Co-application of imatinib and everolimus attenuates the appearance of bronchiolitis obliterans after LTX in a rat model

Aims: Bronchiolitis obliterans (BO) is an inflammatory process that leads to fibrous scarring of the terminal bronchioles and subsequent total occlusion of the airways. We studied Imatinib, a receptor tyrosin kinase inhibitor (RTK) of the plated derived growth factor (PDGF), first alone and second in combination with Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, to attenuate BO in an experimental animal model.

Methods: A total of 75 rats underwent allogenic (F344-to-WKY) and syngenic (WKY-to-WKY) left lung transplantation (LTX). In group 1, animals were untreated during complete postoperative course. In group 2, imatinib-mesylate (20mg/kg/day) was applicated from postoperative day (POD) 0–100. In addition to the application of group 2, in group 3, Everolimus (2.5mg/kg/day) was additionally applied from day 14 to 100. Extend of rejection was classified according to ISHLT.

Results: In group 1, acute rejection (AR) peaked between POD 20 and 30 (12/12) and ended in chronic rejection on POD 60 (6/6) and 100 (6/6). Rats of group 2 showed severe AR on POD 20 (6/6). We observed on POD 30 a borderline form with mild signs of BO (4/6) and vascular intimal thickening (5/6). 30% of imatinib-treated animals on POD 100 were without signs of BO. The additional application of everolimus reduced the amount of animals with severe AR (2/5) Up to POD 100, we recognized a persisting inflammatory infiltration in about 50% of the allografts. 40% of the transplanted lungs were without BO and Vaskulopathy.

Conclusions: Co-application of imatinib and Everolimus showed synergistic effects and attenuated the development of BO after experimental LTx. Thus, the integration of a PDGF-Inhibitor in combination with an mTOR Inhibitor might be an interesting therapeutic approach after LTX.