Protective function of pirfenidone and everolimus on the development of chronic allograft rejection after experimental lung transplantation

M. von Suesskind-Schwendi¹, E. Heigel², S. Pfaehler², A. Haneya³, C. Schmid¹, S.W. Hirt¹ and K. Lehle<sup>1

1</sup>Department of Cardiothoracic Surgery, ²Institute of Pathology, University Medical Center, Regensburg and ³Department of Immunology, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany

Offprint requests to: M.v. Süßkind, Department of Cardiothoracic Surgery, University Hospital of Schleswig-Holstein/Campus Kiel, Kiel, Germany. e-mail: marietta.suesskind-von@klinik.uni-regensburg.de

Summary. Long-term survival of lung allografts is limited by chronic rejection (CR). Oxidative stress (OxS) plays a central role in the development of CR. We investigated the influence of pirfenidone (alone or in combination with everolimus) on OxS and CR. A rat model of left lung allo-transplantation (F344-to-WKY) was used to evaluate the effects of pirfenidone alone [0,85% in chow from postoperative day (POD) -3 to 20/60] and in combination with everolimus [2,5 mg/kg bw daily from POD 7 to 20/60]. Allografts of non-treated animals, everolimus treated animals and right, non-transplanted lungs were used as references. Immunohistology of myeloperoxidase (MPO), haemoxygenase-1 (HO-1), iron and platelet-derived-growth-factor-receptor-alpha (PDGFR-a) were performed. On POD 20, all groups showed severe acute rejection (ISHLT A3-4/B1R-B2R). Groups treated with pirfenidone showed a lower interstitial inflammatory infiltration and a lower participation of highly fibrotic degenerated vessels (ISHLT-D2R). In the long term follow up (POD 60), pirfenidone alone significantly reduced chronic airway rejection (ISHLT-C; p≤0.05), interstitial fibrosis (IF; p≤0.05), content of collagen (p≤0.05), expression of PDGFR-a (p≤0.05) and the deposition of iron (p≤0.05). All groups treated with pirfenidone showed a high expression of the cytoprotective enzyme HO-1 (p≤0.05). The additional application of everolimus resulted in a significant decrease of chronic airway rejection (ISHLT-C; p≤0.05), vasculopathy (ISHLT; p≤0.05) and IF (p≤0.05). In conclusion, early application of pirfenidone inhibited the progression of CR by its anti-fibrotic and anti-oxidative properties. The additional application of an m-TOR-inhibitor increased the anti-fibrotic effects of pirfenidone which resulted in a reduction of CR after experimental LTx. Histol Histopathol 31, 793-805 (2016)

Key words: Lung transplantation, Rat, Chronic rejection, Pirfenidone, Everolimus

DOI: 10.14670/HH-11-712