Am. J. Respir. Crit. Care Med., Vol 155, No. 6, Jun 1997, 2078-2088.
Cytomegalovirus infection enhances experimental obliterative bronchiolitis in rat tracheal allografts
PK Koskinen, EA Kallio, CA Bruggeman and KB Lemstrom
Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, Finland.
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.
