Cytomegalovirus infection enhances experimental obliterative bronchiolitis in rat tracheal allografts

Inbred DA (AG-B4, RT1a) and WF (AG-B2, RT1v) rat immunosuppressed with cyclosporine A (CsA) 2 mg/kg/day subcutaneously were used as donors and recipients of heterotopic rat tracheal allografts. Acute infection was established by inoculating the recipients with 10(5) plaque-forming units of rat cytomegalovirus (RCMV) intraperitoneal on the day of transplantation. Chronic RCMV infection was similarly established 8 wk before transplantation in donors alone, recipients alone, and in both donor and recipients. The control rats were left noninfected. For in vivo cell proliferation, the rats received bromedeoxyuridine intravenously 3 h before being killed. RCMV infection significantly enhanced the generation of experimental obliterative bronchiolitis (OB). First, acute RCMV infection was linked to markedly enhanced MHC class II expression on the respiratory epithelium and prominent airway wall inflammation of W3/25+ T cells (CD4+) and ED1+/ED2+ macrophages. Second, acute infection induced a fivefold increase in luminal occlusion of the trachea, due to proliferating inflammatory and alpha-smooth muscle actin+ myofibroblast-like cells. Acute RCMV infection was particularly associated with markedly increased expression of platelet-derived growth factor (PDGF) AA-isoform in various structures of the graft 10 d after transplantation. At 30 d, RCMV significantly increased PDGF alpha- and beta-receptor expression in alpha-smooth muscle actin+ cells and TNF-alpha expression in capillary endothelial cells of the fibroproliferative lesion. In chronic recipient RCMV infection, the histopathological changes were quite similar to acute infection. Chronic donor infection did not amplify the development of experimental OB. As analyzed by immunohistochemistry from the grafts and by plaque assays from salivary gland biopsies of the recipients, trace RCMV antigen expression, while no infectious RCMV could be recovered in the chronic donor infection group. In other infected groups, RCMV antigen expression was mild to moderate and salivary glands contained plenty of infectious RCMV. To conclude, our results indicate that RCMV infection enhances epithelial MHC class II expression and myofibroproliferation in heterotopic rat tracheal allografts and suggest that these changes may be induced by increased PDGF-AA and PDGF alpha-receptor expression, respectively.