Protective function of Pirfenidone and Everolimus on the development of chronic allograft rejection after experimental lung transplantation.

Protective function of Pirfenidone and Everolimus on the development of chronic allograft rejection after experimental lung transplantation.

Histol Histopathol. 2015 Dec 28;:11712

Authors: von Suesskind-Schwendi M, Heigel E, Pfaehler S, Hanneya A, Schmid C, Hirt SW, Lehle K

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.

PMID: 26707547 [PubMed - as supplied by publisher]

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