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J Thorac Cardiovasc Surg 2005;130:852-858
© 2005 The American Association for Thoracic Surgery

Cardiothoracic Transplantation

Pirfenidone inhibits inflammatory responses and ameliorates allograft injury in a rat lung transplant model

^a Department of Pediatrics University of Florida, Gainesville, Fla
^b Department of Pathology University of Florida, Gainesville, Fla

Received for publication January 28, 2005; revisions received March 29, 2005; accepted for publication April 18, 2005.

^_* Address for reprints: Gary A. Visner, DO, Box 100296, 1600 SW Archer, Department of Pediatrics, University of Florida, Gainesville, FL 32610 (Email: visnerga{at}peds.ufl.edu).

OBJECTIVE: Tumor necrosis factor is a proinflammatory cytokine that has been proved to play a crucial role in inducing posttransplantation lung injury. The present study was performed to determine whether pirfenidone, a new nonpeptide drug with potent anti–tumor necrosis factor activity, promotes protection against acute allograft injury through inhibiting pulmonary inflammatory responses in a rat model of orthotopic lung transplantation.

METHODS: Three transplant groups were formed: isografts, untreated allografts, and allografts treated with pirfenidone (0.5% chow starting on day 1 after transplantation). The implants were harvested on day 21 after transplantation. Acute cellular rejection grade and degree of allograft injury were evaluated on the basis of hematoxylin-and-eosin staining. The pulmonary inflammatory response and inflammation-induced oxidative stress were assessed on the basis of neutrophil accumulation (myeloperoxidase immunoreactivity and enzymatic activity) and iron deposition (Prussian blue staining). In addition, circulating levels of tissue necrosis factor in all animals were measured.

RESULTS: The degree of allograft injury was significantly reduced in pirfenidone-treated allografts relative to untreated allografts (P < .01). The beneficial effect of pirfenidone was associated with decreased lung myeloperoxidase immunoreactivity (P < .05) and enzymatic activity (P < .01). Moreover, the untreated allografts contained a high concentration of iron, which was strikingly reduced by pirfenidone. Treatment with pirfenidone resulted in a lower level of plasma tissue necrosis factor , which correlated positively with lung myeloperoxidase enzymatic activity (P < .0001).

CONCLUSION: These results suggest that pirfenidone, with its anti–tissue necrosis factor activity, reduced neutrophil recruitment and iron accumulation, hence limiting the acute lung allograft injury.

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