INHIBITION OF INDUCIBLE NITRIC-OXIDE SYNTHASE AMELIORATES FUNCTIONAL AND HISTOLOGICAL-CHANGES OF ACUTE LUNG ALLOGRAFT-REJECTION

Background. We recently demonstrated that inhibition of inducible nitr ic oxide synthase (iNOS) ameliorated severe acute lung allograft rejec tion, This study used a rat lung transplant model to determine (1) the time course and cellular localization of iNOS expression during the h istological progression of unmodified acute rejection and (2) whether inhibition of iNOS prevented impaired gas exchange function of the all ograft lung and/or ameliorated the histological changes of acute rejec tion. Methods and Results. iNOS mRNA and enzyme activity were expresse d in allograft lungs during mild, moderate, and severe acute rejection , but not in normal, isograft, or allograft lungs before histological changes of mild acute rejection, iNOS expression in allografts resulte d in elevated serum nitrite/nitrate levels, indicative of increased in vivo nitric oxide (NO) production, In situ hybridization demonstrated iNOS mRNA expression in infiltrating inflammatory cells, but not in a llograft parenchymal cells, Allografts had significantly impaired gas exchange, which was prevented with the selective iNOS inhibitor aminog uanidine (PaO2 of 566+/-19, 76+/-22, and 504+/-105 mmHg for isograft, allograft, and aminoguanidine-treated allograft, respectively; P<0.000 2). Aminoguanidine also significantly improved the histological reject ion scores. Conclusions. (1) iNOS expression and increased NO producti on occurred during the early stages of acute rejection, persisted thro ughout the unmodified rejection process, and localized to infiltrating inflammatory cells, but not allograft parenchymal cells; (2) aminogua nidine ameliorated the histological and functional changes of acute re jection; and (3) increased NO production, detected by the presence of iNOS mRNA, protein, or noninvasively by measuring serum nitrite/nitrat e levels, may serve as an early marker of acute allograft rejection.