ROLE OF NITRIC-OXIDE IN EXPERIMENTAL OBLITERATIVE BRONCHIOLITIS (CHRONIC REJECTION) IN THE RAT

The role of nitric oxide in obliterative bronchiolitis development, i. e., chronic rejection, was investigated in the heterotopic rat trachea l allograft model, An increase in the intragraft inducible nitric oxid e synthase (iNOS) mRNA and mononuclear inflammatory cell iNOS immunore activity was demonstrated during progressive loss of respiratory epith elium and airway occlusion in nontreated allografts compared to syngen eic grafts. In nontreated allografts, however, intragraft nitric oxide production was decreased, most likely because of loss of iNOS epithel ial expression, Treatment with aminoguanidine, a preferential inhibito r of inducible nitric oxide synthase, was associated with enhanced pro liferation of oc-smooth muscle actin immunoreactive cells and the inte nsity of obliterative bronchiolitis early after transplantation, Amino guanidine treatment did not affect iNOS mRNA synthesis or intragraft n itric oxide production, but decreased iNOS immunoreactivity in smooth muscle cells. Treatment with L-arginine, a precursor of nitric oxide, significantly reduced obliterative changes. L.-arginine supplementatio n enhanced intragraft iNOS mRNA synthesis and iNOS immunoreactivity in capillary endothelial and smooth muscle cells as well as intragraft n itric oxide production, Immunohistochemical analysis of allografts sho wed that neither iNOS inhibition nor supplementation of the nitric oxi de pathway affected the number of graft-infiltrating CD4+ and CD8+ T c ells, ED1+ and ED3+ macrophages, immune activation with expression of IL-2R or MHC class II, or production of macrophage or Th1 cytokines, I n contrast, L-arginine treatment was associated with increased stainin g for Th2 cytokines IL-4 and IL-10. In conclusion, this study demonstr ates that nitric oxide has a protective role in obliterative bronchiol itis development in this model, and suggests that nitric oxide either directly or indirectly inhibits smooth muscle cell proliferation and m odulates immune response towards Th2 cytokines.