title: Protective function of pirfenidone and everolimus on the development of chronic allograft rejection after experimental lung transplantation.
abstract: 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.
authors.affiliation: Department of Cardiothoracic Surgery, University Medical Center, Regensburg, Germany. Marietta.Suesskind-von@klinik.uni-regensburg.de.
authors.forename: M
authors.initials: M
authors.lastname: von Suesskind-Schwendi
authors.affiliation: Institute of Pathology, University Medical Center, Regensburg, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Heigel
authors.affiliation: Institute of Pathology, University Medical Center, Regensburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Pfaehler
authors.affiliation: Department of Immunology, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Haneya
authors.affiliation: Department of Cardiothoracic Surgery, University Medical Center, Regensburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Schmid
authors.affiliation: Department of Cardiothoracic Surgery, University Medical Center, Regensburg, Germany.
authors.forename: S W
authors.initials: SW
authors.lastname: Hirt
authors.affiliation: Department of Cardiothoracic Surgery, University Medical Center, Regensburg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Lehle
mesh_terms: D064591:Allografts; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D004195:Disease Models, Animal; D000068338:Everolimus / Q000494:pharmacology*; D006084:Graft Rejection / Q000473:pathology / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016040:Lung Transplantation; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D011921:Rats, Inbred WKY
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007166:Immunosuppressive Agents; D011728:Pyridones; D000068338:Everolimus; C093844:pirfenidone