Effects of Blockade of the Renin–Angiotensin and Endothelin Systems on Experimental Bronchiolitis Obliterans

Abstract

Blockade of the renin-angiotensin and the endothelin (ET) systems ameliorates fibrous airway obliteration in rat tracheal allografts. The aim of this study was to test which of these pharmacologic interventions attenuates the process more effectively, and whether combination therapy confers additional benefit. Rat tracheas were heterotopically transplanted from Brown-Norway donors into Lewis recipients. Recipients received the dual endothelin-1 (ET-1) receptor blocker, bosentan (100 mg/kg), the angiotensin-converting enzyme (ACE) inhibitor, ramipril (5 mg/kg), bosentan plus ramipril (doses as just noted) or vehicle. Grafts were harvested at Days 7 and 21 for morphometric studies and molecular analysis by real-time polymerase chain reaction (PCR). At Day 21, bosentan and ramipril treatment reduced the percentage of luminal occlusion compared with vehicle to a similar extent. In animals that received the combined treatment, luminal obliteration was further reduced compared with the respective monotherapies. Furthermore, rats treated with bosentan plus ramipril showed a lower percent of epithelial necrosis. The beneficial effects of bosentan and ramipril, alone or in combination, were associated with reduced mRNA levels of transforming growth factor (TGF)-beta1 and platelet-derived growth factor (PDGF)-A in the tracheal allografts. Our data suggest that ET receptor blockade prevents fibrous airway obliteration to a similar extent as ACE inhibition in this model. Interruption of both pathways provides superior graft protection as compared with single-system blockade.