Late treatment with angiotensin-converting enzyme inhibitors plus endothelin receptor antagonists ameliorates rat tracheal allograft rejection.
Inhibition of the renin-angiotensin and endothelin (ET) systems prevents the development of obliterative airway disease (OAD) in rat tracheal allografts. In this study, we assessed whether these therapeutic approaches are effective even when the same were started after signs of OAD were already manifest. Rat tracheas were heterotopically transplanted from Brown-Norway donors into Brown-Norway or Lewis recipients. Allograft recipients received bosentan, ramipril, bosentan plus ramipril or vehicle from day 10 to 24. Untreated allografts and isografts were harvested at day 10 or 24. In tracheal grafts, morphometric studies together with molecular analysis by real-time PCR were performed. Fibroproliferative process in untreated tracheal allografts but not in isografts started already at day 10. Neither bosentan nor ramipril treatment alone as monotherapy could modify the development of OAD when administered only between day 10 and day 24. By contrast, the combination treatment of bosentan and ramipril ameliorated airway obstruction by day 24, which was accompanied by reduced mRNA expression of intragraft transforming growth factor-beta1 and platelet-derived growth factor-A and -B chains. Only the combined blockade with angiotensin-converting enzyme inhibitors and ET receptor antagonists can reduce the progression of OAD in this model if the treatment is initiated late in the disease course.
Antus
Balazs
B
Department of Pathophysiology, National Koranyi Institute for TB and Pulmonology, Budapest, Hungary. antbal@net.sote.hu
Fillinger
Janos
J
Sebe
Attila
A
Jeney
Csaba
C
Horvath
Ildiko
I
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000077300:Bosentan; D001989:Bronchiolitis Obliterans / Q000209:etiology / Q000473:pathology* / Q000517:prevention & control; D065128:Endothelin Receptor Antagonists; D006084:Graft Rejection / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D008297:Male; D016133:Polymerase Chain Reaction; D017257:Ramipril / Q000627:therapeutic use*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D013449:Sulfonamides / Q000627:therapeutic use*; D014132:Trachea / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D014185:Transplantation, Isogeneic
D000806:Angiotensin-Converting Enzyme Inhibitors; D065128:Endothelin Receptor Antagonists; D013449:Sulfonamides; D017257:Ramipril; D000077300:Bosentan