title: Synergism of imatinib mesylate and everolimus in attenuation of bronchiolitis obliterans after rat LTX.
abstract: Bronchiolitis obliterans (BO) is a progressive and fatal disease after lung transplantation (LTX). Dysregulated growth factor-induced proliferation of myofibroblasts seems to be responsible for the development of BO. The aim was to confirm the efficacy of both inhibitors of receptor tyrosine kinases (RTKI) and of mammalian target of rapamycin (mTORI) after rat LTX. We used a rat model of left lung allo-transplantation (F344-to-WKY) to evaluate the effect of imatinib (RTKI; 20 mg/kg/day; postoperative day (POD) 0-100) alone or in combination with everolimus (mTORI; 2.5 mg/kg/day; POD 14-100). Non-treated animals were the reference. In non-treated rats, acute rejection (AR) peaked between POD 20 and 30 (19/19) and ended in chronic rejection (CR) on POD 60/100 (12/12). Imatinib alone did not prevent AR (6/6), but attenuated the degree of degenerated bronchioles on POD 30 (non-treated, 57%; imatinib, 4%), and increased the allografts free of CR on POD 60/100 (3/12). A combination of imatinib and everolimus significantly reduced AR, attenuated fibrotic degenerated bronchioles (5%) and vessels (non-treated, 24%; combination therapy, 11%) on POD 30, and reduced fibrotic degenerated vessels (non-treated, 97%; combination therapy, 43%) and bronchioles (non-treated, 88%; combination therapy, 34%) on POD 60/100. Fifty percent of the animals were completely free of BO and vasculopathy. In conclusion, co-application of RTKI and mTORI attenuated the development of BO and vasculopathy. Thus, imatinib might be an interesting therapeutic approach after LTX.
authors.affiliation: Department of Cardiothoracic Surgery, University Medical Centre, Regensburg, Germany. Marietta.Suesskind-von@klinik.uni-regensburg.de.
authors.forename: M
authors.initials: M
authors.lastname: von Suesskind-Schwendi
authors.forename: Verena
authors.initials: V
authors.lastname: Valenti
authors.forename: Assad
authors.initials: A
authors.lastname: Haneya
authors.forename: T
authors.initials: T
authors.lastname: Pühler
authors.forename: B
authors.initials: B
authors.lastname: Bewig
authors.forename: C
authors.initials: C
authors.lastname: Schmid
authors.forename: S W
authors.initials: SW
authors.lastname: Hirt
authors.forename: K
authors.initials: K
authors.lastname: Lehle
mesh_terms: D000818:Animals; D001549:Benzamides / Q000008:administration & dosage*; D001989:Bronchiolitis Obliterans / Q000188:drug therapy* / Q000628:therapy*; D003094:Collagen / Q000737:chemistry; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000068338:Everolimus; D006084:Graft Rejection; D000068877:Imatinib Mesylate; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D008168:Lung / Q000187:drug effects; D016040:Lung Transplantation / Q000379:methods*; D008297:Male; D010879:Piperazines / Q000008:administration & dosage*; D011184:Postoperative Period; D011743:Pyrimidines / Q000008:administration & dosage*; D051381:Rats; D011916:Rats, Inbred F344; D011921:Rats, Inbred WKY; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives*; D013997:Time Factors
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D003094:Collagen; D000068338:Everolimus; D020794:Receptor Protein-Tyrosine Kinases; D020123:Sirolimus