RESPIRATORY VIRAL-INFECTIONS AGGRAVATE AIRWAY DAMAGE CAUSED BY CHRONIC REJECTION IN RAT LUNG ALLOGRAFTS

Airway damage resulting in bronchiolitis obliterans occurs frequently in patients after heart-lung and lung transplantation. Generally, chronic rejection is assumed to be the most important cause of bronchiolitis obliterans. However, viral infections might also be potential causes of airway damage after lung transplantation. In the present study, we investigated whether viral infections could induce airway damage in rat lung transplants in the absence or presence of chronic rejection. We compared the histopathology of the airways in 3 groups of rats: (1) nontransplanted LEW lungs, (2) LEW-to-LEW syngeneic lung transplants, and (3) BN-to-LEW allogeneic lung transplants. Nontransplanted and transplanted rats were treated with CsA to induce permanent graft acceptance of the allografts. Six months after transplantation, 4 noninfected rats of each group were killed for histological investigation (another 4 noninfected allografted rats were killed 56 days later). The remaining 16 rats in each group were infected with Sendai virus (parainfluenza type 1) intratracheally. These rats were killed for histological investigation 4, 7, 21, and 56 days after infection. In the lungs of the noninfected rats of the nontransplanted and syngeneically transplanted groups, airway changes were absent. After viral infection in these lungs, mild inflammation developed in the airways that was transient and completely resolved by day 56 after infection. In contrast, in the allogeneically transplanted lungs the viral infection caused severe and permanent damage of the airways. In the bronchioles and the large airways throughout the allogeneic lung transplants, inflammation with epithelial necrosis and formation of granulation tissue was present. On day 56 after infection, the bronchioles showed scarring in the submucosa and obliteration of the lumen, typical features of bronchiolitis obliterans. This study shows that a respiratory viral infection aggravates the airway damage in rat lung allografts with chronic rejection. The findings suggest that viral infections and chronic rejection play a synergistic role in the development of bronchiolitis obliterans after human heart-lung and lung transplantation: the virus infection may stimulate chronic rejection and rejection may hamper the local defense against the virus.