tracheas from BALB/c mice were implanted into the sub-cutaneous tissue of C57BL/6 mice, and the allografts were evaluated morphologically for airway rejection changes and immunohistochemically for transforming growth factor (TGF)-beta at 16 or 28 days after transplantation. In addition, the potential additive effects of pirfenidone in combination with 2 immunosuppressive agents, cyclosporine or rapamycin, was evaluated.


RESULTS
Compared with untreated controls, pirfenidone-fed mice showed less epithelial cell injury and luminal granulation tissue and fibrosis. Plasma TGF-beta levels and local TGF-beta expression based on immunohistochemistry were decreased in the pirfenidone-treated animals. Pirfenidone given on Day 9 or 16 post-transplant through Day 28 resulted in no significant improvement compared with controls. There was no significant additive effect of pirfenidone in combination with cyclosporine, whereas pirfenidone plus rapamycin demonstrated additive protection against the development of the obstructive airway lesion.


CONCLUSIONS
In aggregate, these results show that the anti-fibrotic agent pirfenidone inhibits the development of the OB-like lesion in this mouse model of human chronic airway rejection, and that these effects may be mediated by TGF-beta. The results also suggest that pirfenidone may be worthy of investigation in human lung transplant recipients at high risk of developing OB.
Zhou
Hailan
H
Department of Pediatrics, University of Florida, Gainesville, Florida 32610, USA.
Latham
Christopher W
CW
Zander
Dani S
DS
Margolin
Solomon B
SB
Visner
Gary A
GA
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D002908:Chronic Disease; D016572:Cyclosporine / Q000008:administration & dosage; D004195:Disease Models, Animal; D005260:Female; D006084:Graft Rejection / Q000097:blood / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011728:Pyridones / Q000008:administration & dosage*; D020123:Sirolimus / Q000008:administration & dosage; D014132:Trachea / Q000637:transplantation*; D016212:Transforming Growth Factor beta / Q000097:blood
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007166:Immunosuppressive Agents; D011728:Pyridones; D016212:Transforming Growth Factor beta; D016572:Cyclosporine; C093844:pirfenidone; D020123:Sirolimus