Abstract
Purpose: Chronic allograft rejection (CR) is the main risk factor after lung transplantation (LTx). According to the pathogenesis of idiopathic pulmonary fibrosis it was speculated that epithelial/endothelial -mesenchymal transition might be responsible for the development of bronchiolitis obliterans (BO) and vasculopathy. Imatinib and Valalanib, two different inhibitors of receptor tyrosin kinases, prevented the development of inflammation-driven experimental fibrosis. The aim was to confirm the efficacy of the combination therapy of imatinib and vatalanib in a rat LTx model to attenuate the development of CR. Methods: To evaluate the antifibrotic effects of imatinib (20 mg/kg/day i.g.) and vatalanib (20 mg/kg/day i.g) after LTx, a rat model of left lung allotransplantation (F344-to-WKY) was used. Allogenic transplanted rats were treated with imatinib/vatalanib from day 0 to 20/60 (n= 12). Non-treated animals were used as a reference (n= 16). Results: In the none-treated reference group, severe acute rejection (ISHLT-A4) and lymphocytic bronchiolitis (ISHLT-B2R) was seen on day 20 after LTx and resulted in chronic rejection (ISHLT-C2R/D2R) on day 60. In 40% of the allografts, dual application of imatinib and vatalanib reduced severe acute rejection (ISHLT-A3/B1R). In the long-term follow up, two allografts developed severe chronic rejection (ISHLT-C2R/D2R). The remaining four allografts showed no evidence of BO, vasculopathy or interstitial fibrosis (ISHLT-C0/D0). Two of these allografts demonstrated slight signs of peribronchiolar/perivascular fibrosis of the medium-sized bronchioles and vessels. Conclusion: In Conclusion, we speculate that a dual inhibition of the platedderived growth factor by imatinib and the vascular endothelial growth factor by vatalanib might be effective to slow down CR after LTx. Thus, the combination of different RTK-Inhibitors might be an interesting tool for patients after LTx to reduce CR.
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