Endothelin-1 receptor blockade and its effect on chronic rejection.

ENDOTHELIN-l (ET-l), a 21 amino acid peptide with potent vasoconstrictive properties has been implicated in the development of acute allograft rejection.) It is primarily produced by endothelial cells and its secretion, during acute rejection episodes, has been shown to be upregulated by TGFf3 and other proinflammatory cytokines released by graft infiltrating cells.) Additionally, ET-l has also been shown to facilitate proliferation of a-smooth muscle actin-positive (a-smA +) cells? Given that proliferation and/or accumulation of a-smA + cells is a prominent feature in neointimal thickening encountered in posttransplant vasculopathy, it is rational to propose that ET-l may play an important role in the pathogenesis of this lesion. To test this tenet, we proceeded to block ET-receptors (both ETA and ET B) by bosentan (a non peptide antagonist of ET -1) and to study its influence on the evolvement of chronic rejection (CR) in an established mouse model of aortic allotransplantation.3