Commentary: Antifibrotic agents in the postoperative period: Friends or foes?

Abstract

Pirfenidone is a Food and Drug Administration-approved drug for idiopathic pulmonary fibrosis (IPF) and can delay the progression of lung disease over time. The underlying mechanism of pirfenidone is not completely understood, but it displays both anti-inflammatory and antifibrotic effects. 1 Thus, pirfenidone's mechanism of action has been postulated to involve the inhibition of production and activation of transforming growth factor (TGF)-b. Amelioration of TGF-b is thought to inhibit collagen deposition and fibrosis. However, recent data in both animals and humans demonstrate clinically important anti-inflammatory effects of pirfenidone as well, including the decrease in acute exacerbations of IPF, as outlined in the accompanying article in this issue of the Journal. 2,3 IPF is the leading indication for lung transplantation in the United States. With the development and clinical use of 2 Food and Drug Administration-approved antifibrotic agents, pirfenidone and nintedanib, the pretransplant management of IPF has changed dramatically. Little is known about the antifibrotic effects of these drugs in the immediate postoperative period. Saito and colleagues, 2 from Kyoto University in Japan, key in on the anti-inflammatory effects of pirfenidone using an acute lung transplantation rat model. They hypothesize that pirfenidone may offer a unique preventative treatment option for ischemiareperfusion injury (IRI) and primary graft dysfunction (PGD). 2 Because PGD is the leading cause of early postlung transplant mortality and increases the risk of chronic allograft dysfunction in lung transplant recipients, any methods to ameliorate this condition would be a welcome addition to current perioperative management. 4 In their novel article, Saito and colleagues 2 clearly show promising results in an IRI model treated with pirfenidone, including an increase in lung compliance, a decrease in the mean airway pressures, an improvement in oxygenation, and a decrease in lung edema. They also demonstrate an improvement in other parameters of lung injury, including perivascular edema and neutrophil infiltration. 2 Although it is clear that TGF-b is a profibrogenic cytokine, with the deleterious side effect of pulmonary fibrosis, it also plays a major role in would healing. 5 Thus, its inhibition in the perioperative period is a topic of major controversy. Sternal wound and airway complications, including anastomotic dehiscence, have been reported in up to 35% of patients after lung transplantation resulting in serious morbidity as well as death. 6 For these reasons, the standard surgical dogma has been to hold antifibrotic agents at the time of listing to prevent such complications. This assumption was primarily based on the mechanistic understanding of pirfenidone's and nintenanib's mechanism of action but not on data-driven clinical science. In the past several years, small retrospective reports have been published arguing against such theoretic complications of the antifibrotic agents continued in the perioperative period. De...